BANet: A Blur-Aware Attention Network for Dynamic Scene Deblurring.

Image motion blur results from a combination of object motions and camera shakes, and such blurring effect is generally directional and non-uniform. Previous research attempted to solve non-uniform blurs using self-recurrent multi-scale, multi-patch, or multi-temporal architectures with self-attention to obtain decent results. However, using self-recurrent frameworks typically leads to a longer inference time, while inter-pixel or inter-channel self-attention may cause excessive memory usage. This paper proposes a Blur-aware Attention Network (BANet), that accomplishes accurate and efficient deblurring via a single forward pass. Our BANet utilizes region-based self-attention with multi-kernel strip pooling to disentangle blur patterns of different magnitudes and orientations and cascaded parallel dilated convolution to aggregate multi-scale content features. Extensive experimental results on the GoPro and RealBlur benchmarks demonstrate that the proposed BANet performs favorably against the state-of-the-arts in blurred image restoration and can provide deblurred results in real-time.

Mitochondrial ROS-induced ERK1/2 activation and HSF2-mediated AT1 R upregulation are required for doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX), one useful chemotherapeutic agent, is limited in clinical use because of its serious cardiotoxicity. Growing evidence suggests that angiotensin receptor blockers (ARBs) have cardioprotective effects in DOX-induced cardiomyopathy. However, the detailed mechanisms underlying the action of ARBs on the prevention of DOX-induced cardiomyocyte cell death have yet to be investigated. Our results showed that angiotensin II receptor type I (AT1 R) plays a critical role in DOX-induced cardiomyocyte apoptosis. We found that MAPK signaling pathways, especially ERK1/2, participated in modulating AT1 R gene expression through DOX-induced mitochondrial ROS release. These results showed that several potential heat shock binding elements (HSE), which can be recognized by heat shock factors (HSFs), located at the AT1 R promoter region. HSF2 markedly translocated from the cytoplasm to the nucleus when cardiomyocytes were damaged by DOX. Furthermore, the DNA binding activity of HSF2 was enhanced by DOX via deSUMOylation. Overexpression of HSF2 enhanced DOX-induced cardiomyocyte cell death as well. Taken together, we found that DOX induced mitochondrial ROS release to activate ERK-mediated HSF2 nuclear translocation and AT1 R upregulation causing DOX-damaged heart failure in vitro and in vivo.

HSF1 phosphorylation by ERK/GSK3 suppresses RNF126 to sustain IGF-IIR expression for hypertension-induced cardiomyocyte hypertrophy.

Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure (HF). Inhibition of extracellular signal-regulated kinases (ERK) efficaciously suppressed angiotensin II (ANG II)-induced cardiomyocyte hypertrophy and apoptosis by blocking insulin-like growth factor II receptor (IGF-IIR) signaling. However, the detailed mechanism by which ANG II induces ERK-mediated IGF-IIR signaling remains elusive. Here, we found that ANG II activated ERK to upregulate IGF-IIR expression via the angiotensin II type I receptor (AT1 R). ERK activation subsequently phosphorylates HSF1 at serine 307, leading to a secondary phosphorylation by glycogen synthase kinase III (GSK3) at serine 303. Moreover, we found that ANG II mediated ERK/GSK3-induced IGF-IIR protein stability by downregulating the E3 ubiquitin ligase of IGF-IIR RING finger protein CXXVI (RNF126). The expression of RNF126 decreased following ANG II-induced HSF1S303 phosphorylation, resulting in IGF-IIR protein stability and increased cardiomyocyte injury. Inhibition of GSK3 significantly alleviated ANG II-induced cardiac hypertrophy in vivo and in vitro. Taken together, these results suggest that HSF1 phosphorylation stabilizes IGF-IIR protein stability by downregulating RNF126 during cardiac hypertrophy. ANG II activates ERK/GSK3 to phosphorylate HSF1, resulting in RNF126 degradation, which stabilizes IGF-IIR protein expression and eventually results in cardiac hypertrophy. HSF1 could be a valuable therapeutic target for cardiac diseases among hypertensive patients.

p53-mediated miR-18 repression activates HSF2 for IGF-IIR-dependent myocyte hypertrophy in hypertension-induced heart failure.

Hypertension-induced cardiac hypertrophy and attenuated cardiac function are the major characteristics of early stage heart failure. Cardiomyocyte death in pathological cardiac conditions is the primary cause of heart failure and mortality. Our previous studies found that heat shock factor 1 (HSF1) protected cardiomyocytes from death by suppressing the IGF-IIR signaling pathway, which is critical for hypertensive angiotensin II-induced cardiomyocyte apoptosis. However, the role of heat shock factor 2 (HSF2) in hypertension-induced cardiac hypertrophy is unknown. We identified HSF2 as a miR-18 target for cardiac hypertrophy. p53 activation in angiotensin II (ANG II)-stimulated NRVMs is responsible for miR-18 downregulation both in vitro and in vivo, which triggers HSF2 expression and the activation of IGF-IIR-induced cardiomyocyte hypertrophy. Finally, we provide genetic evidence that miR-18 is required for cardiomyocyte functions in the heart based on the gene transfer of cardiac-specific miR-18 via adenovirus-associated virus 2 (AAV2). Transgenic overexpression of miR-18 in cardiomyocytes is sufficient to protect against dilated cardiomyopathy during hypertension-induced heart failure. Our results demonstrated that the p53-miR-18-HSF2-IGF-IIR axis was a critical regulatory pathway of cardiomyocyte hypertrophy in vitro and in vivo, suggesting that miR-18 could be a therapeutic target for the control of cardiac functions and the alleviation of cardiomyopathy during hypertension-induced heart failure.

Doxorubicin attenuates CHIP-guarded HSF1 nuclear translocation and protein stability to trigger IGF-IIR-dependent cardiomyocyte death.

Doxorubicin (DOX) is one of the most effective antitumor drugs, but its cardiotoxicity has been a major concern for its use in cancer therapy for decades. Although DOX-induced cardiotoxicity has been investigated, the underlying mechanisms responsible for this cardiotoxicity have not been completely elucidated. Here, we found that the insulin-like growth factor receptor II (IGF-IIR) apoptotic signaling pathway was responsible for DOX-induced cardiotoxicity via proteasome-mediated heat shock transcription factor 1 (HSF1) degradation. The carboxyl-terminus of Hsp70 interacting protein (CHIP) mediated HSF1 stability and nuclear translocation through direct interactions via its tetratricopeptide repeat domain to suppress IGF-IIR expression and membrane translocation under physiological conditions. However, DOX attenuated the HSF1 inhibition of IGF-IIR expression by diminishing the CHIP-HSF1 interaction, removing active nuclear HSF1 and triggering HSF1 proteasomal degradation. Overexpression of CHIP redistributed HSF1 into the nucleus, inhibiting IGF-IIR expression and preventing DOX-induced cardiomyocyte apoptosis. Moreover, HSF1A, a small molecular drug that enhances HSF1 activity, stabilized HSF1 expression and minimized DOX-induced cardiac damage in vitro and in vivo. Our results suggest that the cardiotoxic effects of DOX result from the prevention of CHIP-mediated HSF1 nuclear translocation and activation, which leads to an upregulation of the IGF-IIR apoptotic signaling pathway. We believe that the administration of an HSF1 activator or agonist may further protect against the DOX-induced cell death of cardiomyocytes.

Anti-inflammatory effects of probiotic Lactobacillus paracasi on ventricles of BALB/C mice treated with ovalbumin.

Lactic acid bacteria (LAB) are microorganisms that benefit animals with allergic diseases and intestinal disorders such as inflammatory bowel disease. We propose that LAB can prevent cardiomyocytes inflammation and apoptosis in BALB/c mice using an ovalbumin (OVA)-induced allergy. Thirty-nine male BALB/c mice were divided into five groups: normal control, allergy control and three allergy groups each treated with Kefir I (Kefir I), Kefir II (Kefir II) or GM080 products (GM080). The myocardial architecture and apoptotic molecules in the excised left ventricle from these mice were investigated and post-treatment effects were evaluated. The inflammatory pathway, including toll-like receptor 4 (TLR4), phospholate-Jun-N-terminal kinase (p-JNK), JNK1/2 and tumor necrosis factor- alpha (TNF-α) and the mitochondria-dependent apoptosis phospholate-p38 (p-p38), Bcl-2 associated agonist of cell death (Bad), Bcl-2 associated X (Bax) and activated caspase 3, were found to be significant- ly increased in the hearts of allergy mice. The expression of phospholate-nuclear factor-κB (p-NFκB), TNF-α, p-p38 and Bad protein products were reduced or retarded in the Kefir I- or II-treated allergy group. The GM080-treated allergy group exhibited significantly lower p-JNK, JNK1/2, phospholate- Ikappa B (p-IκB), Bax and Bad protein products than the Kefir I and Kefir II allergy groups. These results indicate that LAB can reduce inflammation and prevent apoptosis of cardiomyocytes in the heart of OVA-induced allergy mice.

Development of a high-resolution melting method for the screening of Wilson disease-related ATP7B gene mutations.

BACKGROUND: Wilson disease is an autosomal recessive inherited disorder of copper metabolism. The condition is characterized by excessive deposition of copper in many organs and tissues. The major physiologic aberration is excessive absorption of copper from the small intestine and impaired biliary copper excretion. The genetic defect is located at copper-transporting adenosine triphosphatase (ATPase) gene (ATP7B). METHODS: A high-resolution melting analysis (HRM) was designed to characterize the ATP7B hotspot mutations. Genomic DNA was extracted from peripheral blood samples from 14 patients and 50 normal controls. The 21 exons of ATP7B were screened by HRM analysis. Our methodology was confirmed by direct DNA sequencing. RESULTS: We have confirmed the 10 different hotspot mutations and 7 polymorphisms in the ATP7B gene, and also identified 1 newly-identified sequence variant (p.A476T) and 1 novel SNP (p.L776L) in 50 normal Taiwanese individuals. We estimate that the carrier frequency of WD in the Taiwanese population as probably 0.03. CONCLUSIONS: HRM analysis is accepted as a rapid, accurate and low-cost method to screen ATP7B gene mutations.

Early detection of Pompe disease by newborn screening is feasible: results from the Taiwan screening program.

OBJECTIVE: Pompe disease is an autosomal recessive lysosomal storage disorder that is caused by deficient acid alpha-glucosidase activity and results in progressive, debilitating, and often life-threatening symptoms involving the musculoskeletal, respiratory, and cardiac systems. Recently, enzyme replacement therapy with alglucosidase alpha has become possible, but the best outcomes in motor function have been achieved when treatment was initiated early. The aim of this study was to test the feasibility of screening newborns in Taiwan for Pompe disease by using a fluorometric enzymatic assay to determine acid alpha-glucosidase activity in dried blood spots. METHODS: We conducted a large-scale newborn screening pilot program between October 2005 and March 2007. The screening involved measuring acid alpha-glucosidase activity in dried blood spots of approximately 45% of newborns in Taiwan. The unscreened population was monitored as a control. RESULTS: Of the 132 538 newborns screened, 1093 (0.82%) repeat dried blood-spot samples were requested and retested, and 121 (0.091%) newborns were recalled for additional evaluation. Pompe disease was confirmed in 4 newborns. This number was similar to the number of infants who received a diagnosis of Pompe disease in the control group (n = 3); however, newborn screening resulted in an earlier diagnosis of Pompe disease: patients were <1 month old compared with 3 to 6 months old in the control group. CONCLUSIONS: To our knowledge, this is the first large-scale study to show that newborn screening for Pompe disease is feasible. Newborn screening allows for earlier diagnosis of Pompe disease and, thus, for assessment of the value of an earlier start of treatment.