Small sized EGFR1 and HER2 specific bifunctional antibody for targeted cancer therapy

licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Received: 2014.07.10; Accepted: 2015.01.05; Published: 2015.01.21 Targeting tumors using miniature antibodies is a novel and attractive therapeutic approach, as these biomolecules exhibit low immunogenicity, rapid clearance, and high targeting specificity. However, most of the small-sized antibodies in existence do not exhibit marked anti-tumor ef-fects, which limit their use in targeted cancer immunotherapy. To overcome this difficulty in targeting multiple biomarkers by combination therapies, we designed a new bifunctional antibody, named MaAbNA (multivalent antibody comprised of nanobody and affibody moieties), capable of targeting EGFR1 and HER2, which are widely overexpressed in a variety of tumor types. The small-sized (29 kDa) MaAbNA, which was expressed in E.coli, consists of one anti-EGFR1 nano-body and two anti-HER2 affibodies, and possesses high affinity (KD) for EGFR1 (~4.1 nM) and HER2 (~4.7 nM). In order to enhance its anti-tumor activity, MaAbNA was conjugated with adriamycin (ADM) using a PEG2000 linker, forming a new complex anticancer drug, MaAbNA-PEG2000-ADM. MaAbNA exhibited high inhibitory effects on tumor cell

Multi-Grained Named Entity Recognition

This paper presents a novel framework, MGNER, for Multi-Grained Named Entity Recognition where multiple entities or entity mentions in a sentence could be non-overlapping or totally nested. Different from traditional approaches regarding NER as a sequential labeling task and annotate entities consecutively, MGNER detects and recognizes entities on multiple granularities: it is able to recognize named entities without explicitly assuming non-overlapping or totally nested structures. MGNER consists of a Detector that examines all possible word segments and a Classifier that categorizes entities. In addition, contextual information and a self-attention mechanism are utilized throughout the framework to improve the NER performance. Experimental results show that MGNER outperforms current state-of-the-art baselines up to 4.4% in terms of the F1 score among nested/non-overlapping NER tasks.Comment: In ACL 2019 as a long pape

Digital twin brain: a bridge between biological intelligence and artificial intelligence

In recent years, advances in neuroscience and artificial intelligence have paved the way for unprecedented opportunities for understanding the complexity of the brain and its emulation by computational systems. Cutting-edge advancements in neuroscience research have revealed the intricate relationship between brain structure and function, while the success of artificial neural networks highlights the importance of network architecture. Now is the time to bring them together to better unravel how intelligence emerges from the brain's multiscale repositories. In this review, we propose the Digital Twin Brain (DTB) as a transformative platform that bridges the gap between biological and artificial intelligence. It consists of three core elements: the brain structure that is fundamental to the twinning process, bottom-layer models to generate brain functions, and its wide spectrum of applications. Crucially, brain atlases provide a vital constraint, preserving the brain's network organization within the DTB. Furthermore, we highlight open questions that invite joint efforts from interdisciplinary fields and emphasize the far-reaching implications of the DTB. The DTB can offer unprecedented insights into the emergence of intelligence and neurological disorders, which holds tremendous promise for advancing our understanding of both biological and artificial intelligence, and ultimately propelling the development of artificial general intelligence and facilitating precision mental healthcare

Coronary Artery Calcium and Cognitive Function in Dutch Adults:Cross-Sectional Results of the Population-Based ImaLife Study

Background The aim of this study was to investigate whether increased severity of coronary artery calcium (CAC), an imaging biomarker of subclinical coronary atherosclerosis, is associated with worse cognitive function independent of cardiovascular risk factors in a large population-based Dutch cohort with broad age range. Methods and Results A cross-sectional analysis was performed in 4988 ImaLife participants (aged 45-91 years, 58.3% women) without history of cardiovascular disease. CAC scores were obtained using nonenhanced cardiac computed tomography scanning. The CogState Brief Battery was used to assess 4 cognitive domains: processing speed, attention, working memory, and visual learning based on detection task, identification task, 1-back task, and 1-card-learning task, respectively. Differences in mean scores of each cognitive domain were compared among 4 CAC categories (0, 1-99, 100-399, >= 400) using analysis of covariates to adjust for classical cardiovascular risk factors. Age-stratified analysis (45-54, 55-64, and >= 65 years) was performed to assess whether the association of CAC severity with cognitive function differed by age. Overall, higher CAC was associated with worse performance on 1-back task after adjusting for classical cardiovascular risk factors, but CAC was not associated with the other cognitive tasks. Age-stratified analyses revealed that the association of CAC severity with working memory persisted in participants aged 45 to 54 years, while in the elderly this association lost significance. Conclusions In this Dutch population of >= 45 years, increased CAC severity was associated with worse performance of working memory, independent of classical cardiovascular risk factors. The inverse relationship of CAC score categories with working memory was strongest in participants aged 45 to 54 years

Problematika Penyelesaian Sengketa Kewenangan Lembaga Negara Oleh Mahkamah Konstitusi

According to Article 24C verse (1) of the 1945 Constitution, Constitutional court has an authority to examine the dispute among the state institution in which its authority is given by the constitution directly. But there is a certain problem in practice which is related to definition of “state institution” and “authorities are granted the Constitution” in the 1945 Constitution. This condition opens a debate the interpretation in executing the settlement on authority dispute among the institutions. In addition, should be considered the settlement of disputes the authority of institutions, whose authority derived from regulation other than the Constitution Menurut ketentuan Pasal 24C ayat (1) UUD NRI Tahun 1945, penyelesaian sengketa kewenangan lembaga negara yang kewenangannya diberikan oleh UUD merupakan kewenangan Mahkamah Konstitusi. Namun dalam praktiknya, proses penyelesaian sengketa kewenangan lembaga negara menghadapi problem tersendiri seiring tidak adanya batasan ruang lingkup dan definisi “lembaga negara” dan frasa “kewenangannya diberikan UUD” secara pasti dalam UUD NRI Tahun 1945. Situasi ini pada akhirnya menimbulkan multitafsir yang berpotensi mengakibatkan tidak efektifnya penyelesaian sengketa kewenangan lembaga negara di Indonesia. Selain itu, perlu dipikirkan mekanisme penyelesaian sengketa kewenangan lembaga yang kewenangannya bersumber dari peraturan selain UUD

I13 overrides resistance mediated by the T315I mutation in chronic myeloid leukemia by direct BCR-ABL inhibition

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by a BCR-ABL fusion gene. Imatinib has significantly improved the treatment of CML as a first-generation tyrosine kinase inhibitor (TKIs). The T315I mutant form of BCR-ABL is the most common mutation that confers resistance to imatinib or the second-generation TKIs, resulting in poor clinical prognosis. In this work, we assessed the effect of a potent histone deacetylase (HDAC) inhibitor, I13, on the differentiation blockade in CML cells harboring T315I-mutated and wild-type BCR-ABL by MTT assay, flow cytometery, cell colony formation assay, mRNA Sequencing, Quantitative real-time PCR and Western blotting analysis. We found that I13 possessed highly potent activity against T315I-mutated BCR-ABL mutant-expressing cells and wild-type BCR-ABL-expressing cells. I13 induced cell differentiation and significantly suppressed the proliferation of these CML cells via the cell cycle G0/G1-phase accumulation. Moreover, it was revealed that I13 triggered the differentiation of BaF3-T315I cells, which was attributed to the block of the chronic myeloid leukemia signaling pathway via the depletion of BCR-ABL that was mediated by the inhibition of HDAC activity presented by the acetylation of histones H3 and H4. Taken together, I13 efficiently depleted BCR-ABL in CML cells expressing the BCR-ABL-T315I mutation, which blocked its function, serving as a scaffold protein that modulated the chronic myeloid leukemia signaling pathway mediating cell differentiation. The present findings demonstrate that I13 is a BCR-ABL modulator for the development of CML therapy that can override resistance caused by T315I-mutated BCR-ABL

ABO genotype alters the gut microbiota by regulating GalNAc levels in pigs.

peer reviewedThe composition of the intestinal microbiome varies considerably between individuals and is correlated with health1. Understanding to what extend and how host genetics contributes to this variation is paramount yet has proven difficult as few associations have been replicated, particularly in humans2. We herein study the effect of host genotype on the composition of the intestinal microbiota in a large mosaic pig population. We show that, under conditions of exacerbated genetic diversity and environmental uniformity, microbiota composition and abundance of specific taxa are heritable. We map a quantitative trait locus affecting the abundance of Erysipelotrichaceae species and show that it is caused by a 2.3-Kb deletion in the N-acetyl-galactosaminyl-transferase gene underpinning the ABO blood group in humans. We show that this deletion is a ≥3.5 million years old trans-species polymorphism under balancing selection. We demonstrate that it decreases the concentrations of N-acetyl-galactosamine in the gut thereby reducing the abundance of Erysipelotrichaceae that can import and catabolize N-acetyl-galactosamine. Our results provide very strong evidence for an effect of host genotype on the abundance of specific bacteria in the intestine combined with insights in the molecular mechanisms that underpin this association. They pave the way towards identifying the same effect in human rural populations

A global view of porcine transcriptome in three tissues from a full-sib pair with extreme phenotypes in growth and fat deposition by paired-end RNA sequencing

<p>Abstract</p> <p>Background</p> <p>Elucidation of the pig transcriptome is essential for interpreting functional elements of the genome and understanding the genetic architecture of complex traits such as fat deposition, metabolism and growth.</p> <p>Results</p> <p>Here we used massive parallel high-throughput RNA sequencing to generate a high-resolution map of the porcine mRNA and miRNA transcriptome in liver, longissimus dorsi and abdominal fat from two full-sib F₂hybrid pigs with segregated phenotypes on growth, blood physiological and biochemical parameters, and fat deposition. We obtained 8,508,418-10,219,332 uniquely mapped reads that covered 78.0% of the current annotated transcripts and identified 48,045-122,931 novel transcript fragments, which constituted 17,085-29,499 novel transcriptional active regions in six tested samples. We found that about 18.8% of the annotated genes showed alternative splicing patterns, and alternative 3' splicing is the most common type of alternative splicing events in pigs. Cross-tissue comparison revealed that many transcriptional events are tissue-differential and related to important biological functions in their corresponding tissues. We also detected a total of 164 potential novel miRNAs, most of which were tissue-specifically identified. Integrated analysis of genome-wide association study and differential gene expression revealed interesting candidate genes for complex traits, such as <it>IGF2, CYP1A1, CKM </it>and <it>CES1 </it>for heart weight, hemoglobin, pork pH value and serum cholesterol, respectively.</p> <p>Conclusions</p> <p>This study provides a global view of the complexity of the pig transcriptome, and gives an extensive new knowledge about alternative splicing, gene boundaries and miRNAs in pigs. Integrated analysis of genome wide association study and differential gene expression allows us to find important candidate genes for porcine complex traits.</p

Accurate Analysis of Multi-Mode Interferometric Optical Fiber Sensor

Abstract In view of the problem that the sensing characteristics of the multi-mode interferometric fiber sensors cannot be accurately analyzed, an analysis method based on the fast Fourier transform (FFT) and inverse fast Fourier transform (IFFT) is proposed and demonstrated theoretically and experimentally. The suitabilities of the rectangular window function with the narrow main lobe (high spectrum resolution) and low side lobe (high main mode energy leakage) and the Hanning window function with the wide main lobe (low spectrum resolution) and high side lobe (high energy concentration) in this kind of sensor analysis are discussed, respectively. This method can not only realize the sensing performance analysis of the various modes, but also overcome the inconsistency of the different interference wavelength (dip) sensing characteristics in the conventional analysis methods. At the same time, this method is also beneficial to solve the repetitive problem of such sensors