Discriminative context-aware network for camouflaged object detection.

Introduction: Animals use camouflage (background matching, disruptive coloration, etc.) for protection, confusing predators and making detection difficult. Camouflage Object Detection (COD) tackles this challenge by identifying objects seamlessly blended into their surroundings. Existing COD techniques struggle with hidden objects due to noisy inferences inherent in natural environments. To address this, we propose the Discriminative Context-aware Network (DiCANet) for improved COD performance. Methods: DiCANet addresses camouflage challenges through a two-stage approach. First, an adaptive restoration block intelligently learns feature weights, prioritizing informative channels and pixels. This enhances convolutional neural networks' ability to represent diverse data and handle complex camouflage. Second, a cascaded detection module with an enlarged receptive field refines the object prediction map, achieving clear boundaries without post-processing. Results: Without post-processing, DiCANet achieves state-of-the-art performance on challenging COD datasets (CAMO, CHAMELEON, COD10K) by generating accurate saliency maps with rich contextual details and precise boundaries. Discussion: DiCANet tackles the challenge of identifying camouflaged objects in noisy environments with its two-stage restoration and cascaded detection approach. This innovative architecture surpasses existing methods in COD tasks, as proven by benchmark dataset experiments.

Comparative genomics with evolutionary lineage in Streptomyces bacteria reveals high biosynthetic potentials.

Genome mining in silico approaches allow scientists to proficiently evaluate the genomic potency of secondary bioactive chemical producers and find new bioactive compounds in different bacteria. Streptomyces is one of the most ubiquitous bacterial genera in the environments, and well-known as prolific producers of diverse and valuable natural products (NPs) with significant biological activities. Mining and prioritizing of NP biosynthetic gene clusters (BGCs) would be the most important stage in the identification of novel compounds. Comparative genomics and genetic similarity network analysis of 62 Streptomyces public reference genomes demonstrated that individuals of these species exhibit a huge number of distinct NP BGCs, the most of which are cryptic and unconnected to any reported NPs with high phylogenetic variation among individuals. It was assumed that substantial heterogeneity across the varieties of species of Streptomyces drives outstanding biosynthetic and metabolic potential, making them plausible candidates for the identification of novel molecules.

Enhancement of cranial nerves in Lyme neuroborreliosis: incidence and correlation with clinical symptoms and prognosis.

PURPOSE: Symptoms of cranial neuritis are a common presentation of Lyme neuroborreliosis (LNB). Imaging studies are scarce and report contradictory low prevalence of enhancement compared to clinical studies of cranial neuropathy. We hypothesized that MRI enhancement of cranial nerves in LNB is underreported, and aimed to assess the prevalence and clinical impact of cranial nerve enhancement in early LNB. METHODS: In this prospective, longitudinal cohort study, 69 patients with acute LNB were examined with MRI of the brain. Enhancement of cranial nerves III-XII was rated. MRI enhancement was correlated to clinical findings of neuropathy in the acute phase and after 6 months. RESULTS: Thirty-nine of 69 patients (57%) had pathological cranial nerve enhancement. Facial and oculomotor nerves were most frequently affected. There was a strong correlation between enhancement in the distal internal auditory canal and parotid segments of the facial nerve and degree of facial palsy (gamma = 0.95, p < .01, and gamma = 0.93, p < .01), despite that 19/37 nerves with mild-moderate enhancement in the distal internal auditory canal segment showed no clinically evident palsy. Oculomotor and abducens nerve enhancement did not correlate with eye movement palsy (gamma = 1.00 and 0.97, p = .31 for both). Sixteen of 17 patients with oculomotor and/or abducens nerve enhancement had no evident eye movement palsy. CONCLUSIONS: MRI cranial nerve enhancement is common in LNB patients, but it can be clinically occult. Facial and oculomotor nerves are most often affected. Enhancement of the facial nerve distal internal auditory canal and parotid segments correlate with degree of facial palsy.

In silico genome mining of potential novel biosynthetic gene clusters for drug discovery from Burkholderia bacteria.

As an emerging resource, Gram-negative Burkholderia bacteria were able to produce a wide range of bioactive secondary metabolites with potential therapeutic and biotechnological applications. Genome mining has emerged as an influential platform for screening and pinpointing natural product diversity with the increasing number of Burkholderia genome sequences. Here, for genome mining of potential biosynthetic gene clusters (BGCs) and prioritizing prolific producing Burkholderia strains, we investigated the relationship between species evolution and distribution of main BGC groups using computational analysis of complete genome sequences of 248 Burkholderia species publicly available. We uncovered significantly differential distribution patterns of BGCs in the Burkholderia phyla, even among strains that are genetically very similar. We found various types of BGCs in Burkholderia, including some representative and most common BGCs for biosynthesis of encrypted or known terpenes, non-ribosomal peptides (NRPs) and some hybrid BGCs for cryptic products. We also observed that Burkholderia contain a lot of unspecified BGCs, representing high potentials to produce novel compounds. Analysis of BGCs for RiPPs (Ribosomally synthesized and posttranslationally modified peptides) and a texobactin-like BGC as examples showed wide classification and diversity of RiPP BGCs in Burkholderia at species level and metabolite predication. In conclusion, as the biggest investigation in silico by far on BGCs of the particular genus Burkholderia, our data implied a great diversity of natural products in Burkholderia and BGC distributions closely related to phylogenetic variation, and suggested different or concurrent strategies used to identify new drug molecules from these microorganisms will be important for the selection of potential BGCs and prolific producing strains for drug discovery.

Strategies for Natural Products Discovery from Uncultured Microorganisms.

Microorganisms are highly regarded as a prominent source of natural products that have significant importance in many fields such as medicine, farming, environmental safety, and material production. Due to this, only tiny amounts of microorganisms can be cultivated under standard laboratory conditions, and the bulk of microorganisms in the ecosystems are still unidentified, which restricts our knowledge of uncultured microbial metabolism. However, they could hypothetically provide a large collection of innovative natural products. Culture-independent metagenomics study has the ability to address core questions in the potential of NP production by cloning and analysis of microbial DNA derived directly from environmental samples. Latest advancements in next generation sequencing and genetic engineering tools for genome assembly have broadened the scope of metagenomics to offer perspectives into the life of uncultured microorganisms. In this review, we cover the methods of metagenomic library construction, and heterologous expression for the exploration and development of the environmental metabolome and focus on the function-based metagenomics, sequencing-based metagenomics, and single-cell metagenomics of uncultured microorganisms.

Genotypic characterization of multidrug resistant Escherichia coli isolates reveals co-existence of ESBL- and carbapenemase- encoding genes linked to ISCR1.

Antimicrobial resistance in food-producing animals has not yet judiciously been reported from Pakistan. Here, we report on the isolation rate of poultry-associated multidrug resistant extended spectrum ß-lactamase (ESBL) -producing Escherichia coli in Peshawar, Pakistan. A total of 200 samples, 50 from retail-poultry meat, 50 from sick birds, 50 from the boiler farm-environment, and 50 from human beings working on or exposed to poultry were analyzed for isolation of ESBL -producing E. coli, ESBL -encoding genes and antimicrobial susceptibility. A total of 81 E. coli isolates [(50.0% Phylogroup-A, 33.3% D and 16.7% phylogroup B2)], were recovered, 36 (44.4%) of them were found to be ESBL -producers. PCR revealed that blaCTXM was the most prevalent (14/36 = 38.9%) ESBL -encoding gene followed by blaSHV2 (9/36 = 25%). Strikingly, co-occurrence of multiple ESBL - and/or carbapenemase-encoding genes in a single isolate was observed, and combination of blaCTXM + blaSHV2 was the most predominant (19.4%) followed by blaCTXM + blaNDM1 + blaOXA-48 (11.1%) and blaCTXM + blaOXA-48 (8.8%). All these ESBL producers were found to be multidrug resistant (MDR) and were carrying either integron 1 (48.5%) or 2 (51.5%). Finally, 14 of the 36 isolates were also found positive for variable region and insertion sequence common region 1, which was found linked to ESBL/carbapenemase encoding genes in 5/14 isolates suggesting its role in dissemination.

Optimization, Characteristics, and Functions of Alkaline Phosphatase From Escherichia coli.

Weaning of piglets could increase the risk of infecting with Gram-negative pathogens, which can further bring about a wide array of virulence factors including the endotoxin lipopolysaccharide (LPS). It is in common practice that the use of antibiotics has been restricted in animal husbandry. Alkaline phosphatase (AKP) plays an important role in the detoxification and anti-inflammatory effects of LPS. This study investigated the protective effects of AKP on intestinal epithelial cells during inflammation. Site-directed mutagenesis was performed to modulate the AKP activity. The enzyme activity tests showed that the activity of the DelSigD153G-D330N mutants in B. subtilis was nearly 1,600 times higher than that of the wild-type AKP. In this study, an in vitro LPS-induced inflammation model using IPEC-J2 cells was established. The mRNA expression of interleukin-(IL-) 6, IL-8, and tumor necrosis factor-α (TNF-α) were extremely significantly downregulated, and that of ASC amino acid transporter 2 (ASCT-2), zonula occludens protein-1 (ZO-1), and occludin-3 (CLDN-3) were significantly upregulated by the DelSigD153G-D330N mutant compared with LPS treatment. This concludes the anti-inflammatory role of AKP on epithelial membrane, and we are hopeful that this research could achieve a sustainable development for the pig industry.

Functional probiotics of lactic acid bacteria from Hu sheep milk.

BACKGROUND: Probiotics are being considered as valuable microorganisms related to human health. Hu sheep is referred as one of the important sheep breeds in China. Goat milk produced by Hu sheep is characterized with high nutritional value and hypoallergenic in nature. Particularly, this milk contains plenty of milk prebiotic and probiotic bacteria. This study was aimed to scrutinize more bacterial strains from Hu sheep milk with potential probiotic activity. RESULTS: Based on 16S rRNA sequence analysis, pool of forty bacterial strains were identified and evaluated their antimicrobial activities against Staphylococcus aureus, enterohemorrhagic Escherichia coli (EHEC), Salmonella typhimurium, Listeria monocytogenes enterotoxigenic E. coli (ETEC) and Aeromonas caviae. Four out of these isolated strains demonstrated their efficient bacteriostatic ability and potential healthy properties. We also examined the safety aspects of these bacterial candidates including three Lactococcus lactis strains (named as HSM-1, HSM-10, and HSM-18) and one Leuconostoc lactis strain (HSM-14), and were further evaluated via in vitro tests, including antimicrobial activity, cell surface characteristics (hydrophobicity, co-aggregation, and self-aggregation), heat treatment, antibiotic susceptibility, simulated transport tolerance in the gastrointestinal tract, and acid/bile tolerance. The obtained results revealed that HSM-1, HSM-10, HSM-14, and HSM-18 showed high survival rate at different conditions for example low pH, presence of bovine bile and demonstrated high hydrophobicity. Moreover, HSM-14 had an advantage over other strains in terms of gastrointestinal tract tolerance, antimicrobial activities against pathogens, and these results were significantly better than other bacterial candidates. CONCLUSION: Hu sheep milk as a source of exploration of potential lactic acid bacteria (LAB) probiotics open the new horizon of probiotics usage from unconventional milk sources. The selected LAB strains are excellent probiotic candidates which can be used for animal husbandry in the future. Rationale of the study was to utilize Hu sheep milk as a source of potential probiotic LABs. The study has contributed to the establishment of a complete bacterial resource pool by exploring the Hu sheep milk microflora.

Recombineering for Genetic Engineering of Natural Product Biosynthetic Pathways.

Microbial genomes encode many cryptic and uncharacterized biosynthetic gene clusters (BGCs). Exploiting this unexplored genetic wealth to discover microbial novel natural products (NPs) remains a challenging issue. We review homologous recombination (HR)-based recombineering, mediated by the recombinases RecE/RecT from Rac prophage and Redα/Redß from lambda phage, which has developed into a highly inclusive tool for direct cloning of large DNA up to 100 kb, seamless mutation, multifragment assembly, and heterologous expression of microbial NP BGCs. Its utilization in the refactoring, engineering, and functional expression of long BGCs for NP biosynthesis makes it easy to elucidate NP-producing potential in microbes. This review also highlights various applications of recombineering in NP-derived drug discovery.

Fingolimod Plays Role in Attenuation of Myocardial Injury Related to Experimental Model of Cardiac Arrest and Extracorporeal Life Support Resuscitation.

BACKGROUND: Sudden cardiac arrest is a major global health concern, and survival of patients with ischemia-reperfusion injury is a leading cause of myocardial dysfunction. The mechanism of this phenomenon is not well understood because of the complex pathophysiological nature of the disease. Aim of the study was to investigate the cardioprotective role of fingolimod in an in vivo model of cardiac arrest and resuscitation. METHODS: In this study, an in vivo rat model of cardiac arrest using extracorporeal membrane oxygenation resuscitation monitored by invasive hemodynamic measurement was developed. At the beginning of extracorporeal life support (ECLS), animals were randomly treated with fingolimod (Group A, n = 30) or saline (Group B, n = 30). Half of the animals in each group (Group A1 and B1, n = 15 each) were sacrificed after 1 h, and the remaining animals (Group A2 and B2) after 24 h of reperfusion. Blood and myocardial tissues were collected for analysis of cardiac features, inflammatory biomarkers, and cell signaling pathways. RESULTS: Treatment with fingolimod resulted in activation of survival pathways resulting into reduced inflammation, myocardial oxidative stress and apoptosis of cardiomyocytes. This led to significant improvement in systolic and diastolic functions of the left ventricle and improved contractility index. CONCLUSIONS: Sphingosine1phosphate receptor activation with fingolimod improved cardiac function after cardiac arrest supported with ECLS. Present study findings strongly support a cardioprotective role of fingolimod through sphingosine-1-phosphate receptor activation during reperfusion after circulatory arrest.

Adaptive Filtering on GPS-Aided MEMS-IMU for Optimal Estimation of Ground Vehicle Trajectory.

Fusion of the Global Positioning System (GPS) and Inertial Navigation System (INS) for navigation of ground vehicles is an extensively researched topic for military and civilian applications. Micro-electro-mechanical-systems-based inertial measurement units (MEMS-IMU) are being widely used in numerous commercial applications due to their low cost; however, they are characterized by relatively poor accuracy when compared with more expensive counterparts. With a sudden boom in research and development of autonomous navigation technology for consumer vehicles, the need to enhance estimation accuracy and reliability has become critical, while aiming to deliver a cost-effective solution. Optimal fusion of commercially available, low-cost MEMS-IMU and the GPS may provide one such solution. Different variants of the Kalman filter have been proposed and implemented for integration of the GPS and the INS. This paper proposes a framework for the fusion of adaptive Kalman filters, based on Sage-Husa and strong tracking filtering algorithms, implemented on MEMS-IMU and the GPS for the case of a ground vehicle. The error models of the inertial sensors have also been implemented to achieve reliable and accurate estimations. Simulations have been carried out on actual navigation data from a test vehicle. Measurements were obtained using commercially available GPS receiver and MEMS-IMU. The solution was shown to enhance navigation accuracy when compared to conventional Kalman filter.

Cardioprotective Effects of Sphingosine-1-Phosphate Receptor Immunomodulator FTY720 in a Clinically Relevant Model of Cardioplegic Arrest and Cardiopulmonary Bypass.

Objective: FTY720, an immunomodulator derived from sphingosine-1-phosphate, has recently demonstrated its immunomodulatory, anti-inflammatory, anti-oxidant, anti-apoptotic and anti-inflammatory properties. Furthermore, FTY720 might be a key pharmacological target for preconditioning. In this preclinical model, we have investigated the effects of FTY720 on myocardium during reperfusion in an experimental model of cardioplegic arrest (CPA) and cardiopulmonary bypass. Methods: 30 Sprague-Dawley rats (300-350 g) were randomized into two groups: Group-A, treated with FTY720 1 mg/kg via intravenous cannulation, and Group-B, as control. After 15 min of treatment, rats underwent CPA for 30 min followed by initiation of extracorporeal life support for 2 h. Support weaning was done, and blood and myocardial tissues were collected for analysis. Hemodynamic parameters, inflammatory mediators, nitro-oxidative stress, neutrophil infiltration, immunoblotting analysis, and immunohistochemical staining were analyzed and compared between groups. Results: FTY720 treatment activated the Akt/Erk1/2 signaling pathways, reduced the level of inflammatory mediators, activated antiapoptotic proteins, and inhibited proapoptotic proteins, leading to reduced nitro-oxidative stress and cardiomyocyte apoptosis. Moreover, significant preservation of high-energy phosphates were observed in the FTY720-treated group. This resulted in improved recovery of left ventricular systolic and diastolic functions. Conclusion: The cardioprotective mechanism in CPA is associated with activation of prosurvival cell signaling pathways that prevents myocardial damage. FTY720 preserves high-energy phosphates attenuates myocardial inflammation and oxidative stress, and improves cardiac function.

Adaptive hysteresis thresholding segmentation technique for localizing the breast masses in the curve stitching domain.

BACKGROUND AND OBJECTIVE: Massive work by distinguished researchers in the domain of breast segmentation has been proposed. However, no significant solution reduces the limitations of the false positive rate of cancerous cells in the breast body for probing the abnormalities of particular features. This problem is challenging in its nature and essential to be solved. It is needed to reach the optimal measurements of the breast parenchyma, the breast patchy regions of the mammogram, or the breast registration for searching of precise oddities. METHODS: In this work, we propose a novel approach for observing the abnormal breast cells identification with high sensitivity. A cancer tumor often produces a specific protein in the blood that serves as a marker for the cancer cells. These cells break off from the cancer and move into the blood stream. However, presence of pectoral muscle in breast mammogram highly affects the detection process of breast tumor. A novel aspect of the proposed method is that the curve stitching technique is developed for removing of pectoral muscle. Following this, an adaptive hysteresis thresholding is used for segmentation. This hybrid technique is used for segmenting a breast region of digital mammogram with suppression of pectoral muscle. RESULTS: The proposed method attains a highest sensitivity rate of 96.6% for the MIAS dataset and 96.4% for the DDSM dataset as compared to existing methods. CONCLUSION: The main idea behind this is to improve the threshold based segmentation techniques to create an adaptive threshold and apposite templates, in order to conserve tumor salient features about suspicious regions to classify benign and malignant mass in mammogram. First, a spline based curve fitting is applied on edges of the breast parenchyma and fill the region with a very low intensity value and map on original image to preserve the original intensity of breast region free of pectoral muscle. The results of the experiments show that the proposed segmentation technique is efficient when tested on MIAS and DDSM dataset.

Correction: A novel encryption scheme for high-contrast image data in the Fresnelet domain.

[This corrects the article DOI: 10.1371/journal.pone.0194343.].

Removal of pectoral muscle based on topographic map and shape-shifting silhouette.

BACKGROUND: In digital mammography, finding accurate breast profile segmentation of women's mammogram is considered a challenging task. The existence of the pectoral muscle may mislead the diagnosis of cancer due to its high-level similarity to breast body. In addition, some other challenges due to manifestation of the breast body pectoral muscle in the mammogram data include inaccurate estimation of the density level and assessment of the cancer cell. The discrete differentiation operator has been proven to eliminate the pectoral muscle before the analysis processing. METHODS: We propose a novel approach to remove the pectoral muscle in terms of the mediolateral-oblique observation of a mammogram using a discrete differentiation operator. This is used to detect the edges boundaries and to approximate the gradient value of the intensity function. Further refinement is achieved using a convex hull technique. This method is implemented on dataset provided by MIAS and 20 contrast enhanced digital mammographic images. RESULTS: To assess the performance of the proposed method, visual inspections by radiologist as well as calculation based on well-known metrics are observed. For calculation of performance metrics, the given pixels in pectoral muscle region of the input scans are calculated as ground truth. CONCLUSIONS: Our approach tolerates an extensive variety of the pectoral muscle geometries with minimum risk of bias in breast profile than existing techniques.

A novel encryption scheme for high-contrast image data in the Fresnelet domain.

In this paper, a unique and more distinctive encryption algorithm is proposed. This is based on the complexity of highly nonlinear S box in Flesnelet domain. The nonlinear pattern is transformed further to enhance the confusion in the dummy data using Fresnelet technique. The security level of the encrypted image boosts using the algebra of Galois field in Fresnelet domain. At first level, the Fresnelet transform is used to propagate the given information with desired wavelength at specified distance. It decomposes given secret data into four complex subbands. These complex sub-bands are separated into two components of real subband data and imaginary subband data. At second level, the net subband data, produced at the first level, is deteriorated to non-linear diffused pattern using the unique S-box defined on the Galois field [Formula: see text]. In the diffusion process, the permuted image is substituted via dynamic algebraic S-box substitution. We prove through various analysis techniques that the proposed scheme enhances the cipher security level, extensively.

Correction: A novel encryption scheme for high-contrast image data in the Fresnelet domain.

[This corrects the article DOI: 10.1371/journal.pone.0194343.].

Neurochemical Alterations in Sudden Unexplained Perinatal Deaths-A Review.

Sudden unexpected perinatal collapse is a major trauma for the parents of victims. Sudden infant death syndrome (SIDS) is unexpected and mysterious death of an apparently healthy neonate from birth till 1 year of age without any known causes, even after thorough postmortem investigations. However, the incidence of sudden intrauterine unexplained death syndrome (SIUDS) is seven times higher as compared with SIDS. This observation is approximated 40-80%. Stillbirth is defined as death of a fetus after 20th week of gestation or just before delivery at full term without a known reason. Pakistan has the highest burden of stillbirth in the world. This basis of SIDS, SIUDS, and stillbirths eludes specialists. The purpose of this study is to investigate factors behind failure in control of these unexplained deaths and how research may go ahead with improved prospects. Animal models and physiological data demonstrate that sleep, arousal, and cardiorespiratory malfunctioning are abnormal mechanisms in SIUDS risk factors or in newborn children who subsequently die from SIDS. This review focuses on insights in neuropathology and mechanisms of SIDS and SIUDS in terms of different receptors involved in this major perinatal demise. Several studies conducted in the past decade have confirmed neuropathological and neurochemical anomalies related to serotonin transporter, substance P, acetylcholine α7 nicotine receptors, etc., in sudden unexplained fetal and infant deaths. There is need to focus more on research in this area to unveil the major curtain to neuroprotection by underlying mechanisms leading to such deaths.

A novel classification scheme to decline the mortality rate among women due to breast tumor.

Early screening of skeptical masses or breast carcinomas in mammograms is supposed to decline the mortality rate among women. This amount can be decreased more on development of the computer-aided diagnosis with reduction of false suppositions in medical informatics. Our aim is to provide a robust tumor detection system for accurate classification of breast masses using normal, abnormal, benign, or malignant classes. The breast carcinomas are classified on the basis of observed classes. This is highly dependent on feature extraction process. In propose work, a novel algorithm for classification based on the combination of top Hat transformation and gray level co-occurrence matrix with back propagation neural network. The aim of this study is to present a robust classification model for automated diagnosis of the breast tumor with reduction of false assumptions in medical informatics. The proposed method is verified on two datasets MIAS and DDSM. It is observed that rate of false positives decreased by the proposed method to improve the performance of classification, efficiently.

Sphingosine 1-Phosphate Receptor Modulator Fingolimod (FTY720) Attenuates Myocardial Fibrosis in Post-heterotopic Heart Transplantation.

Background and Objective: Sphingosine 1-phosphate (S1P), and S1P receptor modulator fingolimod have been suggested to play important cardioprotective role in animal models of myocardial ischemia/reperfusion injuries. To understand the cardioprotective function of S1P and its mechanism in vivo, we analyzed apoptotic, inflammatory biomarkers, and myocardial fibrosis in an in vivo heterotopic rat heart transplantation model. Methods: Heterotopic heart transplantation is performed in 60 Sprague-Dawley (SD) rats (350-400 g). The heart transplant recipients (n = 60) are categorized into Group A (control) and Group B (fingolimod treated 1 mg/kg intravenous). At baseline with 24 h after heart transplantation, blood and myocardial tissue are collected for analysis of myocardial biomarkers, apoptosis, inflammatory markers, oxidative stress, and phosphorylation of Akt/Erk/STAT-3 signaling pathways. Myocardial fibrosis was investigated using Masson's trichrome staining and L-hydroxyline. Results: Fingolimod treatment activates both Reperfusion Injury Salvage Kinase (RISK) and Survivor Activating Factor Enhancement (SAFE) pathways as evident from activation of anti-apoptotic and anti-inflammatory pathways. Fingolimod treatment caused a reduction in myocardial oxidative stress and hence cardiomyocyte apoptosis resulting in a decrease in myocardial reperfusion injury. Moreover, a significant (p < 0.001) reduction in collagen staining and hydroxyproline content was observed in fingolimod treated animals 30 days after transplantation demonstrating a reduction in cardiac fibrosis. Conclusion: S1P receptor activation with fingolimod activates anti-apoptotic and anti-inflammatory pathways, leading to improved myocardial salvage causing a reduction in cardiac fibrosis.