causative mechanism
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2022 ◽  
Vol 115 (1) ◽  
pp. 75-81
Kikyo Shiomizu ◽  
Takashi Nasu ◽  
Shintaro Amano ◽  
Akiko Amano ◽  
Kazunori Futai

2021 ◽  
R.K. van der Merwe ◽  
J.A. Nadel ◽  
D. Copes-Finke ◽  
S. Pawelko ◽  
J.S. Scott ◽  

AbstractBehavioral flexibility is key to survival in a dynamic environment. While flexible, goal-directed behaviors are initially dependent on dorsomedial striatum, they become dependent on lateral striatum with extended training as behaviors become inflexible. Similarly, dopamine release shifts from ventromedial to lateral striatum across learning, and impairment of lateral dopamine release disrupts habitual, inflexible responding. This raises the possibility that lateral dopamine release is a causative mechanism in establishing inflexible behaviors late in training, though this has not been directly tested. Here, we utilized optogenetics to activate dopamine terminals in dorsal medial (DMS), dorsal lateral (DLS), and ventral (NAc) striatum in DATcre mice to determine how specific dopamine subpopulations impact behavioral flexibility. Mice performed a reversal task in which they self-stimulated DMS, DLS, or NAc dopamine terminals by pressing one of two levers before action-outcome lever contingencies were reversed. Consistent with presumed ventromedial/lateral striatal function, we found that mice self-stimulating ventromedial dopamine terminals rapidly reversed lever preference following contingency reversal, while mice self-stimulating dopamine terminals in DLS showed impaired reversal learning. These impairments were characterized by more regressive errors and reliance on lose-stay strategies following reversal, suggesting reward insensitivity and overreliance on previously learned actions. This study supports a model of striatal function in which dorsomedial dopamine facilitates goal-directed responding, and dorsolateral dopamine release is a key mechanism in supporting the transition toward inflexible behaviors.

2021 ◽  
Vol 17 (2) ◽  
pp. 73-78
Jianwei Zhou ◽  
Yu Li ◽  
Cui Kong ◽  
Yizhao Li ◽  
Yao Liang

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is still a severe threaft for human health currently, and the researches about it is a focus topic worldwide. Aim of the study: In this study, we will collect some laboratory results of the patients with coronavirus disease (COVID-19) to assess the function of liver, heart, kidney and even pancreas.  Subjects and Methods: Laboratory results of the patients with COVID-19 are collected. The biochemical indices are classified and used to assess the according function of liver, heart, kidney; meantime, and blood glucose is also observed and taken as an index to roughly evaluate pancreas. Results: There were some indices exhibited abnormal. For patient 1, the ratio of albumin and globulin slightly was lower than the down-limit of reference range. For patient 2, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), creatine kinase (CK), creatinine kinase-MB isoenzyme (CK-MB), lactate dehydrogenase (LDH), alpha-hydroxybutyric dehydrogenase (HBDH), and beta-2 microglobulin (β2-MG) were respectively higher than the according upper limit of the reference range, while prealbumin (PA) was lower than the down limit. For patient 3, GGT, CK, PA were high than normal range. For patient 4, CK, LDH, HBDH were higher than the upper range. Conclusion: Infection of SARS-Cov-2 could cause liver and heart injury, and it is suggested that clinicians and researchers should pay more attention on the prevention, treatment and causative mechanism of such an injury.

2021 ◽  
Vol 36 (Supplement_1) ◽  
Eva Mangelsen ◽  
Michael Rothe ◽  
Juliane Bolbrinker ◽  
Aikaterini Kourpa ◽  
Daniela Panáková ◽  

Abstract Background and Aims We recently identified prostaglandin reductase 2 (Ptgr2) and the prostaglandin E2 (PGE2) pathway as potential causative mechanism in the Munich Wistar Frömter (MWF) non-diabetic rat model of chronic kidney disease. MWF is characterized by early onset of spontaneous albuminuria during a critical time window between 4 and 8 weeks of age, that associates with hyperfiltration, due to low nephron number, and podocyte injury. Ptgr2 plays an important role in the prostaglandin metabolism, in which PGE2 is metabolized by 15-prostaglandin dehydrogenase (15-PGDH) to 15-keto-PGE2. The latter is terminally degraded by prostaglandin reductases (PTGRs) 1, 2, and 3 to 13,14-dihydro-15-keto-PGE2. Recently, we detected elevated glomerular levels of PGE2 and 15-keto-PGE2 in MWF compared to spontaneously hypertensive rats (SHR) with no albuminuria. The aim of the present study was to characterize in detail the renal PGE2 metabolic pathway in MWF by lipidomic analysis during the time window of albuminuria onset. Method Male MWF and SHR rats were studied at week 4 and 8, respectively; 24 h-urine was collected in metabolic cages. In addition, plasma and kidney tissues including kidney cortex and isolated glomeruli were obtained from anesthetized rats. Lipidomic analysis was done by liquid chromatography electrospray ionization tandem mass spectrometry. Statistical analysis was performed by unpaired, two-tailed Student’s t-test, or otherwise the Mann-Whitney test. Results Urinary PGE2 was significantly lower (p<0.01), while urinary 15-keto-PGE2 and 13,14-dihydro-15-keto PGE2 levels were significantly increased in MWF compared to SHR at week 4 (p<0.01, respectively). All three analytes were significantly decreased in urine of MWF with increased albuminuria at week 8 (p<0.05 vs. SHR). The urinary metabolic ratio of 15-keto-PGE2/13,14-dihydro-15-keto-PGE2 as a surrogate for PTGRs activities was significantly increased at week 4 (p<0.01), whereas it was significantly decreased in MWF vs. SHR at week 8 (p<0.05). Plasma levels of PGE2 and 13,14-dihydro-15-keto-PGE2 did not differ between strains at both time points, while 15-keto-PGE2 was below the detection limit. Glomerular levels of PGE2 and 15-keto-PGE2 were increased in MWF at week 4 and 8 (p<0.01, respectively). In contrast, 13,14-dihydro-15-keto-PGE2 was only significantly higher at week 4 compared to SHR (p<0.01). In isolated glomeruli, the metabolic ratios of PTGRs were similar between the strains at week 4, but significantly increased in MWF compared to SHR at week 8 (p<0.01, respectively). In kidney cortex, 15-keto-PGE2 and 13,14-dihydro-15-keto-PGE2 were increased in MWF at week 4 (p<0.05 and p<0.01, respectively), whereas PGE2 levels were comparable to SHR. No difference for cortical levels of PGE2 and its metabolites was observed at week 8. Conclusion This study provides the first insights into age-dependent dynamic changes in the PGE2 pathway that support potential causality for the onset of albuminuria in the setting of non-diabetic hyperfiltration due to low nephron number. Notably, the increased glomerular levels of PGE2 and its downstream metabolites in 4-week-old MWF point towards an early activation of this pathway, i.e. before albuminuria occurs. This finding corroborates the hypothesis that glomerular PGE2 signaling is relevant in the early stages of hyperfiltration and suggests this pathway as a target for future therapeutics to modify the manifestation and progression of renal disease.

2021 ◽  
Vol 6 (4) ◽  
pp. e210616
Harpreet S. Bhatia ◽  
Ryan R. Reeves

2020 ◽  
Vol 5 (1) ◽  
pp. e000462
Leah K Winer ◽  
Christen Salyer ◽  
Nadine Beckmann ◽  
Charles C Caldwell ◽  
Vanessa Nomellini

There are sparse clinical data addressing the persistence of disordered coagulation in sepsis and its role in chronic critical illness. Coagulopathy in the absence of anticoagulant therapy and/or liver disease can be highly variable in sepsis, but it tends to be prolonged in patients in the intensive care unit with a length of stay greater than 14 days. These coagulation abnormalities tend to precede multisystem organ failure and persistence of these coagulation derangements can predict 28-day mortality. The studies evaluated in this review consistently link sepsis-associated coagulopathy to poor long-term outcomes and indicate that disordered coagulation is associated with unfavorable outcomes in chronic critical illness. However, the causative mechanism and the definitive link remain unclear. Longer follow-up and more granular data will be required to fully understand coagulopathy in the context of chronic critical illness.

2020 ◽  
Zhu Kuikui ◽  
Zhao Yangchao ◽  
Wu Lu ◽  
Zhang Sijia ◽  
Zong Yan ◽  

Abstract Background: Lung cancer is the most prevalent malignancy worldwide. Most patients were sporadic and carried somatic mutations in hotspot genes. At present, accumulating researches had identified several germline mutations that predispose patients to lung cancer. In this report, two siblings were diagnosed as lung squamous cell carcinoma and lung adenocarcinoma, respectively. Results: The two siblings shared similar features of a germline insertion of 11 bp (GCCCTGGCATT) in BCAR1 producing a frameshift at codon 314 which is located at the substrate domain. The BCAR1 was previously demonstrated to be associated with lung cancer. The variant detected in this report would impair the regulation and functions of BRCA1 in some extent, thus may promote lung cancer tumorigenesis. Our findings suggest that BCAR1 is a possible susceptibility gene for lung cancer, and its functional analyses in lung cancer need further investigation.Conclusions: In this study, we first reported a novel causative mechanism of Lung cancer: an insertion of 11 bp in BCAR1 gene, which can be helpful in the genetic diagnosis of this disease.

2020 ◽  
Vol 77 (7) ◽  
pp. 878 ◽  
Akram Y. Elgendy ◽  
Jeffrey L. Saver ◽  
Zahid Amin ◽  
Konstantinos Dean Boudoulas ◽  
John D. Carroll ◽  

2020 ◽  
Vol 206 ◽  
pp. 102902 ◽  
Alexander L. Peace ◽  
J.J.J. Phethean ◽  
D. Franke ◽  
G.R. Foulger ◽  
C. Schiffer ◽  

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