bluuebunny/crossref_metadata_2025_split huggingface dataset:
The next frontier: cytomegalovirus antiviral stewardship programs in solid organ transplant
Authors: Kleiboeker Hanna L. , Saddler Christopher M. , Jorgenson Margaret R. 
Published: October 2023

Purpose of review
Cytomegalovirus (CMV) is a driver of negative patient and allograft outcomes after solid organ transplantation (SOT) and new tools are needed to circumvent these outcomes. We will review key elements of CMV antiviral stewardship in SOT, discuss the available evidence for CMV antiviral stewardship programs and feature areas for expansion in the current landscape of CMV management.

Recent findings
CMV remains a common complication after SOT. While consensus guidelines provide recommendations for the prevention and treatment of CMV, a one-size-fits-all approach is not necessarily appropriate for all unique patients and posttransplant courses, types of SOT recipients and transplant centers. Additionally, consensus guidelines have not been updated since the approval of two new antiviral therapies for the treatment of CMV after SOT or emerging evidence for the incorporation of immune functional assays into clinical practice.
From the models provided in recent literature, CMV antiviral stewardship programs have demonstrated efficacy by increasing successful treatment of viremia, optimizing and reducing unnecessary use of (val)ganciclovir for both prophylaxis and treatment, and preventing development of ganciclovir-resistant CMV infections. These models highlight the multidisciplinary approach required of CMV antiviral stewardship programs to provide standardization of management, including incorporation of new therapies and diagnostic tools.

Summary
CMV antiviral stewardship programs represent a promising avenue to considerably improve the management of CMV after SOT. Future studies are needed to evaluate a potential positive impact on graft outcomes and patient survival.
Sonographic Evaluation of the Lateral Femoral Cutaneous Nerve
Authors: Lee Susan C. , Ko Lydia , Gornbein Chase , Nwawka Ogonna Kenechi 
Published: October 2023

Abstract
The location of the lateral femoral cutaneous nerve (LFCN) makes it susceptible to injury with trauma, external compression, and iatrogenic injury. The objectives of this study were to report the single-institution efficacy of LFCN visualization on ultrasound (US), define the clinical characteristics of patients with LFCN palsy, and describe sonographic appearances of LFCN abnormalities by pictorial review. A retrospective chart review of LFCN cases evaluated using US at a single institution was performed, documenting rate of visibility on US, mode of nerve injury, and US imaging findings. Nerve visibility rates on US were correlated with magnetic resonance imaging (MRI) when both modalities were used. Imaging findings were confirmed with clinical/surgical history and follow-up. Retrospective review found that 170 patients underwent US for LFCN evaluation in the last 10 years. Injury was associated with surgical intervention in 56% of cases, and perineural scarring was the most common pathology described using US. Lateral femoral cutaneous nerve was visible on US in 97% of cases; MRI visualized LFCN in 60%. Chart review showed US as an effective tool in evaluating LFCN pathology, with a higher visualization rate than MRI. Through pictorial review, the array of LFCN pathology sonographically detectable is demonstrated.
Assessing Kidney Transplantation Using ECMO-Supported Donors Within a KDPI-Based Allocation System
Authors: Altshuler Peter J. , Pace Devon J. , Preston William A. , Vincent Sage A. , Shah Ashesh P. , Glorioso Jaime M. , Maley Warren R. , Frank Adam M. , Ramirez Carlo B. , West Sharon , Hasz Richard , Bodzin Adam S. 
Published: October 2023

Background.
Organ donors supported by extracorporeal membrane oxygenation (ECMO) have historically been considered high-risk and are judiciously utilized. This study examines transplant outcomes using renal allografts from donors supported on ECMO for nondonation purposes.

Methods.
Retrospective review of the Gift of Life (Pennsylvania, New Jersey, Delaware) organ procurement organization database, cross-referenced to the Organ Procurement and Transplantation Network database, assessed kidney transplants using donors supported on venoarterial (VA) and venovenous (VV) ECMO for nondonation purposes. Transplants using VA- and VV-ECMO donors were compared with Kidney Donor Profile Index (KDPI)-stratified non-ECMO donors. Regression modeling of the entire ECMO and non-ECMO populations assessed ECMO as predictive of graft survival. Additional regression of the ECMO population alone assessed for donor features associated with graft survival.

Results.
Seventy-eight ECMO donors yielded 128 kidney transplants (VA: 80, VV: 48). Comparing outcomes using these donors to kidney transplants using organs from KDPI-stratified non-ECMO donors, VA- and VV-ECMO donor grafts conferred similar rates of delayed graft function and posttransplant renal function to KDPI-matched non-ECMO counterparts. VA-ECMO kidneys demonstrated superior graft survival compared with the lowest-quality (KDPI 86%–100%) non-ECMO kidneys and similar graft survival to KDPI <85% non-ECMO kidneys. VV-ECMO showed inferior graft survival to all but the lowest-quality (KDPI 86%–100%) non-ECMO kidneys. VV-ECMO, but not VA-ECMO, was associated with increased risk of graft loss on multivariable regression (hazard ratios—VA: 1.02, VV: 2.18). Higher KDPI, advanced age, increased body mass index, hypertension, and diabetes were identified as high-risk features of ECMO donors.

Conclusions.
Kidney transplantation using appropriately selected ECMO donors can safely expand the donor pool. Ongoing studies are necessary to determine best practice patterns using kidneys from these donors.
Reproductive biology of the mudskippersBoleophthalmus boddartiandPeriophthalmus novemradiatusin the Indian Sundarbans
Authors: Ray Ishita , Himberg Benjamin E. , Sengupta Sanghita , Homechaudhuri Sumit 
Published: October 2023

AbstractReproductive biology of mudskippersBoleophthalmus boddartiandPeriophthalmus novemradiatusare investigated along the mudflats of the Indian Sundarbans. We investigated a total of 794 sampes for both male and femaleBoleophthalmus boddartiandPeriophthalmus novemradiatusfish species to explore properties such as the size-at-50% maturity, fecundity, spawning, gona-dosomatic and hepatosomatic indices along with the characterization of the macroscopic and histological attributes of the female gonads. Our work reports for the first time the weight-length relationships for these fish species in the Sundarbans region depicting a negative allometric growth pattern. The size-at-50% maturity which is often a crucial parameter for stock and reserve management is found for the female and maleBoleophthalmus boddartias 10.2 cm and 9.9 cm respectively, whereas, for thePeriophthalmus novemradiatus, the same were 4.0 cm and 4.4 cm, respectively. Fully matured femaleBoleophthalmus boddartiwere found to be multiple spawners in comparison toPeriophthalmus novemradiatuswith monthly variation of Le Cren’s relative condition ≤1, indicating good physiological conditions of the fish. The relationships between batch fecundity (F), body weight (i.e., BW, gm) and total length (i.e., TL, cm) were Log10F = 1.12 Log10BW + 2.41 and Log10F = 1.93 Log10TL + 1.82, respectively forBoleoph-thalmus boddartiand for thePeriophthalmus novemradiatus, it was Log10F = 2.15 Log10BW + 2.57 and Log10F = 5.43 Log10TL - 0.81. The reproductive parameters estimated in this study are important information for studying population dynamics and stock assessments of these mudskippers in the Indian Sundarbans and will contribute to the management, conservation and prediction of environmental changes as these mudskippers are often studied as bio-indicators for climate-change effects.
Analysis of the effect of the scorpion toxin AaH-II on action potential generation in the axon initial segment
Authors: Abbas Fatima , Blömer Laila Ananda , Millet Hugo , Montnach Jérôme , De Waard Michel , Canepari Marco 
Published: October 2023

AbstractThe toxin AaH-II, from the scorpionAndroctonus australis Hectorvenom, is a 64 amino acid peptide that targets voltage-gated Na+channels (VGNCs) and slows their inactivation. While at macroscopic cellular level AaH-II prolongs the action potential (AP), a functional analysis of the effect of the toxin in the axon initial segment (AIS), where VGNCs are highly expressed, was never performed so far. Here, we report an original analysis of the effect of AaH-II on the AP generation in the AIS of neocortical layer-5 pyramidal neurons from mouse brain slices. After determining that AaH-II does not discriminate between Nav1.2 and Nav1.6, i.e. between the two VGNC isoforms expressed in this neuron, we established that 7 nM was the smallest toxin concentration producing a minimal detectable deformation of the somatic AP after local delivery of the toxin. Using membrane potential imaging, we found that, at this minimal concentration, AaH-II substantially widened the AP in the AIS. Using ultrafast Na+imaging, we found that local application of 7 nM AaH-II caused a large increase in the slower component of the Na+influx in the AIS. Finally, using ultrafast Ca2+imaging, we observed that 7 nM AaH-II produces a spurious slow Ca2+influx via Ca2+-permeable VGNCs. Molecules targeting VGNCs, including peptides, are proposed as potential therapeutic tools. Thus, the present analysis in the AIS can be considered a general proof-of-principle on how high-resolution imaging techniques can disclose drug effects that cannot be observed when tested at the macroscopic level.
KINNTREX: A Neural Network Unveils Protein Mechanism from Time Resolved X-ray Crystallography
Authors: Biener Gabriel , Malla Tek Narsingh , Schwander Peter , Schmidt Marius 
Published: October 2023

AbstractHere, a machine learning method based on a kinetically informed neural network (NN) is introduced. The proposed method is designed to analyze a time series of difference electron density (DED) maps from a time-resolved X-ray crystallographic experiment. The method is named KINNTREX (Kinetics Inspired NN for Time-Resolved X-ray Crystallography). To validate KINNTREX, multiple realistic scenarios were simulated with increasing level of complexity. For the simulations, time-resolved X-ray data was generated that mimic data collected from the photocycle of the photoactive yellow protein (PYP).KINNTREX only requires the number of intermediates and approximate relaxation times (both obtained from a singular valued decomposition) and does not require an assumption of a candidate mechanism. It successfully predicts a consistent chemical kinetic mechanism, together with difference electron density maps of the intermediates that appear during the reaction. These features make KINNTREX attractive for tackling a wide range of biomolecular questions. In addition, the versatility of KINNTREX can inspire more NN-based applications to time-resolved data from biological macromolecules obtained by other methods.
Pleiotropy alleviates the fitness costs associated with resource allocation trade-offs in immune signaling networks
Authors: Martin Reese , Tate Ann.T. 
Published: October 2023

AbstractMany genes and signaling pathways within plant and animal taxa drive the expression of multiple organismal traits. This form of genetic pleiotropy instigates trade-offs among life-history traits if a mutation in the pleiotropic gene improves the fitness contribution of one trait at the expense of another. Whether or not pleiotropy gives rise to conflict among traits, however, likely depends on the resource costs and timing of trait deployment during organismal development. To investigate factors that could influence the evolutionary maintenance of pleiotropy in gene networks, we developed an agent-based model of co-evolution between parasites and hosts. Hosts comprise signaling networks that must faithfully complete a developmental program while also defending against parasites, and trait signaling networks could be independent or share a pleiotropic component as they evolved to improve host fitness. We found that hosts with independent developmental and immune networks were significantly more fit than hosts with pleiotropic networks when traits were deployed asynchronously during development. When host genotypes directly competed against each other, however, pleiotropic hosts were victorious regardless of trait synchrony because the pleiotropic networks were more robust to parasite manipulation, potentially explaining the abundance of pleiotropy in immune systems despite its contribution to life history trade-offs.
Above- and below-ground links mediated by arboreal ants and host tree modify soil aggregation scaling, infiltration, and chemistry
Authors: Medina Nicholas , Schmitt Lauren , Perfecto Ivette , Vandermeer John 
Published: October 2023

AbstractSoils are increasingly recognized as complex systems, emphasizing a need to study unique properties such as long-tailed scaling laws and the role of indirect interactions among arboreal above- and below-ground soil invertebrates. However, few studies consider the above-below-ground connections mediated by invertebrates’ activity and behavior compared to mediated by tree physiology. Given previous work showing that arboreal ants can compete and affect ground foragers as well as alter foraging behavior on different host trees, it is plausible that persistent above-ground ant nesting could extend to affect soil properties including structure and chemistry, mediated by ground ant exclusion. This study analyzes soil aggregation, water infiltration, and macro-chemical data associated with longer-term (5+ year) ant nesting in a rustic tropical agroforest. Results show that, 1) ant nesting maintained scaling law exponents or fractal dimensions of soil aggregate size distributions, and was significantly associated with relatively larger micro-aggregate diameters and log-normal variance in macro-aggregate size distributions, suggesting more consistent (less variable) underlying aggregation processes similar to host tree species effects; 2) areas in the vicinity of trees with no dominant ant nests had three-times faster water infiltration than in the vicinity of trees with dominant ant nests; and 3) a tendency toward changes in soil carbon and nitrogen stocks by one-quarter depending on host tree. These patterns are consistent with expected effects of ground ant suppression by an aggressive keystone arboreal ant, and are supported by previous studies reporting positive ground ant nest effects on soil chemistry and documenting ground ant foraging as a source of soil aggregate fragmentation. This study presents new ecological processes affecting ecosystem-scale functions, and suggests that future research on indirect interaction cascades would be beneficial to advance fundamental understanding of whole-ecosystem processes.
Cell autonomous role of leucine-rich repeat kinase in protection of dopaminergic neuron survival
Authors: Kang Jongkyun , Huang Guodong , Ma Long , Tong Youren , Shahapal Anu , Chen Phoenix , Shen Jie 
Published: October 2023

AbstractMutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson’s disease (PD), which is the leading neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). However, whether LRRK2 mutations cause PD and degeneration of DA neuronsviaa toxic gain-of-function or a loss-of-function mechanism is unresolved and has pivotal implications for LRRK2-based PD therapies. In this study, we investigate whether LRRK2 and its functional homologue LRRK1 play an essential, intrinsic role in DA neuron survival through the development of DA neuron-specificLRRKconditional double knockout (cDKO) mice. We first generated and characterized floxedLRRK1andLRRK2mice and then confirmed that germline deletions of the floxedLRRK1andLRRK2alleles result in null mutations, as evidenced by the absence ofLRRK1andLRRK2mRNA and protein in the respective homozygous deleted mutant mice. We further examined the specificity of Cre-mediated recombination driven by thedopamine transporter-Cre(DAT-Cre) knockin (KI) allele using a GFP reporter line and confirmed thatDAT-Cre-mediated recombination is restricted to DA neurons in the SNpc. Crossing these validated floxedLRRK1andLRRK2mice withDAT-CreKI mice, we then generated DA neuron-restrictedLRRKcDKO mice and further showed that levels of LRRK1 and LRRK2 are reduced in dissected ventral midbrains ofLRRKcDKO mice. While DA neuron-restrictedLRRKcDKO mice of both sexes exhibit normal mortality and body weight, they develop age-dependent loss of DA neurons in the SNpc, as demonstrated by the progressive reduction of DA neurons in the SNpc ofLRRKcDKO mice at the ages of 20 and 24 months but the unaffected number of DA neurons at the age of 15 months. Moreover, DA neurodegeneration is accompanied with increases of apoptosis and elevated microgliosis in the SNpc as well as decreases of DA terminals in the striatum, and is preceded by impaired motor coordination. Taken together, these findings provide the unequivocal evidence for the importance of LRRK in DA neurons and raise the possibility that LRRK2 mutations may impair its protection of DA neurons, leading to DA neurodegeneration in PD.
Intercellular contact and cargo transfer between Müller glia and to microglia precede apoptotic cell clearance in the developing retina
Authors: Morales Michael , Findley Anna P , Mitchell Diana M. 
Published: October 2023

AbstractTo clarify our understanding of glial phagocytosis in retinal development, we used real-time imaging of larval zebrafish to provide cell-type specific resolution of this process. We show that radial Müller glia frequently participate in microglial phagocytosis while also completing a subset of phagocytic events. Müller glia (MG) actively engage with dying cells through initial target cell contact and phagocytic cup formation after which an exchange of the dying cell from MG to microglia often takes place. Additionally, we find evidence that Müller glia cellular material, possibly from the initial Müller cell’s phagocytic cup, is internalized into microglial compartments. Previously undescribed Müller cell behaviors were seen, including cargo splitting, wrestling for targets, lateral passing of cargo to neighbors, and engulfment of what is possibly synaptic puncta. Collectively, our work provides new insight into glial functions and intercellular interactions, which will allow future work to understand these behaviors on a molecular level.Summary StatementReal-time imaging of developing zebrafish retinas reveals intercellular exchanges between Müller glial cells and to microglia during the clearance of apoptotic cells.
Landscape of Large-Scale Somatic Genomic Insertions in Non-Small Cell Lung Carcinoma Revealed by Nanopore Sequencing
Authors: Xie Dan , Xia Lin , Wang Zhoufeng , Zeng Tianfu , Pi Xuenan , Wang Huan , Zhu Guonian , Wu Xinyue , Li Yangqian , Deng Yan , Qi Yawen , liu Xuyan , Zhang Fengmei , Li Weimin 
Published: October 2023

AbstractPrevious NSCLC genomic studies were mostly based on the next-generation sequencing of short reads, which is an efficient approach for identifying single nucleotide variants and small indels but ineffective for identifying structural variants, especially large-scale insertions. Here, we studied 151 lung adenocarcinoma (LUAD) and 106 lung squamous cell carcinoma (LUSC) samples and paired blood samples using nanopore sequencing technology. We developed a rigorous computational pipeline and characterized the landscape of large-scale somatic insertions in NSCLC. Combining other omics data, we report three findings: 1. we identified an LUSC-enriched somatic simple repeat expansion shared by approximately 40% of LUSC patients that regulatesPTPRZ1gene expression through distal enhancers; 2. the somatic insertion of transposable elements (TEs) in NSCLC were mostly ‘complex TEs’ consisting of multiple TE elements; and 3. the insertion of short interspersed nuclear elements, especially from the Alu family in young lineages, is a frequent somatic mutation type that shapes the transcriptome of NSCLC through the expression of these elements.
Whole Genome Methylation Sequencing via Enzymatic Conversion (EM-seq): Protocol, Data Processing and Analysis
Authors: Olova Nelly N. , Andrews Simon 
Published: October 2023

AbstractWhole genome bisulfite sequencing (WGBS) has been the gold standard technique for base resolution analysis of DNA methylation for the last 15 years. It has been, however, associated with technical biases, which lead to overall overestimation of global and regional methylation values, and significant artifacts in extreme cytosine-rich DNA sequence contexts. Enzymatic conversion of cytosine is the newest approach, set to replace entirely the use of the damaging bisulfite conversion of DNA. The EM-seq technique utilises TET2, T4-BGT and APOBEC in a two-step conversion process, where the modified cytosines are first protected by oxidation and glucosylation, followed by deamination of all unmodified cytosines to uracil. As a result, EM-seq is degradation-free and bias-free, requires low DNA input, and produces high library yields with longer reads, little batch variation, less duplication, uniform genomic coverage, accurate methylation over a larger number of captured CpGs, and no sequence-specific artifacts.
BRD2 and BRD3 genes independently evolved RNA structures to control unproductive splicing
Authors: Petrova Marina , Margasyuk Sergey , Vorobeva Margarita , Skvortsov Dmitry , Dontsova Olga , Pervouchine Dmitri D. 
Published: October 2023

AbstractThe mammalianBRD2andBRD3genes encode structurally related proteins from the bromodomain and extraterminal domain (BET) protein family. The expression ofBRD2is regulated by unproductive splicing upon inclusion of exon 3b, which is located in the region encoding a bromodomain. Bioinformatic analysis indicated thatBRD2exon 3b inclusion is controlled by a pair of conserved complementary regions (PCCR) located in the flanking introns. Furthermore, we identified a highly conserved element encoding a cryptic poison exon 5b and a previously unknown PCCR in the intron between exons 5 and 6 ofBRD3, however outside of the homologous bromodomain. Minigene mutagenesis and blockage of RNA structure by antisense oligonucleotides demonstrated that RNA structure controls the rate of inclusion of poison exons. The patterns ofBRD2andBRD3expression and splicing show downregulation upon inclusion of poison exons, which become skipped in response to transcription elongation slowdown, further confirming a role of PCCRs in unproductive splicing regulation. We conclude thatBRD2andBRD3independently acquired poison exons and RNA structures to dynamically control unproductive splicing. This study describes a convergent evolution of regulatory unproductive splicing mechanisms in these genes providing implications for selective modulation of their expression in therapeutic applications.