Improving awareness of kidney function through electronic urine output monitoring: a comparative study.

BACKGROUND: The current classification for acute kidney injury (AKI) according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria integrates both serum creatinine (SCr) and urine output (UO). Most reports on AKI claim to use KDIGO guidelines but fail to include the UO criterion. It has been shown that patients who had intensive UO monitoring, with or without AKI, had significantly less cumulative fluid volume and fluid overload, reduced vasopressor use, and improved 30-day mortality. We examined whether real-time monitoring of this simple, sensitive, and easy-to-use biomarker in the ICU led to more appropriate intervention by healthcare providers and better outcomes.  METHODS: RenalSense Clarity RMS Consoles were installed in the General ICU at the Hadassah Medical Center, Israel, from December 2019 to November 2020. The Clarity RMS system continuously and electronically monitors UO in real-time. 100 patients were randomly selected from this period as the study group (UOelec) and compared to a matched control group (UOmanual) from the same period two years earlier. To test whether there was an association between oliguric hours and fluid treatment in each group, the correlation was calculated and analyzed for each of the different UO monitoring methods. RESULTS: Therapeutic intervention: The correlation of the sum of all oliguric hours on Day 1 and 2 with the sum of any therapeutic intervention (fluid bolus or furosemide) showed a significant correlation for the study group UOelec (P = 0.017). The matched control group UOmanual showed no such correlation (P = 0.932). Length of Stay (LOS): Median LOS [IQR] in the ICU of UOelec versus UOmanual was 69.46 [44.7, 125.9] hours and 116.5 [62.46, 281.3] hours, respectively (P = 0.0002). CONCLUSIONS: The results of our study strongly suggest that ICU patients had more meaningful and better medical intervention, and improved outcomes, with electronic UO monitoring than with manual monitoring.

Differential Gene Expression Analysis Reveals Global LMTK2 Regulatory Network and Its Role in TGF-ß1 Signaling.

Lemur tyrosine kinase 2 (LMTK2) is a transmembrane Ser/Thr kinase whose role has been increasingly recognized; however, when compared to other kinases, understanding of the LMTK2 networks and biological functions is still limited. Recent data have shown that transforming growth factor (TGF)-ß1 plays a role in modulating LMTK2 function by controlling its endocytic trafficking in human bronchial epithelial cells. Here, we aimed to unveil the LMTK2 regulatory network and elucidate how it affects cellular functions and disease pathways in either TGF-ß1 dependent or independent manner. To understand how the LMTK2 and TGF-ß1 pathways interconnect, we knocked down (KD) LMTK2 using small(si)RNA-mediated silencing in human bronchial epithelial CFBE41o- cells, treated cells with TGF-ß1 or vehicle control, and performed differential gene expression analysis by RNA sequencing (RNAseq). In vehicle-treated cells, LMTK2 KD affected expression of 2,506 genes while it affected 4,162 genes after TGF-ß1 stimulation. Bioinformatics analysis shows that LMTK2 is involved in diverse cellular functions and disease pathways, such as cell death and survival, cellular development, and cancer susceptibility. In summary, our study increases current knowledge about the LMTK2 network and its intersection with the TGF-ß1 signaling pathway. These findings will serve as basis for future exploration of the predicted LMTK2 interactions and signaling pathways.

TGF-ß1 Augments the Apical Membrane Abundance of Lemur Tyrosine Kinase 2 to Inhibit CFTR-Mediated Chloride Transport in Human Bronchial Epithelia.

The most common disease-causing mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, F508del, leads to cystic fibrosis (CF), by arresting CFTR processing and trafficking to the plasma membrane. The FDA-approved modulators partially restore CFTR function and slow down the progression of CF lung disease by increasing processing and delivery to the plasma membrane and improving activity of F508del-CFTR Cl- channels. However, the modulators do not correct compromised membrane stability of rescued F508del-CFTR. Transforming growth factor (TGF)-ß1 is a well-established gene modifier of CF associated with worse lung disease in F508del-homozygous patients, by inhibiting CFTR biogenesis and blocking the functional rescue of F508del-CFTR. Lemur tyrosine kinase 2 (LMTK2) is a transmembrane protein localized at the apical and basolateral membrane domain of human bronchial epithelial cells. Phosphorylation of the apical membrane CFTR by LMTK2 triggers its endocytosis and reduces the abundance of membrane-associated CFTR, impairing the CFTR-mediated Cl- transport. We have previously shown that LMTK2 knockdown improves the pharmacologically rescued F508del-CFTR abundance and function. Thus, reducing the LMTK2 recruitment to the plasma membrane may provide a useful strategy to potentiate the pharmacological rescue of F508del-CFTR. Here, we elucidate the mechanism of LMTK2 recruitment to the apical plasma membrane in polarized CFBE41o- cells. TGF-ß1 increased LMTK2 abundance selectively at the apical membrane by accelerating its recycling in Rab11-positive vesicles without affecting LMTK2 mRNA levels, protein biosynthesis, or endocytosis. Our data suggest that controlling TGF-ß1 signaling may attenuate recruitment of LMTK2 to the apical membrane thereby improving stability of pharmacologically rescued F508del-CFTR.

Unraveling the Function of Lemur Tyrosine Kinase 2 Network.

Lemur Tyrosine Kinase 2 (LMTK2) is a recently cloned transmembrane protein, actually a serine/threonine kinase named after the Madagascar primate lemur due to the long intracellular C-terminal tail. LMTK2 is relatively little known, compared to other kinases but its role has been increasingly recognized. Published data show that LMTK2 regulates key cellular events, including endocytic trafficking, nerve growth factor signaling, apoptosis, and Cl- transport. Abnormalities in the expression and function of LMTK2 are associated with human disease, such as neurodegeneration, cancer and infertility. We summarized the current state of knowledge on LMTK2 structure, regulation, interactome, intracellular localization, and tissue expression and point out future research directions to better understand the role of LMTK2.

Combining Image Analysis, Genome Wide Association Studies and Different Field Trials to Reveal Stable Genetic Regions Related to Panicle Architecture and the Number of Spikelets per Panicle in Rice.

Number of spikelets per panicle (NSP) is a key trait to increase yield potential in rice (O. sativa). The architecture of the rice inflorescence which is mainly determined by the length and number of primary (PBL and PBN) and secondary (SBL and SBN) branches can influence NSP. Although several genes controlling panicle architecture and NSP in rice have been identified, there is little evidence of (i) the genetic control of panicle architecture and NSP in different environments and (ii) the presence of stable genetic associations with panicle architecture across environments. This study combines image phenotyping of 225 accessions belonging to a genetic diversity array of indica rice grown under irrigated field condition in two different environments and Genome Wide Association Studies (GWAS) based on the genotyping of the diversity panel, providing 83,374 SNPs. Accessions sown under direct seeding in one environement had reduced Panicle Length (PL), NSP, PBN, PBL, SBN, and SBL compared to those established under transplanting in the second environment. Across environments, NSP was significantly and positively correlated with PBN, SBN and PBL. However, the length of branches (PBL and SBL) was not significantly correlated with variables related to number of branches (PBN and SBN), suggesting independent genetic control. Twenty- three GWAS sites were detected with P ≤ 1.0E-04 and 27 GWAS sites with p ≤ 5.9E-04. We found 17 GWAS sites related to NSP, 10 for PBN and 11 for SBN, 7 for PBL and 11 for SBL. This study revealed new regions related to NSP, but only three associations were related to both branching number (PBN and SBN) and NSP. Two GWAS sites associated with SBL and SBN were stable across contrasting environments and were not related to genes previously reported. The new regions reported in this study can help improving NSP in rice for both direct seeded and transplanted conditions. The integrated approach of high-throughput phenotyping, multi-environment field trials and GWAS has the potential to dissect complex traits, such as NSP, into less complex traits and to match single nucleotide polymorphisms with relevant function under different environments, offering a potential use for molecular breeding.