bluuebunny/crossref_metadata_2025_split huggingface dataset:
Podocyte‐parietal epithelial cell cross‐talk: a role for paracrine KLF4‐STAT3 signaling in parietal epithelial cell proliferation in proliferative glomerulopathies
Authors: Pace Jesse , Guo Yiqing , Estrada Chelsea , Mallipattu Sandeep 
Published: April 2020

Podocyte injury contributing to parietal epithelial cell (PEC) proliferation is a dominant histologic feature in both rapidly progressive glomerulonephritis (RPGN) and subtypes of focal segmental glomerulosclerosis (FSGS). Activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling is critical to the progression of both. We recently showed that podocyte‐specific loss of Krüppel‐Like Factor 4 (KLF4), a zinc‐finger transcription factor, activates STAT3 signaling leading to mitotic catastrophe in podocytes and eventual FSGS, while triggering PEC proliferation.To determine the mechanism by which podocyte‐specific knockdown of KLF4 leads to podocyte loss and triggers PEC proliferation with dysregulated STAT3 signaling, we generated cultured human podocytes with KLF4 knockdown (KLF4‐shRNA) and screened several pharmacological STAT3‐specific inhibitors to determine that S3I‐201 prevented podocyte loss to a higher degree than other STAT3 inhibitors or DMSO‐treated KLF4‐shRNA podocytes. Furthermore, we demonstrated that S3I‐201‐treated PodCre‐KLF4fl/fl mice exhibited less proteinuria and improved renal function as compared to DMSO‐treated PodCre‐KLF4fl/fl mice. We further validated the reno‐protective effects of S3I‐201 in HIV‐1 transgenic mice, a known model of podocyte‐specific Klf4 loss and STAT3 activation, by demonstrating reduced albuminuria, podocyte loss, FSGS lesions, and parietal epithelial cell activation, with improved renal function.We previously demonstrated that supernatant harvested from KLF4‐shRNA podocytes induces PEC proliferation. To elucidate the mechanism by which loss of KLF4 specifically in podocytes triggers PEC activation and proliferation, we performed unbiased quantitative proteomics on the supernatant of KLF4‐shRNA podocytes as compared to EV‐shRNA podocytes. We subsequently cross‐matched proteins upregulated in supernatant of KLF4‐shRNA podocytes with differentially expressed transcripts from RNA‐sequencing of isolated glomeruli from PodCre‐KLF4fl/fl mice as compared to wildtype KLF4fl/fl mice. Enrichment analysis of these differentially expressed targets revealed activation of STAT‐dependent and independent pathways involved in inflammation, extracellular matrix organization, and proliferation. Interestingly, the highest expressed STAT3 downstream targets were Plasminogen Activator Inhibitor 1 (PAI‐1) and Galectin‐1 (LGALS1), which are key mediators of epithelial cell migration and proliferation.Collectively, these findings demonstrate the role of dysregulated KLF4‐STAT3 signaling in proliferative glomerulopathies and identify potential paracrine mediators of podocyte‐PEC cross‐talk.Support or Funding InformationNIH/NIDDK, SBU URECAThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High Fructose Consumption during Pregnancy and Lactation Leads to Maternal Renal Function Alteration
Authors: Gomes Guiomar Nascimento , Kimura Lichtenecker Debora C. , Argeri Rogerio 
Published: April 2020

The consumption of foods that have fructose in its formulations has grown in the last decades. Nevertheless, increased consumption of this sugar has been related to the development of diseases such as obesity, diabetes and others. Many physiological changes occur during pregnancy and lactation and high consumption of fructose in these periods can interfere with maternal health. Thus, this study aims to evaluate the effects of increased fructose consumption on gestation and lactation on blood pressure and renal function.MethodsFemales Wistar rats were randomly assigned to groups: Control (C) and Fructose (F). The group C received food and drinking water ad libitum, and F received food and D‐fructose solution (20%) for drinking ad libitum. In F, the offer of D‐fructose solution begun 1week before mating and continued during pregnancy and lactation. Renal function was evaluated 21 days after offspring birth. Indirect measurement of systolic blood pressure (BPi), body weight, arterial blood pH, glycemia, ureia concentration in plasma, glomerular filtration rate ‐ GFR (creatinine clearance), excreted load of sodium (ENa+) and potassium (EK+) were measured. Ethic Committee on Animal Use of the Federal University of Sao Paulo approval number 757270117.ResultsCompared with C group, F presented higher values of BPi (129.7±1.4 vs 118.4±1.9 mmHg; p=0.0012), body weight (281.7±4.9 vs 232.7± 22.9 g; p=0.0245) and urinary flow (33.4±3.6 vs 14.6±2.1 mL; p=0.0035). F also had decreased GFR (3.8±0.4 vs 6.0± 0.5 mL/min/kg; p=0.0082), ENa+ (0.88±0.12 vs 1.42±0.25 mEq/24h; p=0.0350) and EK+ (2.24±0.38 vs 3.73±0.51 mEq/24h, p=0.0350). There were no significant differences between the groups regarding the arterial blood pH (7.40±0.01 vs 7.39±0.02; p=0.7599), glycemia (160.7± 3.5 vs 146.7±4.7 mg/dL; p=0.0565) and ureia concentration in plasma (36.7±1.2 vs 34.9±1.1 mg/dL; p=0.4645). Values presented as mean ± sem, Mann‐Whitney test, p ≤ 0.05; number of animals: C=6, F=7.ConclusionsThe results suggest that in rats, fructose overload during pregnancy and lactation can lead to maternal renal dysfunction (reduced GFR and sodium excretion), changes probably related to the increase in blood pressure observed in these animals.Support or Funding InformationFAPESP, CNPqThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Biosynthesis of Complex Plant‐Derived Natural Products
Authors: Smolke Christina 
Published: April 2020

Plants are a rich source of unique molecules, including 25% of natural‐product‐derived drugs. However, the discovery, synthesis, and overall material supply chains for sourcing plant‐based medicines remain ad hoc, biased, and tedious. While microbial biosynthesis presents compelling alternatives to traditional approaches based on extraction from natural plant hosts, many challenges exist in the reconstruction of plant specialized metabolic pathways in microbial hosts. We have developed approaches to address the challenges that arise in the reconstruction of complex plant biosynthetic pathways in microbial hosts. We have utilized these strategies to develop yeast production platforms for an important class of plant alkaloids, which include the medicinal opioids and noscapinoids. The intersection of synthetic biology, genomics, and informatics will lead to transformative advances in how we make and discover essential medicines.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
MicroRNA‐181b Regulates Ca2+ Influx by Targeting TRPC6 in PASMC from Patients with Idiopathic Pulmonary Arterial Hypertension
Authors: Babicheva Aleksandra , Makino Ayako , Yuan Jason X.‐J. 
Published: April 2020

IntroductionWe have previously showed that upregulated canonical transient receptor potential 6 (TRPC6) contributes to elevated cytosolic Ca2+ concentration ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) isolated from patients with idiopathic pulmonary arterial hypertension (IPAH). An increase in [Ca2+]cyt is a major stimulus for pulmonary vasoconstriction and PASMC proliferation. Pulmonary vascular remodeling characterized by excessive PASMC proliferation, and sustained vasoconstriction are two important factors for elevated pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in IPAH patients. However, the molecular mechanisms that regulate [Ca2+]cyt and PASMC proliferation still remain unknown. In this study, we investigate the role of microRNA (miRNA), small non‐coding RNA, which is able to regulate gene expression post‐transcriptionally by inhibiting translation and stability of mRNAs. We hypothesized that decreased miRNA‐181b (miR‐181b) resulted in the enhanced [Ca2+]cyt by upregulating TRPC6 in PASMC isolated from IPAH patients.MethodsPASMC from healthy subjects and patients with IPAH were used for this study. miRNA expression profile was explored using the Human Cancer Pathway Finder miRNA PCR Array. In silico analysis was performed by using standard online software (Targetscan.org) to predict direct targets of miR‐181b. miR‐181b level was quantified by real‐time RT‐PCR in normal and IPAH PASMC. Normal PASMC were transfected with miR‐181b inhibitor while IPAH‐PASMC were overexpressed with miR‐181b. mRNA and protein expression of TRPC6 channels were measured by RT‐PCR and Western blot, respectively. [Ca2+]cyt was measured using fura‐2 AM, a membrane‐permeable Ca2+‐sensitive fluorescent indicator.ResultsmiRNA PCR microarray showed that 5 out of 89 miRNAs were significantly downregulated in IPAH‐PASMC compared to normal PASMC. In silico analysis revealed that out of 5 candidates miR‐181b has the most potential to directly target TRPC6. Downregulated miR‐181b is correlated with increased TRPC6 expression and [Ca2+]cyt in PASMC from IPAH patients compared to PASMC isolated from healthy subjects. Inhibition of miR‐181b in normal PASMC significantly enhanced [Ca2+]cyt and upregulates TRPC6 expression while overexpression of miR‐181b in IPAH‐PASMC inhibits [Ca2+]cyt and decreases TRPC6 level.ConclusionIncreased TRPC6 and elevated Ca2+ influx mediated by downregulated miR‐181b could contributes to excessive PASMC and sustained vasoconstriction in patients with IPAH.Support or Funding InformationThis work was supported, in part, by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL125208, HL135807, and HL126609).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Stability of Early Auditory Evoked Potential Components Over Extended Test-Retest Intervals in Young Adults
Authors: Bieber Rebecca E. , Fernandez Katharine , Zalewski Chris , Cheng Hui , Brewer Carmen C. 
Published: April 2020

Objectives:
Synaptic damage from noise exposures can occur even in the absence of changes in hearing sensitivity in animal models. There is an unmet clinical need for measurements sensitive to such damage to the human auditory system that can augment the pure-tone audiogram. Early components (i.e., <10 msec) of the auditory evoked potential (AEP) may be useful noninvasive indicators of synaptic integrity. Wave I is a measure of synchronous neural activity at the level of the synapse between cochlear inner hair cells and the auditory nerve and may be of particular clinical utility. This amplitude measure has historically been classified as too variable in humans to be used for clinical waveform interpretation, though several recent reliability studies have challenged this view. The focus of the present study is to examine across-session stability of early AEP amplitude measures.

Design:
In this study, amplitudes of early components (wave I, wave V, summating potential [SP]) of the AEP were measured in a cohort of 38 young adults aged 19 to 33 years (21 female). Stability of these amplitude measures was examined in a subset of 12 young adults (8 female), at time intervals ranging from 15 hr to 328 days between tests. Eligibility criteria included normal pure-tone hearing sensitivity, normal tympanometry, and intact acoustic reflexes. Participants were tested at up to four time points. Each evaluation included pure-tone thresholds, tympanometry, speech-in-noise testing, distortion-product otoacoustic emissions (DPOAE), and early AEPs. AEPs were collected in response to click and tone burst stimuli, with both ear canal and mastoid electrode montages.

Results:
No clinical changes in pure-tone hearing were found between baseline and follow-up visits. Intraclass correlation coefficients (ICCs) indicated good to excellent reliability for wave I and wave V peak-to-trough amplitudes within individuals across time, with greatest reliability (0.92, 95% confidence interval [0.81 to 0.96]) and largest amplitudes for wave I when measured from the ear canal in response to a click stimulus. Other measures such as amplitude ratios of waves V/I and the SP and action potential (AP) showed lower ICC values when measured from the ear canal, with SP/AP ratio demonstrating the lowest reliability.

Conclusions:
The results of this study suggest that, when recorded under certain conditions, wave I amplitude can be a stable measure in humans. These findings are consistent with previous work and may inform the development of clinical protocols that utilize wave I amplitude to infer inner ear integrity.
Gut microbiota dysbiosis in preeclampsia patients in the second and third trimesters
Authors: Wang Jing , Shi Zhong-Hua , Yang Jing , Wei Yuan , Wang Xiao-Ye , Zhao Yang-Yu 
Published: April 2020

Abstract

Background
Preeclampsia (PE) is a serious complication that affects maternal and perinatal outcomes. However, the mechanisms have not been fully explained. This study was designed to analyze longitudinal gut microbiota alterations in pregnant women with and without PE in the second (T2) and third trimesters (T3).

Methods
In this nested case-control study, which was conducted at Nanjing Maternity and Child Health Care Hospital, fecal samples from 25 PE patients (25 fecal samples obtained in T2 and 15 fecal samples obtained in T3) and 25 matched healthy controls (25 fecal samples obtained in T2 and 22 fecal samples obtained in T3) were collected, and the microbiota were analyzed using 16S rRNA gene sequencing. The diversity and composition of the microbiota of PE cases and controls were compared.

Results
No significant differences in diversity were found between the PE and control groups (P > 0.05). In the control group, from T2 to T3, the relative abundances of Proteobacteria (median [Q1, Q3]: 2.25% [1.24%, 3.30%] vs. 0.64% [0.20%, 1.20%], Z = −3.880, P < 0.05), and Tenericutes (median [Q1, Q3]: 0.12% [0.03%, 3.10%] vs. 0.03% [0.02%, 0.17%], Z = −2.369, P < 0.05) decreased significantly. In the PE group, the relative abundance of Bacteroidetes in T2 was lower than in T3 (median [Q1, Q3]: 18.16% [12.99%, 30.46%] vs. 31.09% [19.89%, 46.06%], Z = −2.417, P < 0.05). In T2, the relative abundances of mircrobiota showed no significant differences between the PE group and the control group. However, in T3, the relative abundance of Firmicutes was significantly lower in the PE group than in the control group (mean ± standard deviation: 60.62% ± 15.17% vs. 75.57% ± 11.53%, t = −3.405, P < 0.05). The relative abundances of Bacteroidetes, Proteobacteria, and Enterobacteriaceae were significantly higher in the PE group than in the control group (median [Q1, Q3]: 31.09% [19.89%, 46.06%] vs. 18.24% [12.90%, 32.04%], Z = −2.537, P < 0.05; 1.52% [1.05%, 2.61%] vs. 0.64% [0.20%, 1.20%], Z = −3.310, P < 0.05; 0.75% [0.20%, 1.00%] vs. 0.01% [0.004%, 0.023%], Z = −4.152, P < 0.05). Linear discriminant analysis combined effect size measurements analysis showed that the relative abundances of the phylum Bacteroidetes, class Bacteroidia and order Bacteroidales were increased in the PE group, while those of the phylum Firmicutes, the class Clostridia, the order Clostridiales, and the genus unidentified Lachnospiraceae were decreased in the PE group; and these differences were identified as taxonomic biomarkers of PE in T3.

Conclusion
From T2 to T3, there was an obvious alteration in the gut microbiota. The gut microbiota of PE patients in T3 was significantly different from that of the control group.
Comparison of fresh frozen plasma vs. coagulation factor concentrates for reconstitution of blood
Authors: Gratz Johannes , Ponschab Martin , Iapichino Giacomo E. , Schlimp Christoph J. , Cadamuro Janne , Grottke Oliver , Zipperle Johannes , Oberladstätter Daniel , Gabriel Christian , Ziegler Bernhard , Schöchl Herbert 
Published: April 2020

BACKGROUND
Many trauma centres have adopted the administration of fixed ratios of packed red blood cells (PRBCs), platelet concentrates and fresh frozen plasma (FFP) for bleeding patients. However, the haemostatic efficacy of this concept is not well proven.

OBJECTIVE
Our objective was to characterise the haemostatic profile of different ratios (2 : 1 : 1, 1 : 1 : 1 and 1 : 1 : 2) of PRBCs, platelet concentrates and FFP in comparison with coagulation factor concentrates (fibrinogen and/or prothrombin complex concentrate).

DESIGN
An in vitro study.

SETTING
Research laboratories of the department of transfusion medicine, Linz, Austria.

MATERIALS
Whole blood donations from a total of 20 male volunteers.

INTERVENTION
Reconstitution of blood at different ratios of PRBCs, platelet concentrates and FFP or coagulation factor concentrates.

MAIN OUTCOME MEASURES
Cell count, conventional and thromboelastometric coagulation parameters, single coagulation factor activities as well as endogenous thrombin potential.

RESULTS
Fibrinogen levels and haematocrit were lower in the FFP group at any ratio compared with the concentrate-based groups (P < 0.0001). Reconstitution of blood with FFP at different ratios resulted in haematocrit or fibrinogen levels that were borderline with regard to recommended substitution triggers (haematocrit 41 ± 2% and fibrinogen 1.5 ± 0.3 g l−1 at the 2 : 1 : 1 ratio vs. 21 ± 1% and 2.1 ± 0.4 g l−1 respectively at the 1 : 1 : 2 ratio). Compared with FFP at any ratio, maximum clot firmness showed higher values in the groups using fibrinogen concentrate (P < 0.0001), whereas endogenous thrombin potential revealed higher values in the groups using prothrombin complex concentrate (P < 0.0001).

CONCLUSION
Use of coagulation factor concentrates for the reconstitution of blood allows for delivery of a higher haematocrit and a higher fibrinogen content compared with FFP. However, prothrombin complex concentrate might result in an unnecessary excess of thrombin generation. Clinical studies are warranted to further investigate these in vitro findings.
The role of organizational learning and resilience for change in building quality improvement capacity in primary care
Authors: Schuttner Linnaea , Coleman Katie , Ralston James , Parchman Michael 
Published: April 2020

Background
The extent that organizational learning and resilience for the change process, that is, adaptive reserve (AR), is a component of building practice capacity for continuous quality improvement (QI) is unknown.

Purpose
The aim of the study was to examine the association of AR and development of QI capacity.

Methodology
One hundred forty-two primary care practices were evaluated at baseline and 12 months in a randomized trial to improve care quality. Practice AR was measured by staff survey along with a validated QI capacity assessment (QICA). We assessed the association of baseline QICA with baseline AR and both baseline and change in AR with change in QICA from 0 to 12 months. Effect modification by presence of QI infrastructure in parent organizations and trial arm was examined.

Results
Mean QICA increased from 6.5 to 8.1 (p < .001), and mean AR increased from 71.8 to 73.9 points (p < .001). At baseline, there was a significant association between AR and QICA scores: The QICA averaged 0.34 points higher (95% CI [0.04, 0.64], p = .03) per 10-point difference in AR. There was a significant association between baseline AR and 12-month QICA—which averaged 0.30 points higher (95% CI [0.02, 0.57], p = .04) per 10 points in baseline AR. There was no association between changes in AR and the QICA from 0 to 12 months and no effect modification by trial arm or external QI infrastructure.

Conclusions
Baseline AR was positively associated with both baseline and follow-up QI capacity, but there was no association between change in AR and change in the QICA, suggesting AR may be a precondition to growth in QI capacity.

Practice Implications
Findings suggest that developing AR may be a valuable step prior to undertaking QI-oriented growth, with implications for sequencing of development strategies, including added gain in QI capacity development from building AR prior to engaging in transformation efforts.
Depressive Disorders in HIV/AIDS: A Clinically Focused Narrative Review
Authors: Medeiros Gustavo C. , Smith Felicia A. , Trivedi Madhukar H. , Beach Scott R. 
Published: April 2020

Learning objectives
After participating in this activity, learners should be better able to:
• Assess strategies for diagnosing depressive disorders in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)
• Identify factors that contribute to the development of depressive disorders in HIV/AIDS
• Evaluate strategies for managing depressive disorders in HIV/AIDS

Abstract
Depressive disorders and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) are associated with major socioeconomic burdens. The negative impact of depressive disorders on HIV/AIDS is well known, including on treatment outcomes. Unfortunately, depressive disorders are underdiagnosed and undertreated in seropositive persons. This review summarizes clinically useful information on depressive disorders in HIV/AIDS. More specifically, we address assessment, differential diagnosis, contributing factors, management, and common challenges in the treatment of depressive disorders in seropositive individuals. Assessment and diagnosis of depression may be challenging in seropositive persons because of several biopsychosocial particularities associated with HIV/AIDS. One of the difficulties is the overlap between depression and HIV/AIDS symptoms, particularly in individuals with advanced AIDS, requiring consideration of a broad differential diagnosis. Several factors related to HIV/AIDS status contribute to the higher rates of depressive disorders, including infectious-immunological, psychosocial, and exogenous factors. The treatment of depressive disorders in HIV/AIDS involves three groups of interventions: (1) pharmacological interventions, (2) psychotherapeutic interventions, and (3) management of other contributing factors. Challenges in management include poor adherence to treatment and the risk of suicide. We provide evidence-based recommendations to improve assessment and management of depressive disorders in seropositive persons.