Dapagliflozin prevents ERK activation and SGLT2-dependent endoglin upregulation in a mechanically provoked cardiac injury model.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are rapidly gaining ground in the treatment of heart failure (HF) with reduced ejection fraction (HFrEF) and acute myocardial infarction (AMI) by an unknown mechanism. Upregulation of Na+/H+ exchanger 1 (NHE1), SGLT1, and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the diseased hearts was found to be attenuated by prolonged SGLT2i treatment. Unfortunately, dapagliflozin is not well understood as to how Na+/Ca2+ homeostasis is affected in cardiomyocytes. In this study, we aimed to investigate whether mechanical stretch in cardiomyocytes upregulate SGLT2, resulted to loss of Na+/Ca2+ homeostasis via ERK and eNOS signaling. AMI (+) and AMI (-) serum levels were estimated using ELISA assays of TGFß-1 or endoglin (CD105). Human cardiomyocyte cell line AC16 was subjected to different stresses: 5% mild and 25% aggressive, at 1 Hz for 24 h. Immunofluorescence assays were used to estimate troponin I, CD105, SGLT1/2, eNOSS633, and ERK1/2T202/Y204 levels was performed for 5% (mild), and 25% elongation for 24 h. AMI (+) serum showed increased TGFß1 and CD105 compared to AMI (-) patients. In consistent, troponin I, CD105, SGLT1/2, eNOSS633 and ERK1/2T202/Y204 were upregulated after 25% of 24 h cyclic stretch. Dapagliflozin addition caused SGLT2 inhibition, which significantly decreased troponin I, CD105, SGLT1/2, eNOSS633, and ERK1/2T202/Y204 under 25% cyclic stretching. In summary, SGLT2 may have sensed mechanical stretch in a way similar to cardiac overloading as in vivo. By blocking SGLT2 in stretched cardiomyocytes, the AMI biomarkers (CD105, troponin I and P-ERK) were decreased, potentially to rescue eNOS production to maintain normal cellular function. This discovery of CD105 and SGLT2 increase in mechanically stretched cardiomyocytes suggests that SGLT2 may conceive a novel role in direct or indirect sensing of mechanical stretch, prompting the possibility of an in vitro cardiac overloaded cell model, an alternative to animal heart model.

An FM-Index Based High-Throughput Memory-Efficient FPGA Accelerator for Paired-End Short-Read Mapping.

This article presents an Ferragina-Manzini index (FM-index) based paired-end short-read mapping hardware accelerator. Four techniques are proposed to significantly reduce the number of memory accesses and operations to improve the throughput. First, an interleaved data structure is proposed to reduce the processing time by 51.8% by leveraging the data locality. Second, the boundaries of possible mapping location candidates can be retrieved within only one memory access by constructing a lookup table along with the FM-index. This reduces the number of DRAM accesses by 60% with only a 64 MB memory overhead. Third, an additional step is added to skip the time-consuming repetitive location candidates filtering conditionally, avoiding unnecessary operations. Lastly, an early termination method is proposed to terminate the mapping process if any location candidate with a high enough alignment score is detected, greatly decreasing the execution time. Overall, the computation time is reduced by 92.6% with only a 2% memory overhead in DRAM. The proposed methods are realized on a Xilinx Alveo U250 FPGA. The proposed FPGA accelerator processes 1,085,812,766 short-reads from the U.S. Food and Drug Administration (FDA) dataset within 35.4 minutes at 200 MHz. It achieves a 1.7-to-18.6× higher throughput and the highest 99.3% accuracy by exploiting the paired-end short-read mapping, compared to state-of-the-art FPGA-based designs.

Achieving Accurate Automatic Sleep Apnea/Hypopnea Syndrome Assessment Using Nasal Pressure Signal.

Automatic assessment of sleep apnea/ hypopnea syndrome (SAHS) based on fewer physiological signals is critical for the success of healthcare at home. However, previous studies that use such settings only achieve a lower assessment accuracy, causing fewer syndromes to be separated for effective diagnosis. This paper presents a 3-stage support vector machines (SVM)-based algorithm for SAHS assessment using a single-channel nasal pressure (NP) signal. In this work, NP signal is utilized for feature extraction. Amplitude features, as well as those extracted using discrete Fourier transform and discrete wavelet transform, are used for machine learning. A total of 58 sets of polysomnography recordings, each with approximately 7 h in duration, were analyzed. This work achieves a sensitivity of 95.7% and a positive predictive value of 90.9%, outperforming previous works using NP signal. Compared with prior studies using only SpO2 signal, this work still achieves better performance and supports more classification levels. Thanks to the low-complexity settings based only on the NP signal, the proposed approach provides a promising solution to SAHS assessment for remote healthcare.

Mechanical Stretching-Induced Traumatic Brain Injury Is Mediated by the Formation of GSK-3ß-Tau Complex to Impair Insulin Signaling Transduction.

Traumatic brain injury confers a significant and growing public health burden. It is a major environmental risk factor for dementia. Nonetheless, the mechanism by which primary mechanical injury leads to neurodegeneration and an increased risk of dementia-related diseases is unclear. Thus, we aimed to investigate the effect of stretching on SH-SY5Y neuroblastoma cells that proliferate in vitro. These cells retain the dopamine-ß-hydroxylase activity, thus being suitable for neuromechanistic studies. SH-SY5Y cells were cultured on stretchable membranes. The culture conditions contained two groups, namely non-stretched (control) and stretched. They were subjected to cyclic stretching (6 and 24 h) and 25% elongation at 1 Hz. Following stretching at 25% and 1 Hz for 6 h, the mechanical injury changed the mitochondrial membrane potential and triggered oxidative DNA damage at 24 h. Stretching decreased the level of brain-derived neurotrophic factors and increased amyloid-ß, thus indicating neuronal stress. Moreover, the mechanical injury downregulated the insulin pathway and upregulated glycogen synthase kinase 3ß (GSK-3ß)S9/p-Tau protein levels, which caused a neuronal injury. Following 6 and 24 h of stretching, GSK-3ßS9 was directly bound to p-TauS396. In contrast, the neuronal injury was improved using GSK-3ß inhibitor TWS119, which downregulated amyloid-ß/p-Taus396 phosphorylation by enhancing ERK1/2T202/Y204 and AktS473 phosphorylation. Our findings imply that the neurons were under stress and that the inactivation of the GSK3ß could alleviate this defect.

Design and In Vivo Verification of a CMOS Bone-Guided Cochlear Implant Microsystem.

OBJECTIVE: To develop and verify a CMOS bone-guided cochlear implant (BGCI) microsystem with electrodes placed on the bone surface of the cochlea and the outside of round window for treating high-frequency hearing loss. METHODS: The BGCI microsystem consists of an external unit and an implanted unit. The external system-on-chip is designed to process acoustic signals through an acquisition circuit and an acoustic DSP processor to generate stimulation patterns and commands that are transmitted to the implanted unit through a 13.56 MHz wireless power and bidirectional data telemetry. In the wireless power telemetry, a voltage doubler/tripler (2X/3X) active rectifier is used to enhance the power conversion efficiency and generate 2 and 3 V output voltages. In the wireless data telemetry, phase-locked loop based binary phase-shift keying and load-shift keying modulators/demodulators are adopted for the downlink and uplink data through high-Q coils, respectively. The implanted chip with four-channel high-voltage-tolerant stimulator generates biphasic stimulation currents up to 800 µA. RESULTS: Electrical tests on the fabricated BGCI microsystem have been performed to verify the chip functions. The in vivo animal tests in guinea pigs have shown the evoked third wave of electrically evoked auditory brainstem response waveforms. It is verified that auditory nerves can be successfully stimulated and acoustic hearing can be partially preserved. CONCLUSION AND SIGNIFICANCE: Different from traditional cochlear implants, the proposed BGCI microsystem is less invasive, preserves partially acoustic hearing, and provides an effective alternative for treating high-frequency hearing loss.

Effect of Resveratrol on Reactive Oxygen Species-Induced Cognitive Impairment in Rats with Angiotensin II-Induced Early Alzheimer's Disease †.

Recent studies have indicated that several anti-hypertensive drugs may delay the development and progression of Alzheimer's disease (AD). However, the relationships among AD, hypertension, and oxidative stress remain to be elucidated. Here, we aimed to determine whether reactive oxygen species (ROS) reduction by resveratrol in the brain leads to cognitive impairment reduction in rats with angiotensin II (Ang-II)-induced early AD. Male Wistar Kyoto (WKY) rats with Ang-II-induced AD were treated with losartan or resveratrol for two weeks. Our results show decreased blood pressure, increased hippocampal brain-derived neurotrophic factor (BDNF) level, and decreased nucleus tractus solitarius (NTS) ROS production in the Ang-II groups with losartan (10 mg/kg), or resveratrol (10 mg/kg/day) treatment. Furthermore, losartan inhibition of hippocampal TauT231 phosphorylation activated AktS473 phosphorylation, and significantly abolished Ang-II-induced Aß precursors, active caspase 3, and glycogen synthase kinase 3ß (GSK-3ß)Y216 expressions. Consistently, resveratrol showed similar effects compared to losartan. Both losartan and resveratrol restored hippocampal-dependent contextual memory by NADPH oxidase 2 (NOX2) deletion and superoxide dismutase 2 (SOD2) elevation. Our results suggest that both losartan and resveratrol exert neuroprotective effects against memory impairment and hippocampal damage by oxidative stress reduction in early stage AD rat model. These novel findings indicate that resveratrol may represent a pharmacological option similar to losartan for patients with hypertension at risk of AD during old age.

A 135-mW Fully Integrated Data Processor for Next-Generation Sequencing.

Next-generation sequencing (NGS) enables high-throughput sequencing, in which short DNA fragments can be sequenced in a massively parallel fashion. However, the essential algorithm behind the succeeding NGS data analysis, DNA mapping, is still excessively time consuming. DNA mapping can be partitioned into two parts: suffix array (SA) sorting and backward searching. Dedicated hardware designs for the less-complex backward searching have been proposed, but feasible hardware for the most complicated part, SA sorting, has never been explored. Based on the memory-efficient sBWT algorithm, this work is the first integrated NGS data processor for the entire DNA mapping. The -ordered Ferragina and Manzini index used in the sBWT algorithm is leveraged to improve storage capacity and reduce hardware complexity. The proposed NGS data processor realizes the sBWT algorithm through bucket sorting, suffix grouping, and suffix sorting circuits. Key design parameters are analyzed to achieve the optimal performance with respect to hardware cost and execution time. Fabricated in 40-nm CMOS, the NGS data processor dissipates 135 mW at 200 MHz from a 0.9-V supply. With 1-GB external memory, the chip can analyze human DNA within 10 min. This work achieves 43 065 and 8 971 [3208 and 402 ] higher energy efficiency (throughput-to-area ratio) than the high-end CPU and GPU solutions, respectively.

sBWT: memory efficient implementation of the hardware-acceleration-friendly Schindler transform for the fast biological sequence mapping.

MOTIVATION: The Full-text index in Minute space (FM-index) derived from the Burrows-Wheeler transform (BWT) is broadly used for fast string matching in large genomes or a huge set of sequencing reads. Several graphic processing unit (GPU) accelerated aligners based on the FM-index have been proposed recently; however, the construction of the index is still handled by central processing unit (CPU), only parallelized in data level (e.g. by performing blockwise suffix sorting in GPU), or not scalable for large genomes. RESULTS: To fulfill the need for a more practical, hardware-parallelizable indexing and matching approach, we herein propose sBWT based on a BWT variant (i.e. Schindler transform) that can be built with highly simplified hardware-acceleration-friendly algorithms and still suffices accurate and fast string matching in repetitive references. In our tests, the implementation achieves significant speedups in indexing and searching compared with other BWT-based tools and can be applied to a variety of domains. AVAILABILITY AND IMPLEMENTATION: sBWT is implemented in C ++ with CPU-only and GPU-accelerated versions. sBWT is open-source software and is available at http://jhhung.github.io/sBWT/Supplementary information: Supplementary data are available at Bioinformatics online. CONTACT: chyee@ntu.edu.tw or jhhung@nctu.edu.tw (also juihunghung@gmail.com).

Cancer incidence in patients with schizophrenia or bipolar disorder: a nationwide population-based study in Taiwan, 1997-2009.

BACKGROUND: Both genetic and environmental factors have been reasoned for cancer development in schizophrenia patients. However, the influence of age of onset and duration of schizophrenia on cancer incidence has rarely been emphasized. Besides, bipolar disorder tends to resemble schizophrenia from the perspective of multiple rare mutations. Comparing pattern and risk of cancers between schizophrenia and bipolar patients is illuminating. METHODS: This study used the Taiwan National Health Insurance Database. A total of 71,317 schizophrenia and 20,567 bipolar disorder patients from 1997 to 2009 were enrolled. Both cohorts were followed up for cancer during the same period by record linkage with the cancer certification in Taiwan. Age and gender standardized incidence ratios (SIRs) of overall and site-specific cancers were calculated. RESULTS: The SIR for all cancers was 1.17 for the schizophrenia cohort. Increased cancer risk (SIR: 1.31, 95% CI: 1.17-1.48) was observed in females but not males. For the bipolar disorder cohort, the SIR for all cancers was 1.29, but the excess risk was found in males (SIR: 1.42, 95% CI: 1.14-1.77) and not females. Cancer risk decreases as the duration and age of onset of schizophrenia increases. If schizophrenia is diagnosed before 50, the SIRs for colorectal, breast, cervical, and uterine cancers increase but if diagnosed after 50, the SIRs for all cancers decrease except for breast cancer. In bipolar disorder, the SIRs for all site-specific cancers were insignificant. CONCLUSIONS: Among schizophrenia patients, overall cancer risk varies inversely with age at diagnosis and disease duration. Besides, gender-specific cancer risks differ between schizophrenia and bipolar disorder.

(99m)Tc-TRODAT-1 and (123)I-IBZM SPECT studies in a patient with extrapontine myelinolysis with parkinsonian features.

Osmotic demyelination syndrome can result from the rapid correction of hyponatremia, and is categorized by central pontine myelinolysis and extrapontine myelinolysis (EPM). Magnetic resonance imaging (MRI) is currently the most useful modality for visualizing EPM lesions. However, MRI is unable to delineate the severity of involvement in the nigrostriatal dopaminergic pathway. The authors describe the case of a 48-year-old woman who developed isolated EPM with predominantly right-sided parkinsonian symptoms after rapid correction of hyponatremia. MRI revealed symmetrical demyelinating lesions in the bilateral striatum without central pontine involvement. (99m)Tc-TRODAT-1 and (123)I-iodobenzamide ((123)I-IBZM) single-photon emission computed tomography (SPECT) images showed unequally decreased uptake in the bilateral striatum. Treatment with carbidopa/levodopa improved the clinical parkinsonian symptoms. (99m)T(C)-TRODAT-1 and (123)I-IBZM SPECT images provide presynaptic and postsynaptic molecular information of the nigrostriatal dopaminergic pathway. The lesions demonstrated in the (99m)T(C)-TRODAT-1 and (123)I-IBZM SPECT images show higher correlation with the severity of clinical features in EPM than MRI, and the modalities may be useful in the evaluation of patients with parkinsonian symptoms.