Myelodysplasia-associated mutations in serine/arginine-rich splicing factor SRSF2 lead to alternative splicing of CDC25C

Additional file 2: Figure S1. HA-tagged SRSF2 protein expression in uninduced TF-1 cell lines

Fission Yeast Mitotic Regulator DSK1 is an SR Protein-Specific Kinase

Intricate interplay may exist between pre-mRNA splicing and the cell division cycle, and fission yeast Dsk1 appears to play a role in such a connection. Previous genetic analyses have implicated Dsk1 in the regulation of chromosome segregation at the metaphase/anaphase transition. Yet, its protein sequence suggests that Dsk1 may function as a kinase specific for SR proteins, a family of pre-mRNA splicing factors containing arginine-serine repeats. Using an in vitro system with purified components, we showed that Dsk1 phosphorylated human and yeast SR proteins with high specificity. The Dsk1-phosphorylated SF2/ASF protein was recognized strongly by a monoclonal antibody (mAb104) known to bind the in vivo phosphoepitope shared by SR proteins, indicating that the phosphorylation sites resided in the RS domain. Moreover, the fission yeast U2AF65 homolog, Prp2/Mis11 protein, was phosphorylated more efficiently by Dsk1 than by a human SR protein-specific kinase, SRPK1. Thus, these in vitro results suggest that Dsk1 is a fission yeast SR protein-specific kinase, and Prp2/Mis11 is likely an in vivo target for Dsk1. Together with previous genetic data, the studies support the notion that Dsk1 may play a role in coordinating pre-mRNA splicing and the cell division cycle

Biochemical and Genetic Conservation of Fission Yeast DSK1 and Human SRPK1

Arginine/serine-rich (RS) domain-containing proteins and their phosphorylation by specific protein kinases constitute control circuits to regulate pre-mRNA splicing and coordinate splicing with transcription in mammalian cells. We present here the finding that similar SR networks exist in Schizosaccharomyces pombe. We previously showed that Dsk1 protein, originally described as a mitotic regulator, displays high activity in phosphorylating S. pombe Prp2 protein (spU2AF59), a homologue of human U2AF65. We now demonstrate that Dsk1 also phosphorylates two recently identified fission yeast proteins with RS repeats, Srp1 and Srp2, in vitro. The phosphorylated proteins bear the same phosphoepitope found in mammalian SR proteins. Consistent with its substrate specificity, Dsk1 forms kinase-competent complexes with those proteins. Furthermore, dsk1+ gene determines the phenotype of prp2+ overexpression, providing in vivo evidence that Prp2 is a target for Dsk1. The dsk1-null mutant strain became severely sick with the additional deletion of a related kinase gene. Significantly, human SR protein-specific kinase 1 (SRPK1) complements the growth defect of the double-deletion mutant. In conjunction with the resemblance of dsk1+ and SRPK1 in sequence homology, biochemical properties, and overexpression phenotypes, the complementation result indicates that SRPK1 is a functional homologue of Dsk1. Collectively, our studies illustrate the conserved SR networks in S. pombe consisting of RS domain-containing proteins and SR protein-specific kinases and thus establish the importance of the networks in eucaryotic organisms

Toward Optimal Resource Allocation of Virtualized Network Functions for Hierarchical Datacenters

Telecommunications service providers (TSPs) previously provided network functions to end users with dedicated hardware, but they are resorting to virtualized infrastructure for reducing costs and increasing flexibility in resource allocation. A representative case is the Central Office Re-architected as Datacenter (CORD) project from AT&T, which aims to deploy virtualized network functions (VNFs) to over 4000 central offices (COs) across the U.S. However, there is a wide spectrum of options for deploying VNFs over the COs, varying from highly distributed to highly centralized manners. The former benefits end users with short response time but has its inherent limitation on utilizing geographically dispersed resources, while the latter allows resources to be better utilized at a cost of longer response time. In this work, we model the TSP's virtualized infrastructure as hierarchical datacenters, namely hierarchical CORD, and provide a resource allocation solution to strike the optimal balance between the two extreme options. Our evaluations reveal that in general, the 3-tier architecture incurs the least cost in case of deploying VNFs under moderate or loose delay constraints. Furthermore, the margin of improvement on the resource allocation cost increases inversely with the overall system utilization rate. Our results also suggest that as heavy request load overwhelms the network infrastructure, the relevant VNFs shall be migrated to lower-tier edge datacenters or to some nearby datacenters with superior network capacity. The evaluations also demonstrate that the proposed model allows highly adaptive VNF deployment in the hierarchical architecture under various conditions.This work was supported in part by H2020 Collaborative Europe/Taiwan Research Project 5G-CORAL under Grant 761586, and in part by the Ministry of Science and Technology, Taiwan, under Grant MOST-106-2218-E-009-018 and Grant MOST-106-2221-E-194-021-MY3

TEL/AML1 Fusion Gene in Childhood Acute Lymphoblastic Leukemia in Southern Taiwan

Chromosomal abnormalities are found in 80–90% of childhood cases of acute lymphoblastic leukemia (ALL). Leukemia-specific chromosome aberrations not only have prognostic value, but also provide important clues for further investigation into leukogenesis, leukemic cell transformation, and proliferation. This study used reverse transcriptase–polymerase chain reaction techniques to detect transcripts of the leukemia-specific chromosome fusion gene, TEL/AML1, and to monitor the expression levels of the TEL-AML1 fusion transcript in ALL patients at sequential intervals during their treatment course. Twenty-five ALL patients were enrolled, including 20 who were newly diagnosed and five in relapse. The incidence of the TEL/AML1 fusion gene in this study was 32%. The clinical features of our eight TEL/AML1-positive ALL cases were similar to those in other studies. Blotting analysis of the levels of the TEL-AML1 fusion transcript was used to detect minimal residual disease. Reduced levels of TEL/AML1 expression were found in four of the six patients whose bone marrow or peripheral blood samples were obtained after treatment. Further investigation with a larger sample size is warranted

Inference-Time Policy Adapters (IPA): Tailoring Extreme-Scale LMs without Fine-tuning

Large language models excel at a variety of language tasks when prompted with examples or instructions. Yet controlling these models through prompting alone is limited. Tailoring language models through fine-tuning (e.g., via reinforcement learning) can be effective, but it is expensive and requires model access. We propose Inference-time Policy Adapters (IPA), which efficiently tailors a language model such as GPT-3 without fine-tuning it. IPA guides a large base model during decoding time through a lightweight policy adaptor trained to optimize an arbitrary user objective with reinforcement learning. On five challenging text generation tasks, such as toxicity reduction and open-domain generation, IPA consistently brings significant improvements over off-the-shelf language models. It outperforms competitive baseline methods, sometimes even including expensive fine-tuning. In particular, tailoring GPT-2 with IPA can outperform GPT-3, while tailoring GPT- 3 with IPA brings a major performance boost over GPT-3 (and sometimes even over GPT-4). Our promising results highlight the potential of IPA as a lightweight alternative to tailoring extreme-scale language models

Molecular Characteristics and Antimicrobial Resistance of Group B Streptococcus Strains Causing Invasive Disease in Neonates and Adults

We aimed to analyze the molecular characteristics, clonality and antimicrobial resistance profiles of group B streptococcus (GBS) isolates collected in Taiwan from invasive diseases and carriage. Multilocus sequence typing (MLST) was used to assess the genetic diversity of 225 GBS strains from neonates and adults with invasive GBS diseases. 100 GBS strains collected from colonized pregnant women during the same period were compared, and all strains were characterized for one of nine capsule genotypes. We also determined the susceptibilities of all GBS isolates to various antimicrobial agents. The most frequently identified serotypes that caused invasive disease in neonates were III (60.6%) and Ia (17.3%), whereas type VI (32.7%), Ib (19.4%), and V (19.4%) were the most common to cause invasive disease in adults. Serotype VI was the leading type that colonized pregnant women (35.0%). Twenty-six sequence types (STs) were identified, and 90.5% of GBS strains were represented by 6 STs. ST-17 and ST-1 were more prevalent in invasive diseases in neonates and adults, respectively. The majority of serotype III and VI isolates belonged to clonal complex (CC)-17 and CC-1, respectively. ST-17 strains were more likely to cause meningitis and late-onset disease than other strains. In addition, ST-12 and ST-17 GBS strains showed the highest rate of resistance to erythromycin and clindamycin (range: 75.8–100%). In conclusion, CC-17/type III and CC-1/type VI are the most important invasive pathogens in infants and non-pregnant adults in Taiwan, respectively. GBS genotypes vary between different age groups and geographical areas and should be considered during GBS vaccine development

Development of biomaterial surfaces with and without microbial nanosegments

Infections by microorganisms are a major problem in public health throughout the world. Artificial materials, including biomedical goods, inherently lack defense against microbial development. Therefore, microbial cells can adhere on any type of artificial surface, particularly in a moist environment, and start to multiply to form a huge population. In this review, we will discuss a strategy for designing antimicrobial polymers and antimicrobial surfaces. Generally, there are five types of antimicrobial polymers: (a) polymeric biocides, (b) biocidal polymers, (c) biocide-releasing polymers, (d) bioactive oligopeptides, and (e) antimicrobial surfaces. Antimicrobial surfaces preventing the growth of microorganisms are a promising method to inhibit the spread of microbial infections. The antimicrobial surfaces can reject the attachment of microbes and/or kill microbes in the vicinity and can be designed to kill microbes on contact. It is recommended that the material surface not release biocidal substances, therefore preventing exhaustion of biocide release to kill microbes. Furthermore, the antimicrobial surfaces are desired to be nontoxic to human cells. The development of contact-active antimicrobial surfaces by grafting antimicrobial nanosegments onto the material surface will be an important topic in the future

Nanometer Sized Silver Particles Embedded Silica Particles—Spray Method

Spherical shaped, nanometer to micro meter sized silica particles were prepared in a homogeneous nature by spray technique. Silver nanoparticles were produced over the surface of the silica grains in a harmonized manner. The size of silver and silica particles was effectively controlled by the precursors and catalysts. The electrostatic repulsion among the silica spheres and the electro static attraction between silica spheres and silver particles make the synchronized structure of the synthesized particles and the morphological images are revealed by transmission electron microscope. The silver ions are reduced by sodium borohydride. Infra red spectroscopy and X-ray photoelectron spectroscopy analysis confirm the formation of silver–silica composite particles. Thermal stability of the prepared particles obtained from thermal analysis ensures its higher temperature applications. The resultant silver embedded silica particles can be easily suspended in diverse solvents and would be useful for variety of applications