A 4th Order CIFB High Dynamic Range Sigma-Delta Modulator with Multi-level Quantizer and Intrinsically Linear Capacitive DACs

The linearity of the digital-to-analog converter (DAC) is a key bottleneck for high-resolution Sigma-Delta modulators that use multi-level quantizers. To address the DAC non-linearities caused by element mismatches and achieve a high signal-to-noise-and-distortion ratio (SNDR), this work exploits intrinsically linear capacitive DACs to improve the design of a high-resolution Sigma-Delta modulator with 4 th-order, discrete-time architecture realized as a Cascade of Integrators with Feed Back (CIFB), and 3-level/5-level quantizers. The error due to capacitive element mismatch is mitigated by using an extra reference voltage and reconfiguring DAC topologies so that distortions brought by capacitor mismatches are largely reduced. We demonstrate in simulation results that a 128.9 dB modulator SNDR can be obtained in the presence of up to 1% DAC capacitance mismatch combined with 2% reference voltage variation, achieving 60 dB SNDR improvement compared with a design with a conventional DAC structure.</p

Bioactive conformational generation of small molecules: A comparative analysis between force-field and multiple empirical criteria based methods

<p>Abstract</p> <p>Background</p> <p>Conformational sampling for small molecules plays an essential role in drug discovery research pipeline. Based on multi-objective evolution algorithm (MOEA), we have developed a conformational generation method called Cyndi in the previous study. In this work, in addition to Tripos force field in the previous version, Cyndi was updated by incorporation of MMFF94 force field to assess the conformational energy more rationally. With two force fields against a larger dataset of 742 bioactive conformations of small ligands extracted from PDB, a comparative analysis was performed between pure force field based method (FFBM) and multiple empirical criteria based method (MECBM) hybrided with different force fields.</p> <p>Results</p> <p>Our analysis reveals that incorporating multiple empirical rules can significantly improve the accuracy of conformational generation. MECBM, which takes both empirical and force field criteria as the objective functions, can reproduce about 54% (within 1Å RMSD) of the bioactive conformations in the 742-molecule testset, much higher than that of pure force field method (FFBM, about 37%). On the other hand, MECBM achieved a more complete and efficient sampling of the conformational space because the average size of unique conformations ensemble per molecule is about 6 times larger than that of FFBM, while the time scale for conformational generation is nearly the same as FFBM. Furthermore, as a complementary comparison study between the methods with and without empirical biases, we also tested the performance of the three conformational generation methods in MacroModel in combination with different force fields. Compared with the methods in MacroModel, MECBM is more competitive in retrieving the bioactive conformations in light of accuracy but has much lower computational cost.</p> <p>Conclusions</p> <p>By incorporating different energy terms with several empirical criteria, the MECBM method can produce more reasonable conformational ensemble with high accuracy but approximately the same computational cost in comparison with FFBM method. Our analysis also reveals that the performance of conformational generation is irrelevant to the types of force field adopted in characterization of conformational accessibility. Moreover, post energy minimization is not necessary and may even undermine the diversity of conformational ensemble. All the results guide us to explore more empirical criteria like geometric restraints during the conformational process, which may improve the performance of conformational generation in combination with energetic accessibility, regardless of force field types adopted.</p

UniBrain: Universal Brain MRI Diagnosis with Hierarchical Knowledge-enhanced Pre-training

Magnetic resonance imaging~(MRI) have played a crucial role in brain disease diagnosis, with which a range of computer-aided artificial intelligence methods have been proposed. However, the early explorations usually focus on the limited types of brain diseases in one study and train the model on the data in a small scale, yielding the bottleneck of generalization. Towards a more effective and scalable paradigm, we propose a hierarchical knowledge-enhanced pre-training framework for the universal brain MRI diagnosis, termed as UniBrain. Specifically, UniBrain leverages a large-scale dataset of 24,770 imaging-report pairs from routine diagnostics. Different from previous pre-training techniques for the unitary vision or textual feature, or with the brute-force alignment between vision and language information, we leverage the unique characteristic of report information in different granularity to build a hierarchical alignment mechanism, which strengthens the efficiency in feature learning. Our UniBrain is validated on three real world datasets with severe class imbalance and the public BraTS2019 dataset. It not only consistently outperforms all state-of-the-art diagnostic methods by a large margin and provides a superior grounding performance but also shows comparable performance compared to expert radiologists on certain disease types

Symmetry selective cladding modes coupling in ultrafast-written fiber Bragg gratings in two-mode fiber

The lower order cladding mode resonances of a fiber Bragg grating (FBG) are sensitive to fiber bending but their spectral density makes their response to bending very complex. In this work we present a simple method to reduce and control the number of low order cladding mode resonances via FBGs written in a two-mode fiber (TMF) with an ultrafast laser. Owing to the larger core size of the TMF, a slight break of the cylindrical asymmetry of the grating patterns can be induced when using femtosecond side-irradiation with a small change in the writing condition. This allows us to control the mode families coupled by the grating, and in particular to those modes that have positive or negative bending responses along certain bend directions. Experimental results demonstrate that several lower-order neighboring-cladding mode pairs coupled by the asymmetric TMFBG have antagonistic loss responses (by several dB) for different bending directions, thus allowing full 2D bending measurements with many applications in shape sensing. Finally, this device has similar advantages as tilted FBGs, i.e. temperature de-correlation and the possibility of increasing the signal to noise ratio by averaging simultaneous measurements on several pairs of resonances

Transcriptomic analysis reveals novel hub genes associated with astrocyte autophagy in intracerebral hemorrhage

IntroductionNeuroinflammation serves as a critical local defense mechanism against secondary brain injury following intracerebral hemorrhage (ICH), and astrocytes play a prominent role in this process. In this study, we investigated astrocytic changes during the inflammatory state after ICH to identify new targets for improving the inflammatory response.MethodsWe stimulated mouse astrocytes with lipopolysaccharide (LPS) in vitro and analyzed their transcriptomes via ribonucleic acid sequencing. We created an ICH model in living organisms by injecting autologous blood.ResultsRNA sequencing revealed that 2,717 genes were differentially expressed in the LPS group compared to those in the saline group, with notable enrichment of the autophagic pathway. By intersecting the 2,717 differentially expressed genes (DEGs) with autophagy-related genes, we identified 36 autophagy-related DEGs and seven hub genes. Previous studies and quantitative reverse transcription-polymerase chain reaction results confirmed the increased expression of phosphatidylinositol 3-kinase catalytic subunit type 3 (Pik3c3), AKT serine/threonine kinase 1 (Akt1), and unc-51 like autophagy activating kinase 2 (Ulk2) in astrocytes after ICH. Transcription factors and target miRNAs were identified for the final three DEGs, and 3-methyladenine and leupeptin were identified as potential therapeutic agents for ICH.ConclusionOur findings suggest that astrocyte autophagy plays a critical role in ICH complexity, and that Pik3c3, Akt1, and Ulk2 may be potential therapeutic targets

Photocatalytic removal of antibiotics from natural water matrices and swine wastewater via Cu(I) coordinately polymeric carbon nitride framework

The overuse of refractory antibiotics in animal husbandry has caused serious aqueous environment pollution. Polymeric carbon nitride (CN) based photocatalysis, a promising method to address antibiotic pollution issues, has encountered with restricted efficiency because of the sluggish charge transfer and unexploited water matrices influence. In this study, an efficient metal to ligand charge transfer (MLCT) was successfully implanted into the Cu(I) coordinately polymeric carbon nitride framework (Cu-CNF) via the bonds of coordinated Cu(I) with organic N and few inorganic O atoms. The Cu-CNF photocatalysts were endowed with high-efficient chlortetracycline hydrochloride (CTC-HCl) removal in deionized water. To insure the feasibility of the Cu-CNF in antibiotics removal from different water matrices, a systematical exploration covering the reaction kinetics, the physicochemical stability, and the influence of specific water matrices on CTC-HCl removal was carried out by various ways. Results showed that the photo-induced MLCT route with shorter transfer distance was able to broaden light absorption of CN in the whole visible region, contributing to more available excitons and accelerating separation of the photoexcited electron-hole pairs. The boosted active oxidative species (h+, O2− and ∙OH) in porous Cu-CNF were found to promote the dechlorination and benzene ring cleavage process to favor the final mineralization of CTC-HCl molecules. Under the synergistic influence of water constituents, the removal efficiency of CTC-HCl was highest in river water (68.2%), followed by tap water (45.7%), and swine wastewater (33.1%). It was found that the existence of the high concentration NOx-N and NH3-N in the swine wastewater were responsible for the collapsed removal efficiency of CTC-HCl. Natural organic matter in river water and tap water was the main factor for the decreased CTC-HCl removal efficiency.The authors gratefully acknowledge the financial support provided by the Projects of the National Nature Science Foundation of China (No. 51708195、21776066、51521006、51739004)

Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy

Abstract Purpose Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. Methods We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. Results Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. Conclusion Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future

Nesfatin-1 decreases excitability of dopaminergic neurons in the substantia nigra

Nesfatin-1, a newly discovered satiety molecule which reduces feeding behavior, has been recognized as a unique regulatory neuropeptide with its multiple roles, both central and peripheral. However, whether it had neuronal modulation effect on dopaminergic neurons is largely unknown. In the present study, using whole-cell patch clamp under current-clamp mode, we investigate the effects of nesfatin-1 on the electrical activity of rat nigral dopaminergic neurons. Nesfatin-1 could produce a resting membrane potential hyperpolarization on the majority of dopaminergic neurons tested. The spike frequency decreased by 23.13 ± 5.93 and 43.20 ± 5.56 % in 5-nM and 10-nM nesfatin-1 groups, respectively. These effects persisted in the presence of ionotropic glutamate and GABA receptor antagonists. Our study suggests that nesfatin-1 postsynaptically inhibits the electrical activity of nigral dopaminergic neurons.status: publishe

Efficient delivery of a large-size Cas9-EGFP vector in porcine fetal fibroblasts using a Lonza 4D-Nucleofector system

Abstract Background Porcine fetal fibroblasts (PFFs) are important donor cells for generating genetically modified pigs, but the transfection efficiencies of PFFs are often unsatisfactory especially when large-size vectors are to be delivered. In this study, we aimed to optimize the transfection conditions for delivery of a large-size vector in PFFs using Lonza 4D-Nucleofector™ vessels and strips. Methods We firstly delivered a 13 kb Cas9-EGFP and a 3.5 kb pMAX-GFP vector into PFFs via 7 programs recommended by the Lonza basic protocol. We then tested 6 customized dual-electroporation programs for delivering the 13 kb plasmid into PFFs. In addition, we screened potential alternative electroporation buffers to the Nucleofector™ P3 solution. Finally, three CRISPR/Cas9-sgRNAs targeting Rosa26, H11, and Cep112 loci were delivered into PFFs with different single and dual-electroporation programs. Results Notably lower transfection efficiencies were observed when delivering the 13 kb vector than delivering the 3.5 kb vector in PFFs via the single-electroporation programs. The customized dual-electroporation program FF-113 + CA-137 exhibited higher transfection efficiencies than any of the single-electroporation programs using vessels (98.1%) or strips (89.1%) with acceptable survival rates for the 13 kb vector. Entranster-E buffer generated similar transfection efficiencies and 24-hour survival rates to those from the P3 solution, thus can be used as an alternative electroporation buffer. In the genome-editing experiments, the FF-113 + CA-137 and CA-137 + CA-137 programs showed significantly superior (P < 0.01) efficiencies to ones from the single-electroporation programs in vessels and strips. Entranster-E buffer produced higher indel efficiencies than the P3 buffer. Conclusions We markedly increased the delivery efficiencies for a large vector via customized dual-electroporation programs using Lonza 4D-Nucleofector™ system, and Entranster-E buffer can be used as an alternative electroporation buffer to Nucleofector™ P3 buffer