miR-21-mediated Radioresistance Occurs via Promoting Repair of DNA Double Strand Breaks.

miR-21, as an oncogene that overexpresses in most human tumors, is involved in radioresistance; however, the mechanism remains unclear. Here, we demonstrate that miR-21-mediated radioresistance occurs through promoting repair of DNA double strand breaks, which includes facilitating both non-homologous end-joining (NHEJ) and homologous recombination repair (HRR). The miR-21-promoted NHEJ occurs through targeting GSK3B (a novel target of miR-21), which affects the CRY2/PP5 pathway and in turn increases DNA-PKcs activity. The miR-21-promoted HRR occurs through targeting both GSK3B and CDC25A (a known target of miR-21), which neutralizes the effects of targeting GSK3B-induced CDC25A increase because GSK3B promotes degradation of both CDC25A and cyclin D1, but CDC25A and cyclin D1 have an opposite effect on HRR. A negative correlation of expression levels between miR-21 and GSK3ß exists in a subset of human tumors. Our results not only elucidate miR-21-mediated radioresistance, but also provide potential new targets for improving radiotherapy.

DICER-dependent biogenesis of let-7 miRNAs affects human cell response to DNA damage via targeting p21/p27.

Recently, it was reported that knockdown of DICER reduced the ATM-dependent DNA damage response and homologous recombination repair (HRR) via decreasing DICER-generated small RNAs at the damage sites. However, we found that knockdown of DICER dramatically increased cell resistance to camptothecin that induced damage required ATM to facilitate HRR. This phenotype is due to a prolonged G1/S transition via decreasing DICER-dependent biogenesis of miRNA let-7, which increased the p21(Waf1/Cip1)/p27(Kip1) levels and resulted in decreasing the HRR efficiency. These results uncover a novel function of DICER in regulating the cell cycle through miRNA biogenesis, thus affecting cell response to DNA damage.

The effects of fisetin on lipopolysaccharide-induced depressive-like behavior in mice.

Major depressive disorder (MDD) involves a series of pathological changes including the inflammation and increased cytokine levels. Fisetin, a natural flavonoid, has anti-inflammatory and antioxidant, and also has been shown in our previous studies to exert anti-depressant-like properties. The present study aimed to investigate the effect of fisetin on lipopolysaccharide (LPS)-induced depressive-like behavior and inflammation in mice. The results suggested that the immobility time in the forced swimming test (FST) and tail suspension test (TST) were increased at 6 h, 12 h and 24 h after LPS injection (0.83 mg/kg). However, only the group of 24 h treatment did not show any effect on locomotion counts. Pretreatment with fisetin at doses of 20, 40 and 80 mg/kg (p.o.) for 7 days reversed LPS-induced alterations of the immobility time in both of these two tests. Further neurochemical assays suggested that pretreatment with fisetin reversed LPS-induced overexpression of pro-inflammatory cytokine (IL-1ß, IL-6 and TNF-α) in the hippocampus and the prefrontal cortex (PFC). Moreover, higher dose of fisetin effectively antagonized iNOS mRNA expression and nitrite levels via the modulation of NF-κB in the hippocampus and PFC. Taken together, fisetin may be an effective therapeutic agent for LPS-induced depressive-like behaviors, which is due to its anti-inflammatory property.

Distinct roles of Ape1 protein, an enzyme involved in DNA repair, in high or low linear energy transfer ionizing radiation-induced cell killing.

High linear energy transfer (LET) radiation from space heavy charged particles or a heavier ion radiotherapy machine kills more cells than low LET radiation, mainly because high LET radiation-induced DNA damage is more difficult to repair. Relative biological effectiveness (RBE) is the ratio of the effects generated by high LET radiation to low LET radiation. Previously, our group and others demonstrated that the cell-killing RBE is involved in the interference of high LET radiation with non-homologous end joining but not homologous recombination repair. This effect is attributable, in part, to the small DNA fragments (≤40 bp) directly produced by high LET radiation, the size of which prevents Ku protein from efficiently binding to the two ends of one fragment at the same time, thereby reducing non-homologous end joining efficiency. Here we demonstrate that Ape1, an enzyme required for processing apurinic/apyrimidinic (known as abasic) sites, is also involved in the generation of small DNA fragments during the repair of high LET radiation-induced base damage, which contributes to the higher RBE of high LET radiation-induced cell killing. This discovery opens a new direction to develop approaches for either protecting astronauts from exposure to space radiation or benefiting cancer patients by sensitizing tumor cells to high LET radiotherapy.

[Analysis of sulfonamids and their metabolites in drinking water by high Performance liquid chromatography tandem mass spectrometry].

OBJECTIVE: To develop a comprehensive method for simultaneous analysis of sulfonamides and their metabolites in drinking water by high performance liquid chromatography tandem mass spectrometry (LC-MS/MS). METHODS: Different solid-phase extraction columns were compared with respect to the recovery of target drugs from drinking water. The drinking water samples were adjusted to 3 by HCl and purified by a mix mode cation-ion exchange solid-phase extraction (SPE), following determination using LG-MS/MS. A total of 21 sulfonamides were separated by a C15 column (2.1 mm x 100 mm, 1.7 µm) and analyzed under positive ion mode with multi-reaction monitoring. The matrix-matched external standard calibration was used for quantification. RESULTS: The method quantification limits for 21 analytes were 0.03-0.63 ng/L with overall recoveries of 50.1%-114.9%, and the relative standard deviations less than 20%. The method was finally used to analyze sulfonamides in drinking water in Beijing, and 5 target compounds (sulfadiazine, sulfathiazole, sulfapyridine, trimethoprim and sulfamethazine) were detected at a concentration range of 0.08-32.54 ng/L. CONCLUSION: This method could be applied in simultaneous analysis of sulfonamides and their metabolites in drinking water samples.

Dynamic properties of human stapedial annular ligament measured with frequency-temperature superposition.

Stapedial annular ligament (SAL) is located at the end of human ear ossicular chain and provides a sealed but mobile boundary between the stapes footplate and cochlear fluid. Mechanical properties of the SAL directly affect the acoustic-mechanical transmission of the middle ear and the changes of SAL mechanical properties in diseases (e.g., otosclerosis) may cause severe conductive hearing loss. However, the mechanical properties of SAL have only been reported once in the literature, which were obtained under quasi-static condition (Gan, R. Z., Yang, F., Zhang, X., and Nakmali, D., 2011, "Mechanical Properties of Stapedial Annular Ligament," Med. Eng. Phys., 33, pp. 330-339). Recently, the dynamic properties of human SAL were measured in our lab using dynamic-mechanical analyzer (DMA). The test was conducted at the frequency range from 1 to 40 Hz at three different temperatures: 5 °C, 25 °C, and 37 °C. The frequency-temperature superposition (FTS) principle was applied to extend the testing frequency range to a much higher level. The generalized Maxwell model was employed to describe the constitutive relation of the SAL. The storage shear modulus G' and the loss shear modulus G" were obtained from seven specimens. The mean storage shear modulus was 31.7 kPa at 1 Hz and 61.9 kPa at 3760 Hz. The mean loss shear modulus was 1.1 kPa at 1 Hz and 6.5 kPa at 3760 Hz. The dynamic properties of human SAL obtained in this study provide a better description of the damping behavior of soft tissues than the classic Rayleigh type damping, which was widely used in the published ear models. The data reported in this study contribute to ear biomechanics and will improve the accuracy of finite element (FE) model of the human ear.

Effect of homemade peanut oil consumption during pregnancy on low birth weight and preterm birth outcomes: a cohort study in Southwestern China.

BACKGROUND: Homemade peanut oil is widely consumed in rural areas of Southwestern China, which is easily contaminated by aflatoxins (AFs) and associated with adverse birth outcomes. OBJECTIVE: To identify the effect of exposure to homemade peanut oil consumption on low birth weight (LBW), preterm birth (PB) and other associated factors. METHODS: A prospective cohort study was conducted among pregnant women in Guangxi province, Southwestern China. Information of all eligible women on homemade peanut oil consumption and potential factors associated with LBW and PB was collected, and all were followed up until delivery. The effect of homemade peanut oil exposure was analyzed using multiple logistic regression models using the directed acyclic graph (DAG) approach. RESULTS: Of 1611 pregnant women, 1316 (81.7%) had consumed homemade peanut oil, and the rates of LBW and PB were 9.7% and 10.0%, respectively. Increased risks of LBW and PB in women with homemade peanut oil consumption were found with aORs of 1.9 (95% CI 1.1-3.2) and 1.8 (95% CI 1.1-3.0), respectively. Women with a history of PB or LBW were 3-5 times more likely to have higher rates of LBW or PB compared with those without this type of history. The odds of PB were approximately double in those taking medicine during pregnancy. Advanced maternal age, lack of physical exercise during pregnancy, passive smoking, or pregnancy complications were also more likely to have a higher risk of LBW. CONCLUSIONS: Homemade peanut oil consumption was a potential risk factor for both LBW and PB, of which health authorities who are responsible for food safety of the country should pay more attention to providing recommendation for oil consumption during pregnancy.

Main findings: Homemade peanut oil consumption was associated with increased risk of low birth weight and preterm birth, in addition to advanced age, adverse obstetric histories, and health risk behaviors during pregnancy in a county in Southwestern China.Added knowledge: This study identifies the direct and total effects of homemade peanut oil consumption on low birth weight and preterm birth and explains the factors associated with low birth weight and preterm birth in a county in Southwestern China.Global health impact for policy and action: Evidence of associated risk factors for low birth weight and preterm birth should be informed to the community, and precautionary policies for the protection of aflatoxin exposure during pregnancy are needed.

Blended controlled-release nitrogen fertilizer increases rice post-anthesis nitrogen accumulation, translocation and nitrogen-use efficiency.

One-time application of blended controlled-release nitrogen fertilizer (CRN) has the potential to solve the difficulty of top-dressing fertilizer in the cultivation of rice and reduce the cost of CRN fertilizer application. However, its effects on rice dry matter and nitrogen (N) accumulation and translocation, yield and N-use efficiency (NUE) remain uncertain. Field experiments were carried out at three sites (Mingguang, Chaohu, and Guichi) in the Yangtze River Delta in China to compare the effects of the conventional split applications of urea and the blended CRN and on post-anthesis dry matter and N accumulation and translocation, yield, and NUE in rice at 0, 60, 120, 180, and 240 kg N ha-1. The results showed that at the equal N application rates, compared under the conventional N fertilizer treatment, the blended CRN application significantly increased the rice yield by an average of 0.9-6.9%, mainly due to increase the number of spikelets per panicle. The highest yield achieved with blended CRN treatment occurred at 200 kg N ha-1, with an NUE of 45.9%. Moreover, in comparison to the conventional N fertilizer, the blended CRN treatment increased pre-anthesis N translocation (Pre-NT) by 1.0-19.8%, and the contribution of pre-NT to grain N by 0.2-8.7%, and NUE by 3.2-28.4%. Meanwhile, the blended CRN treatment reduced labor costs by 1800 Yuan ha-1 and enhanced the economic gains by 21.5-68.8%. Therefore, one-time application of blended CRN ≤ 200 kg N ha-1 application rate improved rice yield, NUE, and economic profit compared to equivalent rates of split applied conventional N fertilizers.

Black Phosphorus Nanosheets Protect Neurons by Degrading Aggregative α-syn and Clearing ROS in Parkinson's Disease.

Although evidence indicates that the abnormal accumulation of α-synuclein (α-syn) in dopamine neurons of the substantia nigra is the main pathological feature of Parkinson's disease (PD), no compounds that have both α-syn antiaggregation and α-syn degradation functions have been successful in treating the disease in the clinic. Here, it is shown that black phosphorus nanosheets (BPNSs) interact directly with α-syn fibrils to trigger their disaggregation for PD treatment. Moreover, BPNSs have a specific affinity for α-syn through van der Waals forces. And BPNSs are found to activate autophagy to maintain α-syn homeostasis, improve mitochondrial dysfunction, reduce reactive oxygen species levels, and rescue neuronal death and synaptic loss in PC12 cells. It is also observed that BPNSs penetrate the blood-brain barrier and protect against dopamine neuron loss, alleviating behavioral disorders in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model and hA53T α-syn transgenic mice. Together, the study reveals that BPNSs have the potential as a novel integrated nanomedicine for clinical diagnosis and treatment of neurological diseases.

Keratin gene expression profiles after digit amputation in C57BL/6 vs. regenerative MRL mice imply an early regenerative keratinocyte activated-like state.

Mouse strains C57BL/6 (B6) and MRL were studied by whole mouse genome chip microarray analyses of RNA isolated from amputation sites at different times pre- and postamputation at the midsecond phalange of the middle digit. Many keratin genes were highly differentially expressed. All keratin genes were placed into three temporal response classes determined by injury/preinjury ratios. One class, containing only Krt6 and Krt16, were uniquely expressed relative to the other two classes and exhibited different temporal responses in MRL vs. B6. Immunohistochemical staining for Krt6 and Krt16 in tissue sections, including normal digit, flank skin, and small intestine, and from normal and injured ear pinna tissue exhibited staining differences in B6 (low) and MRL (high) that were consistent with the microarray results. Krt10 staining showed no injury-induced differences, consistent with microarray expression. We analyzed Krt6 and Krt16 gene association networks and observed in uninjured tissue several genes with higher expression levels in MRL, but not B6, that were associated with the keratinocyte activated state: Krt6, Krt16, S100a8, S100a9, and Il1b; these data suggest that keratinocytes in the MRL strain, but not in B6, are in an activated state prior to wounding. These expression levels decreased in MRL at all times postwounding but rose in the B6, peaking at day 3. Other keratins significantly expressed in the normal basal keratinocyte state showed no significant strain differences. These data suggest that normal MRL skin is in a keratinocyte activated state, which may provide it with superior responses to wounding.

Lack of p21 expression links cell cycle control and appendage regeneration in mice.

Animals capable of regenerating multiple tissue types, organs, and appendages after injury are common yet sporadic and include some sponge, hydra, planarian, and salamander (i.e., newt and axolotl) species, but notably such regenerative capacity is rare in mammals. The adult MRL mouse strain is a rare exception to the rule that mammals do not regenerate appendage tissue. Certain commonalities, such as blastema formation and basement membrane breakdown at the wound site, suggest that MRL mice may share other features with classical regenerators. As reported here, MRL fibroblast-like cells have a distinct cell-cycle (G2/M accumulation) phenotype and a heightened basal and wound site DNA damage/repair response that is also common to classical regenerators and mammalian embryonic stem cells. Additionally, a neutral and alkaline comet assay displayed a persistent level of intrinsic DNA damage in cells derived from the MRL mouse. Similar to mouse ES cells, the p53-target p21 was not expressed in MRL ear fibroblasts. Because the p53/p21 axis plays a central role in the DNA damage response and cell cycle control, we directly tested the hypothesis that p21 down-regulation could functionally induce a regenerative response in an appendage of an otherwise nonregenerating mouse strain. Using the ear hole closure phenotype, a genetically mapped and reliable quantitative indicator of regeneration in the MRL mouse, we show that the unrelated Cdkn1a(tmi/Tyj)/J p21(-/-) mouse (unlike the B6129SF2/J WT control) closes ear holes similar to MRL mice, providing a firm link between cell cycle checkpoint control and tissue regeneration.

Successful Retreatment with Crizotinib After Crizotinib-Induced Liver Failure in ALK-Positive Advanced Lung Adenocarcinoma: A Case Report.

Patients with non-small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements are treated with crizotinib. However, treatment with crizotinib is often discontinued owing to hepatotoxicity. Herein, we report a case of crizotinib-induced liver failure that was successfully treated. A 70-year-old woman complained of a cough with blood in her sputum and presented to our hospital in September 2020. Imaging examination revealed a mass in the middle and lower lobes of the right lung invading the right pulmonary artery and metastases to the right hilar lymph nodes and pleura. A stage IVa (cT4N1M1a) lung adenocarcinoma with ALK fusion was diagnosed. The patient received crizotinib, an ALK tyrosine kinase inhibitor and achieved partial remission. However, she suffered from acute liver failure, which led to the cessation of treatment. The patient was started on a liver protection treatment, and the liver function subsequently recovered. One year later, crizotinib was readministered at a half-dose because of disease progression, and the patient achieved stable disease without hepatotoxicity for 9 months. Therefore, the patient benefited from crizotinib without hepatotoxicity one year after acute liver failure caused by crizotinib.

Effects of Partial Replacement of Nitrogen Fertilizer with Organic Fertilizer on Rice Growth, Nitrogen Utilization Efficiency and Soil Properties in the Yangtze River Basin.

Cake fertilizer and dairy manure were used as experimental materials to carry out a 9-year (2012-2020) field experiment in the main rice production areas in the Yangtze River basin. Different fertilization modes were used (no fertilization, CK; chemical fertilizer application alone, HY; reduced fertilization with chemical fertilizer application, RF; cake fertilizer replacement of nitrogen fertilizer, CFR; and dairy manure replacement of nitrogen fertilizer, DMR). Changes in the total rice yield, yield components, absorption of nitrogen, soil pH, organic matter, total nitrogen, and soil bulk density under different fertilization treatments were analyzed. The results show that organic fertilizer replacement leads to a stable and high rice yield. The 9-year average rice yields of the CFR and DMR treatments were 60.0% and 61.5% higher than that of CK. The nitrogen uptake of the CFR and DMR treatments was also higher than that of the other treatments. The nitrogen recovery efficiency in the current season could be increased by 16.37-22.89%, and after 9 years of testing, the soil total nitrogen contents of CFR and DMR increased by 0.23-0.85 g·kg-1 compared to the other treatments. The available P and K contents of DMR increased by 30.17 mg·kg-1 and 22.02 mg·kg-1 compared with HY, respectively. The soil bulk density was reduced by 0.08 g·cm-3. Generally, the effects of dairy manure replacement were better than those of cake fertilizer. This is an important method that can be used to fertilize the soil and foster sustainable soil utilization in the rice-growing area of the Yangtze River Basin, as a long-term partial replacement for chemical nitrogen fertilizer.

The optimum economic nitrogen rate of blended controlled-release nitrogen fertilizer for rice in the Chanoyu watershed in the Yangtze River Delta, China.

Introduction: The application of controlled-release nitrogen fertilizer (CRN) has become an important production method to achieve high crop yield and ecological safety. However, the rate of urea-blended CRN for rice is usually determined by conventional urea, and the actual rate is still unclear. Methods: A five-year field experiment was carried out in the Chaohu watershed in the Yangtze River Delta to study rice yield, N fertilizer utilization efficiency (NUE), ammonia (NH3) volatilization and economic benefit under the four urea-blended CRN treatments with a 4:3:3 ratio applied at one time (60, 120, 180, 240 kg/hm2, CRN60, CRN120, CRN180, CRN240), four conventional N fertilizer treatments (N60, N120, N180, N240) and a control without N fertilizer (N0). Results and Discussion: The results showed that the N released from the blended CRNs could well satisfy the N demand of rice growth. Similar to the conventional N fertilizer treatments, a quadratic equation was used to model the relationship between rice yield and N rate under the blended CRN treatments. The blended CRN treatments increased rice yield by 0.9-8.2% and NUE by 6.9-14.8%, respectively, compared with the conventional N fertilizer treatments at the same N application rate. The increase in NUE in response to applied blended CRN was related to the reduction in NH3 volatilization. Based on the quadratic equation, the five-year average NUE under the blended CRN treatment was 42.0% when rice yield reached the maximum, which was 28.9% higher than that under the conventional N fertilizer treatment. Among all treatments, CRN180 had the highest yield and net benefit in 2019. Considering the yield output, environmental loss, labor and fertilizer costs, the optimum economic N rate under the blended CRN treatment in the Chaohu watershed was 180-214 kg/hm2, compared with 212-278 kg/hm2 under the conventional N fertilizer treatment. The findings suggest that blended CRN improved rice yield, NUE and economic income while decreasing NH3 volatilization and negative environmental outcomes.

Alpha lipoic acid ameliorates motor deficits by inhibiting ferroptosis in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease. Ferroptosis shares several features with PD pathophysiology, and anti-ferroptosis molecules are neuroprotective in PD animal models. As an antioxidant and iron chelating agent, alpha lipoic acid (ALA) has a neuroprotective effect on PD; however, the influence of ALA on ferroptosis in PD remains unclear. This study aimed to determine the mechanism of ALA in regulating ferroptosis in PD models. Results showed that ALA could ameliorate motor deficits in PD models and regulate iron metabolism by upregulating ferroportin (FPN) and ferritin heavy chain 1 (FTH1) and downregulating iron importer divalent metal transporter 1 (DMT1). Moreover, ALA decreased the accumulation of reactive oxygen species (ROS) and lipid peroxidation, rescued mitochondrial damage, and prevented ferroptosis effectively by inhibiting the downregulation of glutathione peroxidase 4 (GPX4) and cysteine/glutamate transporter (xCT) in PD. Mechanistic study indicated that the activation of SIRT1/NRF2 pathway was involved in the upregulation effect of GPX4 and FTH1. Thus, ALA ameliorates motor deficits in PD models by regulating iron metabolism and mitigating ferroptosis through the SIRT1/NRF2 signaling pathway.

Characteristics of DNA-binding proteins determine the biological sensitivity to high-linear energy transfer radiation.

Non-homologous end-joining (NHEJ) and homologous recombination repair (HRR), contribute to repair ionizing radiation (IR)-induced DNA double-strand breaks (DSBs). Mre11 binding to DNA is the first step for activating HRR and Ku binding to DNA is the first step for initiating NHEJ. High-linear energy transfer (LET) IR (such as high energy charged particles) killing more cells at the same dose as compared with low-LET IR (such as X or gamma rays) is due to inefficient NHEJ. However, these phenomena have not been demonstrated at the animal level and the mechanism by which high-LET IR does not affect the efficiency of HRR remains unclear. In this study, we showed that although wild-type and HRR-deficient mice or DT40 cells are more sensitive to high-LET IR than to low-LET IR, NHEJ deficient mice or DT40 cells are equally sensitive to high- and low-LET IR. We also showed that Mre11 and Ku respond differently to shorter DNA fragments in vitro and to the DNA from high-LET irradiated cells in vivo. These findings provide strong evidence that the different DNA DSB binding properties of Mre11 and Ku determine the different efficiencies of HRR and NHEJ to repair high-LET radiation induced DSBs.

Circular RNA hsa_circ_0057452 facilitates keloid progression by targeting the microRNA-1225-3p/AF4/FMR2 family member 4 axis.

The circular RNA, hsa_circ_0057452, is highly expressed in keloids, but its specific mechanism of action remains unknown. The levels of hsa_circ_0057452, microRNA (miR)-1225-3p, and AF4/FMR2 family member 4 (AFF4) in keloid tissues and keloid fibroblasts (KFs) were determined using quantitative reverse transcription-polymerase chain reaction. Changes in KFs viability, proliferation, apoptosis, and migration were investigated using the cell counting kit-8, bromodeoxyuridine, flow cytometry, and Transwell assays. Luciferase, RNA immunoprecipitation, and RNA pull-down assays were performed to identify the binding relationship among hsa_circ_0057452, miR-1225-3p, and AFF4. We found that hsa_circ_0057452 and AFF4 expression levels were upregulated, whereas miR-1225-3p expression levels were downregulated in keloids. Knockdown of hsa_circ_0057452 or AFF4 suppressed the viability, proliferation, and migration of KFs and induced apoptosis, whereas hsa_circ_0057452 overexpression and miR-1225-3p knockdown showed the opposite trend. Furthermore, hsa_circ_0057452 affected the biological behavior of KFs by releasing AFF4 via sponging of miR-1225-3p. Therefore, our results show that hsa_circ_0057452 promotes keloid progression by targeting miR-1225-3p and regulating AFF4 levels.

Atrial fibrillation driver identification through regional mutual information networks: a modeling perspective.

PURPOSE: Effective identification of electrical drivers within remodeled tissue is a key for improving ablation treatment for atrial fibrillation. We have developed a mutual information, graph-based approach to identify and propose fault tolerance metric of local efficiency as a distinguishing feature of rotational activation and remodeled atrial tissue. METHODS: Voltage data were extracted from atrial tissue simulations (2D Karma, 3D physiological, and the Multiscale Cardiac Simulation Framework (MSCSF)) using multi-spline open and parallel regional mapping catheter geometries. Graphs were generated based on varied mutual information thresholds between electrode pairs and the local efficiency for each graph was calculated. RESULTS: High-resolution mapping catheter geometries can distinguish between rotational and irregular activation patterns using the derivative of local efficiency as a function of increasing mutual information threshold. The derivative is decreased for rotational activation patterns comparing to irregular activations in both a simplified 2D model (0.0017 ± 1 × 10-4 vs. 0.0032 ± 1 × 10-4, p < 0.01) and a more realistic 3D model (0.00092 ± 5 × 10-5 vs. 0.0014 ± 4 × 10-5, p < 0.01). Average local efficiency derivative can also distinguish between degrees of remodeling. Simulations using the MSCSF model, with 10 vs. 90% remodeling, display distinct derivatives in the grid design parallel spline catheter configuration (0.0015 ± 5 × 10-5 vs. 0.0019 ± 6 × 10-5, p < 0.01) and the flower shaped open spline configuration (0.0011 ± 5 × 10-5 vs. 0.0016 ± 4 × 10-5, p < 0.01). CONCLUSION: A decreased derivative of local efficiency characterizes rotational activation and varies with atrial remodeling. This suggests a distinct communication pattern in cardiac rotational activation detectable via high-resolution regional mapping and could enable identification of electrical drivers for targeted ablation.