bluuebunny/crossref_metadata_2025 huggingface dataset:
A Rationale for Safe Ventilation With Inhalation Injury: An Editorial Review
Authors: Dries David J , Tawfik Pierre N
Published: May 2022

Lung injury from smoke inhalation manifests as airway and parenchymal damage, at times leading to the acute respiratory distress syndrome. From the beginning of this millennium, the approach to mechanical ventilation in the patient with acute respiratory distress syndrome was based on reduction of tidal volume to 6 ml/kg of ideal body weight, maintaining a ceiling of plateau pressure, and titration of driving pressure (plateau pressure minus PEEP). Beyond these broad constraints, there is little specification for the mechanics of ventilator settings, consideration of the metabolic impact of the disease process on the patient, or interaction of patient disease and ventilator settings. Various studies suggest that inhomogeneity of lung injury, which increases the risk of regional lung trauma from mechanical ventilation, may be found in the patient with smoke inhalation. We now appreciate that energy transfer principles may affect optimal ventilator management and come into play in damaged heterogenous lungs. Mechanical ventilation in the patient with inhalation injury should consider various factors. Self-injurious respiratory demand by the patient can be reduced using analgesia and sedation. Dynamic factors beginning with rate management can reduce the incidence of potentially damaging ventilation. Moreover, preclinical study is underway to examine the flow of gas based on the ventilator mode selected, which may also be a factor triggering regional lung injury.
Myofibroblastoma of the Breast: Diagnosis, Pathology, and Management
Authors: Zamora Kathryn W , Talley Rachel , Hermecz Brittany N , Wei Shi
Published: May 2022

Myofibroblastomas are rare benign spindle cell tumors that occur within both male and female breasts. They are composed of fibroblasts and myofibroblasts and are not associated with malignant potential. On mammographic and sonographic imaging, these tumors may present as oval circumscribed masses that overlap with the appearance of many benign entities, including fibroadenomas. Occasionally, the tumors may demonstrate interval growth or mimic imaging features of malignancy and require biopsy. Correct pathologic diagnosis is important because many morphologic variants exist, which complicates pathologic interpretation. The purpose of this article is to review the range of imaging manifestations and histopathological findings and to discuss current management.
Development and validation of a nomogram for prognosis of sinonasal adenocarcinoma (a nomogram for sinonasal adenocarcinoma)
Authors: Huang Hesen , Chen Kaiqin , Deng Lifeng , Chen Yaling , Zhao Dean , Lin Wei
Published: May 2022

Background

The incidence of sinonasal adenocarcinoma is low, and there are few studies on survival and prognosis. Therefore, we aim to develop and validate a prognostic model for predicting the overall survival of sinonasal adenocarcinoma and provide guidance for clinical management.

Methods

Patients who were diagnosed as sinonasal adenocarcinoma through Surveillance, Epidemiology, and End Results database between 1975 and 2015 were randomly divided into a training group and validation group. Univariate, multivariate survival analysis was performed to screen independent survival factors. A nomogram was established to predict the overall survival rate of sinonasal adenocarcinoma. Receiver operating characteristic curve and calibration plot were performed to verify the discrimination and accuracy of the model. A decision curve analysis was performed to verify the clinical applicability of the model.

Results

A total of 423 patients with sinonasal adenocarcinoma were randomly divided into training group (n = 299) and verification group (n = 124). We established and verified the Nomo map including age, marriage, grade, surgery and tumour size. The c-index of Surveillance, Epidemiology, and End Results stage, T stage and this model are 0.635, 0.626 and 0.803, respectively. The survival rate of the high-risk group scored by this model was lower than that of the low-risk group (P < 0.001). Decision curve analysis shows that the model has advantages in predicting survival rates.

Conclusion

Our model is considered to be a useful tool for predicting the overall survival of sinonasal adenocarcinoma, with good discrimination and clinical applicability. We hope that this model will help rhinologists to make clinical decisions and manage patients diagnosed with sinonasal adenocarcinoma.
Big Fish in Small (and Big) Ponds: A Study of Careers
Authors: DeVaro Jed , Gürtler Oliver , Gürtler Marc , Deutscher Christian
Published: May 2022

Talented, ambitious workers (big fish) often join highly competitive organizations (big ponds), though they sometimes instead choose less competitive organizations (small ponds) offering brighter promotion prospects. Big fish exist in both types of organizations, though average worker ability is higher in big ponds. Top executives enjoy higher wages in big ponds. Choosing a big pond allows workers to signal high ability. Workers sometimes overestimate or underestimate their abilities, choosing the wrong pond. Big ponds tend to be larger in total employment. All of the preceding phenomena are shown to be consistent with equilibrium in a new theoretical model of careers. (JEL J24, M53)
How to set up and run a multi-centre trainee-led collaborative project
Authors: Nasser Ahmed A H , Archer James E , Chauhan Govind Singh , Thompson Calum , Osman Khabab , Nandra Rajpal , Dewan Varun
Published: May 2022

The multi-centre trainee-led collaborative research model improves the generalizability of results, efficiency of data collection, quality of data and sample size. Although an enormous amount of effort and resources are sometimes required, the final results lead to a standard that is unachievable by conventional studies. In this article, we summarize a step-by-step guide on how to set up and run a multi-centre trainee-led collaborative project.
Arabidopsis ETHYLENE INSENSITIVE 3 directly regulates the expression of PG1β-like family genes in response to aluminum stress
Authors: Jin Jing , Essemine Jemaa , Xu Zhan , Duan Jianli , Shan Chi , Mei Zhiling , Zhu Jian , Cai Weiming
Published: May 2022

The genes in the subfamily PG1β (beta subunit of poly-galacturonase isoenzyme 1) have a clear effect on the biosynthesis pathway of pectin, a main component of the cell wall. However, the detailed functions of the PG1β-like gene members in Arabidopsis (AtPG1–3) have not yet been determined. In this study, we investigated their functional roles in response to aluminum (Al) stress. Our results indicate that the PG1β-like gene members are indeed involved in the Al-stress response and they can modulate its accumulation in roots to achieve optimum root elongation and hence better seedling growth. We found that transcription factor EIN3 (ETHYLENE INSENSITIVE 3) alters pectin metabolism and the EIN3 gene responds to Al stress to affect the pectin content in the root cell walls, leading to exacerbation of the inhibition of root growth, as reflected by the phenotypes of overexpressing lines. We determined that EIN3 can directly bind to the promoter regions of PG1–3, which act downstream of EIN3. Thus, our results show that EIN3 responds to Al stress in Arabidopsis directly through regulating the expression of PG1–3. Hence, EIN3 mediates their functions by acting as a biomarker in their molecular biosynthesis pathways, and consequently orchestrates their biological network in response to Al stress.
A scoping review of bryophyte microbiota: diverse microbial communities in small plant packages
Authors: Chen Ko-Hsuan , Nelson Jessica
Published: May 2022

Plant health depends not only on the condition of the plant itself but also on its diverse community of microbes, or microbiota. Just like the better-studied angiosperms, bryophytes (mosses, liverworts, and hornworts) harbor diverse communities of bacteria, archaea, fungi, and other microbial eukaryotes. Bryophytes are increasingly recognized as important model systems for understanding plant evolution, development, physiology, and symbiotic interactions. Much of the work on bryophyte microbiota in the past focused on specific symbiont types for each bryophyte group, but more recent studies are taking a broader view acknowledging the coexistence of diverse microbial communities in bryophytes. Therefore, this review integrates studies of bryophyte microbes from both perspectives to provide a holistic view of the existing research for each bryophyte group and on key themes. The systematic search also reveals the taxonomic and geographic biases in this field, including a severe under-representation of the tropics, very few studies on viruses or eukaryotic microbes beyond fungi, and a focus on mycorrhizal fungi studies in liverworts. Such gaps may have led to errors in conclusions about evolutionary patterns in symbiosis. This analysis points to a wealth of future research directions that promise to reveal how the distinct life cycles and physiology of bryophytes interact with their microbiota.
Genetic basis and adaptive implications of temperature-dependent and temperature-independent effects of drought on chickpea reproductive phenology
Authors: Li Yongle , Lake Lachlan , Chauhan Yashvir S , Taylor Julian , Sadras Victor O
Published: May 2022

Water deficit often hastens flowering of pulses partially because droughted plants are hotter. Separating temperature-independent and temperature-dependent effects of drought is important to understand, model, and manipulate phenology. We define a new trait, drought effect on phenology (DEP), as the difference in flowering time between irrigated and rainfed crops, and use FST genome scanning to probe for genomic regions under selection for this trait in chickpea (Cicer arietinum). Owing to the negligible variation in daylength in our dataset, variation in phenology with sowing date was attributed to temperature and water; hence, genomic regions overlapping for early- and late-sown crops would associate with temperature-independent effects and non-overlapping genomic regions would associate with temperature-dependent effects. Thermal-time to flowering was shortened with increasing water stress, as quantified with carbon isotope composition. Genomic regions on chromosomes 4–8 were under selection for DEP. An overlapping region for early and late sowing on chromosome 8 revealed a temperature-independent effect with four candidate genes: BAM1, BAM2, HSL2, and ANT. The non-overlapping regions included six candidate genes: EMF1, EMF2, BRC1/TCP18, BZR1, NPGR1, and ERF1. Modelling showed that DEP reduces the likelihood of drought and heat stress at the expense of increased likelihood of cold stress. Accounting for DEP would improve genetic and phenotypic models of phenology.
Melatonin biosynthesis and signal transduction in plants in response to environmental conditions
Authors: Liu Gaofeng , Hu Qian , Zhang Xin , Jiang Jiafu , Zhang Yang , Zhang Zixin
Published: May 2022

Melatonin, the most widely distributed hormone in nature, plays important roles in plants. Many physiological processes in plants are linked to melatonin, including seed germination, anisotropic cell growth, and senescence. Compared with animals, different plants possess diverse melatonin biosynthetic pathways and regulatory networks. Whereas melatonin biosynthesis in animals is known to be regulated by ambient signals, little is known about how melatonin biosynthesis in plants responds to environmental signals. Plants are affected by numerous environmental factors, such as light, temperature, moisture, carbon dioxide, soil conditions, and nutrient availability at all stages of development and in different tissues. Melatonin content exhibits dynamic changes that affect plant growth and development. Melatonin plays various species-specific roles in plant responses to different environmental conditions. However, much remains to be learned, as not all environmental factors have been studied, and little is known about the mechanisms by which these factors influence melatonin biosynthesis. In this review, we provide a detailed, systematic description of melatonin biosynthesis and signaling and of the roles of melatonin in plant responses to different environmental factors, providing a reference for in-depth research on this important issue.
ABSCISIC ACID INSENSITIVE 5 mediates light–ABA/gibberellin crosstalk networks during seed germination
Authors: Li Zenglin , Luo Xiaofeng , Wang Lei , Shu Kai
Published: May 2022

Appropriate timing of seed germination is crucial for plant survival and has important implications for agricultural production. Timely germination relies on harmonious interactions between endogenous developmental signals, especially abscisic acid (ABA) and gibberellins (GAs), and environmental cues such as light. Recently, a series of investigations of a three-way crosstalk between phytochromes, ABA, and GAs in the regulation of seed germination demonstrated that the transcription factor ABSCISIC ACID INSENSITIVE 5 (ABI5) is a central mediator in the light–ABA/GA cascades. Here, we review current knowledge of ABI5 as a key player in light-, ABA-, and GA-signaling pathways that precisely control seed germination. We highlight recent advances in ABI5-related studies, focusing on the regulation of seed germination, which is strictly controlled at both the transcriptional and the protein levels by numerous light-regulated factors. We further discuss the components of ABA and GA signaling pathways that could regulate ABI5 during seed germination, including transcription factors, E3 ligases, protein kinases, and phosphatases. The precise molecular mechanisms by which ABI5 mediates ABA–GA antagonistic crosstalk during seed germination are also discussed. Finally, some potential research hotspots underlying ABI5-mediated seed germination regulatory networks are proposed.
A mechanistic target of rapamycin inhibitor, everolimus safely ameliorated lupus nephritis in a patient complicated with tuberous sclerosis
Authors: Okita Yasutaka , Yoshimura Maiko , Katada Yoshinori , Saeki Yukihiko , Ohshima Shiro
Published: May 2022

A 26-year-old woman with tuberous sclerosis complex (TSC) received outpatient treatment for the complication of systemic lupus erythematosus (SLE) at our hospital. She visited our hospital with a chief complaint of pitting oedema in bilateral lower legs for 3 days. The urinalysis showed massive proteinuria with a lot of white blood cell casts. The blood tests revealed hypoalbuminaemia, hypercholesterolaemia, hypocomplementaemia, and elevated anti-double-stranded DNA antibody titre. Renal biopsy was not performed because of multiple renal angiomyolipomas, which was one of the features of TSC. She was diagnosed with a nephrotic state due to lupus nephritis. Although she had a standard therapy with high-dose corticosteroid and mycophenolate mofetil and tacrolimus, complete remission had not been achieved leading to a steroid-dependent nephrotic syndrome. During the follow-up, the angiomyolipomas became larger and had a risk of rupture at the age of 29 years. Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, was started for the treatment of angiomyolipomas, and mycophenolate mofetil and tacrolimus were terminated instead. The activity of lupus nephritis was surprisingly ameliorated, and the amount of corticosteroid successfully tapered. Everolimus has been continued for 6 years without severe side effects. Accumulating evidence suggests that the activated mTOR pathway plays a key role in the pathogenesis of SLE. We reported the long-term efficacy and safety of everolimus for refractory SLE in a patient with TSC for the first time. This case suggests that everolimus can be a promising option for the treatment of lupus nephritis.
BioTransformer 3.0—a web server for accurately predicting metabolic transformation products
Authors: Wishart David S , Tian Siyang , Allen Dana , Oler Eponine , Peters Harrison , Lui Vicki W , Gautam Vasuk , Djoumbou-Feunang Yannick , Greiner Russell , Metz Thomas O
Published: May 2022

BioTransformer 3.0 (https://biotransformer.ca) is a freely available web server that supports accurate, rapid and comprehensive in silico metabolism prediction. It combines machine learning approaches with a rule-based system to predict small-molecule metabolism in human tissues, the human gut as well as the external environment (soil and water microbiota). Simply stated, BioTransformer takes a molecular structure as input (SMILES or SDF) and outputs an interactively sortable table of the predicted metabolites or transformation products (SMILES, PNG images) along with the enzymes that are predicted to be responsible for those reactions and richly annotated downloadable files (CSV and JSON). The entire process typically takes less than a minute. Previous versions of BioTransformer focused exclusively on predicting the metabolism of xenobiotics (such as plant natural products, drugs, cosmetics and other synthetic compounds) using a limited number of pre-defined steps and somewhat limited rule-based methods. BioTransformer 3.0 uses much more sophisticated methods and incorporates new databases, new constraints and new prediction modules to not only more accurately predict the metabolic transformation products of exogenous xenobiotics but also the transformation products of endogenous metabolites, such as amino acids, peptides, carbohydrates, organic acids, and lipids. BioTransformer 3.0 can also support customized sequential combinations of these transformations along with multiple iterations to simulate multi-step human biotransformation events. Performance tests indicate that BioTransformer 3.0 is 40–50% more accurate, far less prone to combinatorial ‘explosions’ and much more comprehensive in terms of metabolite coverage/capabilities than previous versions of BioTransformer.
GNAT toxins evolve toward narrow tRNA target specificities
Authors: Bikmetov Dmitry , Hall Alexander M J , Livenskyi Alexei , Gollan Bridget , Ovchinnikov Stepan , Gilep Konstantin , Kim Jenny Y , Larrouy-Maumus Gerald , Zgoda Viktor , Borukhov Sergei , Severinov Konstantin , Helaine Sophie , Dubiley Svetlana
Published: May 2022

Type II toxin–antitoxin (TA) systems are two-gene modules widely distributed among prokaryotes. GNAT toxins associated with the DUF1778 antitoxins represent a large family of type II TAs. GNAT toxins inhibit cell growth by disrupting translation via acetylation of aminoacyl-tRNAs. In this work, we explored the evolutionary trajectory of GNAT toxins. Using LC/MS detection of acetylated aminoacyl-tRNAs combined with ribosome profiling, we systematically investigated the in vivo substrate specificity of an array of diverse GNAT toxins. Our functional data show that the majority of GNAT toxins are specific to Gly-tRNA isoacceptors. However, the phylogenetic analysis shows that the ancestor of GNAT toxins was likely a relaxed specificity enzyme capable of acetylating multiple elongator tRNAs. Together, our data provide a remarkable snapshot of the evolution of substrate specificity.
GeCoViz: genomic context visualisation of prokaryotic genes from a functional and evolutionary perspective
Authors: Botas Jorge , Rodríguez del Río Álvaro , Giner-Lamia Joaquín , Huerta-Cepas Jaime
Published: May 2022

Synteny conservation analysis is a well-established methodology to investigate the potential functional role of unknown prokaryotic genes. However, bioinformatic tools to reconstruct and visualise genomic contexts usually depend on slow computations, are restricted to narrow taxonomic ranges, and/or do not allow for the functional and interactive exploration of neighbouring genes across different species. Here, we present GeCoViz, an online resource built upon 12 221 reference prokaryotic genomes that provides fast and interactive visualisation of custom genomic regions anchored by any target gene, which can be sought by either name, orthologous group (KEGGs, eggNOGs), protein domain (PFAM) or sequence. To facilitate functional and evolutionary interpretation, GeCoViz allows to customise the taxonomic scope of each analysis and provides comprehensive annotations of the neighbouring genes. Interactive visualisation options include, among others, the scaled representations of gene lengths and genomic distances, and on the fly calculation of synteny conservation of neighbouring genes, which can be highlighted based on custom thresholds. The resulting plots can be downloaded as high-quality images for publishing purposes. Overall, GeCoViz offers an easy-to-use, comprehensive, fast and interactive web-based tool for investigating the genomic context of prokaryotic genes, and is freely available at https://gecoviz.cgmlab.org
MDsrv: visual sharing and analysis of molecular dynamics simulations
Authors: Kampfrath Michelle , Staritzbichler René , Hernández Guillermo Pérez , Rose Alexander S , Tiemann Johanna K S , Scheuermann Gerik , Wiegreffe Daniel , Hildebrand Peter W
Published: May 2022

Molecular dynamics simulation is a proven technique for computing and visualizing the time-resolved motion of macromolecules at atomic resolution. The MDsrv is a tool that streams MD trajectories and displays them interactively in web browsers without requiring advanced skills, facilitating interactive exploration and collaborative visual analysis. We have now enhanced the MDsrv to further simplify the upload and sharing of MD trajectories and improve their online viewing and analysis. With the new instance, the MDsrv simplifies the creation of sessions, which allows the exchange of MD trajectories with preset representations and perspectives. An important innovation is that the MDsrv can now access and visualize trajectories from remote datasets, which greatly expands its applicability and use, as the data no longer needs to be accessible on a local server. In addition, initial analyses such as sequence or structure alignments, distance measurements, or RMSD calculations have been implemented, which optionally support visual analysis. Finally, based on Mol*, MDsrv now provides faster and more efficient visualization of even large trajectories compared to its predecessor tool NGL.
Integrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2)
Authors: Karmakar Shilpita , Ramirez Oscar , Paul Kiran V , Gupta Abhishek K , Kumari Vandana , Botti Valentina , de los Mozos Igor Ruiz , Neuenkirchen Nils , Ross Robert J , Karanicolas John , Neugebauer Karla M , Pillai Manoj M
Published: May 2022

Musashi 2 (MSI2) is an RNA binding protein (RBP) that regulates asymmetric cell division and cell fate decisions in normal and cancer stem cells. MSI2 appears to repress translation by binding to 3′ untranslated regions (3′UTRs) of mRNA, but the identity of functional targets remains unknown. Here, we used individual nucleotide resolution cross-linking and immunoprecipitation (iCLIP) to identify direct RNA binding partners of MSI2 and integrated these data with polysome profiling to obtain insights into MSI2 function. iCLIP revealed specific MSI2 binding to thousands of mRNAs largely in 3′UTRs, but translational differences were restricted to a small fraction of these transcripts, indicating that MSI2 regulation is not triggered by simple binding. Instead, the functional targets identified here were bound at higher density and contain more ‘UAG’ motifs compared to targets bound nonproductively. To further distinguish direct and indirect targets, MSI2 was acutely depleted. Surprisingly, only 50 transcripts were found to undergo translational induction on acute loss. Using complementary approaches, we determined eukaryotic translation initiation factor 3A (EIF3A) to be an immediate, direct target. We propose that MSI2 downregulation of EIF3A amplifies these effects on translation. Our results also underscore the challenges in defining functional targets of RBPs since mere binding does not imply a discernible functional interaction.
MO009: Creatine-Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment
Authors: Rodríguez Espinosa Diana , Jesus Broseta Monzo Jose , Cuadrado Elena , Fernando Quintana Porras Luis , Poch Esteban , Piñeiro Gaston , Agraz Irene , Sánchez-Baya Maya , Furlano Monica , Ruiz César , Torra Roser , Blasco Miquel
Published: May 2022

BACKGROUND AND AIMS

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of end-stage kidney disease. Currently, tolvaptan is the only treatment that has proven to delay disease progression. The most notable side-effect of this therapy is drug-induced liver injury; however, recently, there have been two reports of creatine kinase (CK) elevation in ADPKD patients on tolvaptan treatment. We set out to monitor and determine the actual incidence of CK elevation and evaluate its potential association with other clinical factors.

METHOD

This is an observational prospective multicenter study performed in rapidly progressive ADPKD patients on tolvaptan treatment from Barcelona, Spain. Laboratory tests, demographics, treatment dose and reported symptoms were collected from October 2018 to March 2021.

RESULTS

Ninety-five patients initiated tolvaptan treatment during follow-up. The medication had to be discontinued in 31 (32.6%) patients, primarily due to aquaretic effects (12.6%), elevated liver enzymes (8.4%) and symptomatic or persistently elevated CK levels (3.2%). Moreover, a total of 27 (28.4%) patients elevated CK levels, with most of them being either transient (12.6%), mild and asymptomatic (4.2%), or resolved after dose reduction (3.2%) or temporary discontinuation (2.1%).

CONCLUSION

We present the largest cohort that has monitored CK levels in a real-life setting, finding them elevated in 28.4% of patients. More research and monitoring will help us understand the clinical implications and the pathophysiological mechanism of CK elevation in this population.
MO044: Cellular mechanism of the exceptional dominant transmission in NPHS2-associated glomerulopathy
Authors: Seidl Dániel , Antal-Kónya Violetta , Schay Gusztáv , Bertholet-Thomas Aurélia , Török György , Mollet Geraldine , Kellermayer Miklós , Antignac Corinne , Tory Kálmán
Published: May 2022

BACKGROUND AND AIMS

Mutations of NPHS2 cause autosomal recessive steroid-resistant nephrotic syndrome (SRNS). The encoded podocin, a key component of the slit diaphragm, homo-oligomerizes through two C-terminal oligomerization sites. We formerly found that specific podocin variants may exert a dominant negative effect against R229Q podocin variant secondary to an altered oligomerization [1, 2]. Recently, two families with autosomal dominant focal segmental glomerulosclerosis were found to carry a de novo heterozygous NPHS2 last-exon frameshift mutations affecting the second oligomerization site (either c.989_992delTGTC, p.L330Pfs*17 or c.988_989delCT, p.L330Vfs*15) [3]. We hypothesized that these podocin variants exert a dominant negative effect against wild type (WT) podocin.

METHODS

We coexpressed eGFP-tagged WT podocin with either hemagglutinin-tagged (HA) WT, p.L330Pfs*17 or p.L330Vfs*15 podocin variants in cultured podocytes. Plasma membrane was stained with CF405M-conjugated wheat germ agglutinin (WGA), and immunohistochemical staining was performed with primary anti-HA and secondary AlexaFluor568-conjugated antibodies. All analysis was done in a blinded fashion. The membrane-targeting of podocin was assessed by the ratio of the WGA-labeled perimembranous area that colocalized with podocin (Mander's overlap coefficients, MOC) and the colocalization of the coexpressed variants were estimated as Pearson correlation coefficients (PCC) by FiJi software on confocal microscopic images. MOC and PCC were compared by Holmes–Bonferroni adjusted Wilcoxon signed-rank test.

RESULTS

The frameshift podocin variants were not membranous in monoexpression [MOC: HA-p.L330Pfs*17 (n = 26): 0.08 (0.03–0.22) median (interquartile ranges); HA-p.L330Vfs*15 (n = 24): 0.07 (0.02–0.16)]. The GFP-tagged WT podocin strongly colocalized with the HA-tagged WT or frameshift podocin variants [PCC: WT-eGFP + HA-WT (n = 19): 0.64 (0.49–0.71); WT-eGFP + HA-L330Pfs*17 (n = 17): 0.54 (0.35–0.58); WT-eGFP + HA-L330Vfs*15 (n = 17): 0.44 (0.29–0.66)]. The GFP-WT podocin was retained in intracellular compartments in the presence of any of the two frameshift podocin variants [MOCWT(WT) = 0.58 (0.46–0.69)], MOCWT(L330Pfs*17) = 0.01 (0.002–0.029), P = 2x10-6 versus WT(WT); MOCWT(L330Vfs*15) = 0.003 (0.001–0.013), P = 2 x 10−6 versus WT(WT)].

CONCLUSIONS

The dominant podocin variants retain WT podocin in intracellular compartments explaining the exceptional dominant transmission of NPHS2-associated glomerulopathy. This is in accordance with our former results showing the primary role of C-terminal hetero-oligomerization in exerting interallelic interactions of NPHS2 alleles.

FUNDING

MTA-SE Lendulet Research Grant (LP2015-11/2015), OTKA KH125566 and K135798, and ÚNKP-20–3-I-SE-29 from the source of the National Research, Development and Innovation Fund.
MO047: Biallelic pathogenic variants in ROBO1 associate with syndromic CAKUT
Authors: Münch Johannes , Engesser Marie , Schönauer Ria , Hamm J Austin , Akay Gulsen , Tüysüz Beyhan , Shirakawa Toshihiko , Dateki Sumito , Claus Laura , van Eerde Albertien M , Wagner Timo , Bergmann Carsten , Buchan Jillian , Wegner Tara , Posey Jennifer , Lupski James R , Petit Florence , Mccarthy Andrew A , Pazour Gregory J , Lo Cecilia W , Popp Bernt , Halbritter Jan
Published: May 2022

BACKGROUND AND AIMS

Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date.

METHOD

We collected phenotypic data of all participants. Genetic analysis was conducted by either exome or whole genome sequencing, respectively. We used Sanger sequencing for variant confirmation and segregation analysis and performed in-silico analysis of identified missense variants. In an ENU-induced mouse model, we examined mice with the mutation Robo1Ile270Thr/Ile270Thr.

RESULTS

By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses from Germany, France, Turkey, Japan and the USA with biallelic truncating or combined missense and truncating variants in ROBO1. Renal and genitourinary manifestation included unilateral or bilateral renal agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation and increased renal echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects (Figure 1).

By in-silico analysis, we determined the functional significance of identified missense variants and observed absence of renal ROBO1 expression in both human and murine mutant tissues (Figure 2).

CONCLUSION

This study describes six live-born and two non-viable individuals with syndromic CAKUT due to probably deleterious ROBO1 variants. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. In conclusion, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Conversely, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for renal involvement is indicated.
MO049: Correlation of Findings in Urinary Sediment Microscopy and Histological Lesions in Kidney Biopsy: Red Flags Not to be Missed
Authors: Barata Rui , Navarro David , Moreira Fonseca Nuno , Carina Ferreira Ana , Góis Mário , Viana Helena , Nolasco Fernando
Published: May 2022

BACKGROUND AND AIMS

Urinary sediment (U-Sed) is a noninvasive laboratory test that can be performed by an automated analyzer or manually by trained personnel. Manual U-Sed remains the diagnostic standard because it excels at distinguishing isomorphic from dysmorphic red blood cells, identifying renal tubular epithelial cells, lipids, crystals and the composition of casts. Findings in U-Sed reflect damage that is occurring within the kidney, which can be documented by kidney biopsy. This study aimed to investigate the prevalence of a complete profile of U-Sed particles and its associations with histological lesions on kidney biopsy, regardless of renal diagnosis.

METHOD

This retrospective study included 131 patients who had contemporary manual U-Sed evaluation and kidney biopsy at our institution, from 2018 to 2021. Renal transplant patients were excluded. A comprehensive set of urinary particles and histological lesions were quantified, and we analyzed their associations.

Urinary particles evaluated included casts, erythrocytes, leukocytes, renal tubular epithelial cells, urothelial transitional cells (superficial and deep), lipids, crystals, squamous cells and bacteria. They were semi-quantified from 0 (absent) to 3 + . Renal biopsies samples were reviewed, and a systematic evaluation of 32 histological lesions was performed. When present, lesions were semi-quantified from 0 (absent) to 3 + .

Appropriate tests were performed STATA v.16.1.

RESULTS

We found an elevated frequency of findings suggestive of proliferative renal disease, such as dysmorphic hematuria (n = 71, 54.2%), leukocyturia (n = 62, 47.3%), renal tubular epithelial cells (n = 53, 40.5%) and lipiduria (n = 45, 34.4%), and a low frequency of particles evoking urological damage, such as isomorphic hematuria (n = 29, 22.1%), crystals (n = 12, 9.2%) and urothelial transitional cells (n = 26, 9.9%).

The association of histological lesions and urinary particles was explored with a multivariate model that identified U-Sed characteristics, which favored the presence of acute tubular necrosis, endocapillary hypercellularity, neutrophils and/or karyorrhexis, wire loops and/or hyaline deposits, fibrinoid necrosis and cellular/fibrocellular crescents (summarized in Table 1).

CONCLUSION

In a population of patients submitted to kidney biopsy, we found that the presence of some urinary particles (renal tubular epithelial cells, lipids and dysmorphic erythrocytes), which are seldom reported by automated analyzers, conferred an increased likelihood of active proliferative histological lesions. It is important not to misidentify them, as their presence are red flags for relevant proliferative histological lesions. Moreover, given the flare/remission characteristics of proliferative glomerular disease, U-Sed could play a major role in measuring the degree of activity without requiring repeat kidney biopsies.
MO059: Trajectory Analysis of the Kidney Organoid Proteome Extends its Modelling Potential of Disease
Authors: Lassé Moritz , Bonin Léna L , El Saghir Jamal , Eddy Sean F , Hutzfeldt Arvid , Hoxha Elion , Dumoulin Bernhard , Lindenmeyer Maja , Schlüter Hartmut , Beck Bodo B , Brandts Paul , Kretzler Matthias , Demir Fatih , Harder Jennifer L , Rinschen Markus
Published: May 2022

BACKGROUND AND AIMS

Kidney organoids are a valuable and innovative model to understand genetic diseases, kidney development and transcriptomic dynamics. However, their proteome has not been analyzed so far. It is unclear how their proteome changes during differentiation, and if more complex disease processes such as inflammatory tissue responses could be modelled with this approach.

METHOD

Here, we used proteomics to compare organoids with existing model systems such as native glomeruli and cultured cells. We characterize the trajectory of organoid differentiation and delineate innate immune responses in organoids to expand its scope as a model system in nephrology. We also compared our proteomics with bulk and single cell transcriptomic data.

RESULTS

Genes involved in podocytopathies and cystic kidney diseases were abundantly expressed on protein level, distinguishing organoids from almost every available cell culture model. On their pathway to terminal differentiation, organoids developed increased deposition of extracellular matrix. Single cell transcriptomic analysis suggests that most changes locate to podocytes and early podocyte progenitors. This matrix deposition is different from commonly used animal models of glomerular disease. A novel signaling system discovered was the TNFα system, a system also available in podocytes. Incubation of organoids with high concentrations of TNFα led to an activation of NF-kB signaling, and secretion of cytokines and complement components, alongside with extracellular matrix components.

CONCLUSION

Interestingly, this signaling system directly links inflammatory signaling, production of cytokines and complement, and production of extracellular matrix. Thus, we provide a repository of human kidney organoid proteins that revealed the potential to model pathophysiological pathways beyond genetic diseases.
MO079: Treatment with Nebivolol Ameliorates Renovascular Alterations and Oxidative Stress in Tenofovir-Induced Nephrotoxicity in Rats
Authors: Moura Nascimento Mariana , Bernardo Desiree , Carolina de Braganca Ana , Heloisa Massola Shimizu Maria , Carlos Seguro Antonio , Aparecido Volpini Rildo , Canale Daniele
Published: May 2022

BACKGROUND AND AIMS

Human immunodeficiency virus (HIV) continues to be a major global public health issue, having claimed millions of lives so far. Tenofovir disoproxil fumarate (TDF), a widely prescribed component in antiretroviral regimens for HIV treatment, has been associated with nephrotoxicity. Nebivolol (NBV) is a third generation selective β-1 adrenergic receptor blocker currently used in the treatment of hypertension and cardiovascular diseases. The potential mechanisms by which NBV may protect renal structure and function include suppression of oxidative stress and enhancement of nitric oxide synthesis. The aim of this study was to investigate whether NBV could be an effective therapeutic option to mitigate TDF-induced nephrotoxicity.

METHOD

We divided Wistar rats into four groups: control (C, n = 8), received a standard diet for 30 days; TDF (n = 9), received a standard diet with the addition of TDF (300 mg/kg food) for 30 days; NBV (n = 8), received a standard diet for 30 days with the addition of NBV (100 mg/kg food) in the last 15 days; and TDF + NBV (n = 9), received a standard diet with the addition of TDF for 30 days and NBV in the last 15 days. We evaluated inulin clearance (GFR); tubular injury; mean arterial pressure (MAP); renal blood flow (RBF) and calculated renal vascular resistance (RVR); plasma and tissue angiotensin II (AIIp and AIIt, respectively); plasma aldosterone; plasma asymmetric dimethylarginine (ADMA); plasma and urinary thiobarbituric acid reactive substances (TBARSp and TBARSu, respectively); and whole blood glutathione (GSH). In renal tissue, we immunoblotted for endothelial nitric oxide synthase (eNOS), p47phox and p67phox. Data are expressed as mean ± SEM.

RESULTS

TDF + NBV rats showed an improvement in renal function, a normalization of MAP and attenuation in renal vasoconstriction, evidenced by increased RBF and diminished RVR. Administration of NBV also reduced AII and aldosterone levels in TDF-treated animals. Furthermore, the TDF + NBV group showed a lower plasma ADMA concentration and a higher protein expression of eNOS. Treatment with NBV was responsible for the maintenance of an adequate balance of TBARS and GSH levels, and it was associated with reductions in renal p47phox and p67phox. All results are described in Table 1.

CONCLUSION

Our data demonstrated the protective role of NBV in TDF-induced nephrotoxicity. The beneficial effects of NBV include a reduction in oxidative stress and RAAS activation, as well as a decrease in endothelial dysfunction, observed by an upregulation on the NO cascade. Therefore, NBV may be an effective therapeutic strategy in the treatment of patients with TDF-induced nephrotoxicity. Financial support: CAPES and FAPESP (2019/20840–0, 2018/12297–1, 2018/04930–6).
MO096: Chronic Liver Disease and Hepatic Calcium-Oxalate Deposition in Patients with Primary Hyperoxaluria Type I
Authors: Recker Pia , Beck Bodo B , Sikora Przemyslaw , Göbel Heike , Kemper Markus , Nazco Angel , Martin Higueras Cristina , Hoppe Bernd
Published: May 2022

BACKGROUND AND AIMS

Patients with primary hyperoxaluria type I (PH I) are prone to develop early end-stage kidney failure (ESKF). Systemic deposition of calcium-oxalate (CaOx) crystals starts when renal function declines and plasma oxalate (Pox) increases >30 µmol/L. It is anticipated that all parenchymal organs, but also bone (marrow), retina and the central nervous system can be involved. However, liver involvement, either as CaOx deposition or as chronic hepatitis/fibrosis, was never reported.

METHOD

We now examined liver involvement in 19 patients with PH I aged 1.5–52 years. Liver specimen was obtained by biopsy for diagnostic purposes (1), at autopsy (1) or at the time of combined or sequential liver kidney transplantation (17).

RESULTS

With polarization microscopy, crystals with the typical star-like appearance of CaOx were found in 3/19 patients. The crystals were located in small arteries but not within hepatocytes. Cirrhosis was seen in one patient. Fibrosis was seen in 10/19 patients, with porto-portal and nodular fibrosis (n = 1), and a limitation of fibrosis to the portal field in eight and/or to central areas in five patients. Unspecific hepatitis features were observed in seven patients. Fiber proliferations were detectable in 10 cases, and in one sample, transformed Ito-cells (myofibroblasts) were found. Iron deposition but also megakaryocytes as a sign of extramedullary erythropoiesis were found in nine and three patients, respectively.

CONCLUSION

Overall, liver involvement in patients with PH I was more pronounced, as previously described. However, compared with CaOx deposition in other organs/tissue, such crystal accumulations were only minimal in the liver, although the oxalate concentration must be the highest.
MO101: Atypical Haemolytic Uremic Syndrome Associated with COVID-19: Case Report
Authors: Gjyzari (Velaj) Albana , Muco Ermira , Como Najada
Published: May 2022

BACKGROUND AND AIMS

Renal manifestations are common in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report here the case of a patient with confirmed SARS-CoV-2 infection with the clinical picture of atypical haemolytic uremic syndrome (aHUS).

METHOD

Case report

RESULTS

Our case is a 31-year-old man with a nasopharyngeal swab with real-time reverse-transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 positive, who was hospitalized in the Clinic of Infectious Diseases. His medical history had a respiratory illness of 7-day evolution characterized by cough, fever, dyspnoea, muscle pain, nausea, vomiting and non-bloody diarrhoea, and decreased urine output with dark colour urine. The chest computed tomography (CT) scan showed few rounded ground-glass opacities.

Laboratory tests at admission revealed the following: (i) acute kidney injury stage 3 with a serum creatinine of 3.85 mg/dL (basal value 0.9 mg/dL); serum urea 221 mg/dL. His urinary volume in the first 24 h of hospitalization was 800 mL. (ii) Severe haemolytic anaemia with haemoglobin (Hgb) level of 3.7 g/dL, and peripheral smear showing large number of schistocytes, haptoglobin <10 mg/dL and indirect bilirubin 9.7 mg/dL, direct coombs testing was negative; reticulocyte count 8.9%. (iii) Severe thrombocytopaenia with platelet count of 25 000/µL, prothrombin time 45%, international normalized ratio 1.7, D-dimer 1082 ng/dL and fibrinogen 880 mg/dL.

Increased blood levels of enzymes and inflammatory markers were present: lactate dehydrogenase 1867 U/L and protein C reactive 9.1 mg/dL. Electrolyte disturbances characterized by hyperkalaemia, hyperphosphatemia, hypocalcaemia and severe metabolic acidosis. Dynamic changes of laboratory data are presented in Table 1.

The usual liver panel tests, alkaline phosphatase, γ-glutamyl transferase and albuminemia were normal. Toxic hepatitis was excluded. Hepatobiliary and spleen imaging (ultrasonography) was normal.

ELISA serologic tests for HIV, hepatitis B, hepatitis C virus and cytomegalovirus were negative. Serological and virological tests for hepatitis A, B, C, HIV and CMV were negative. Stool was negative for Shiga toxin-producing Escherichia coli (STEC).

The results of antinuclear antibodies and anti-smooth-muscle antibodies were negative, C3 serum level was mildly depressed (82 mg/dL; normal range 88–201 mg/dL) and C4 serum level was normal (20 mg/dL; normal range 10–44 mg/dL). ADAMTS13 activity was 90% on day 10.

He was treated with broad spectrum antibiotics, intravenous dexamethasone and supportive therapy. One week from admission, renal function recovered, and 1 week after intravascular haemolysis and thrombocytopaenia recovered. The patient was hospitalized for 21 days.

CONCLUSION

Close monitoring and early intervention can help for a better outcome of SARS-CoV-2 patients complicated with aHUS.
MO102: Lean Tissue, as Assessed by Bioimpedance Spectroscopy, Is Dependent on Renal Function in Patients with HFREF
Authors: Popa Raluca , Sascau Radu , Statescu Cristian , Siriopol Ianis , Vasiliu Vlad , Neamtu Andreea , Bucur Andreea , Kanbay Mehmet , Siriopol Dimitrie
Published: May 2022

BACKGROUND AND AIMS

Despite impressive improvements in treatment strategies, heart failure (HF) morbidity and mortality remain substantially high worldwide. Muscle wasting is common and is associated with increased morbidity and mortality in patients with HF. The aim of the study was to determine muscle mass, by bioimpedance spectroscopy (BIS), and to identify factors associated with decreased muscle mass in this population.

METHOD

This was a prospective observational study of outpatient adults referred for clinically indicated transthoracic echocardiograms at an academic hospital between 2016 and 2018. A left ventricular ejection fraction below 45% was required for inclusion (HFrEF).

Muscle mass was assessed using BIS (with the body composition monitor—BCM® device).

RESULTS

Our study included 151 patients. The mean age and eGFR values of the population at baseline were 67.1 years and 66.5 mL/min/1.73 m2. The median levels for lean tissue index (LTI, lean tissue mass/height2) were 11.3 (IQR 9.4–12.9) kg/m2.

LTI was positively associated with eGFR and negatively associated with uric acid, ST-2 and galectin-3 levels. Including all these variables in a stepwise multivariable regression only eGFR and ST-2 remained independently associated with LTI (see Table 1).

Based on the LTI median value, we also divided the patients into two groups—group 1 (LTI ≤ 11.3 kg/m2) and group 2 (LTI > 11.3 kg/m2). In the univariable logistic regression age, using the haemoglobin, eGFR and ST-2 levels predicted the group appurtenance. Including all these variables in a stepwise multivariable logistic regression, only eGFR and eGFR remained independently associated with LTI groups (see Table 2).

CONCLUSION

A better understanding of the factors associated with decreased muscle mass is needed to develop preventive strategies for muscle wasting in patients with HF. Muscle mass, as measured by the BCM and expressed as the LTI, is strongly associated with eGFR.