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Bacteria belonging to Streptomyces have the ability to produce a wide range of secondary metabolites through a shift from primary to secondary metabolism regulated by complex networks activated after vegetative growth terminates. Despite considerable effort to understand the regulatory elements governing gene expression related to primary and secondary metabolism in Streptomyces, system-level information remains limited. In this study, we integrated four multi-omics datasets from Streptomyces griseus NBRC 13350: RNA-seq, ribosome profiling, dRNA-seq, and Term-Seq, to analyze the regulatory elements of transcription and translation of differentially expressed genes during cell growth. With the functional enrichment of gene expression in different growth phases, one sigma factor regulon and four transcription factor regulons governing differential gene transcription patterns were found. In addition, the regulatory elements of transcription termination and post-transcriptional processing at transcript 3′-end positions were elucidated, including their conserved motifs, stem-loop RNA structures, and non-terminal locations within the polycistronic operons, and the potential regulatory elements of translation initiation and elongation such as 5′-UTR length, RNA structures at ribosome-bound sites, and codon usage were investigated. This comprehensive genetic information provides a foundational genetic resource for strain engineering to enhance secondary metabolite production in Streptomyces.

Actinomycetes are a rich source of bioactive natural products important for novel drug leads. Recent genome mining approaches have revealed an enormous number of secondary metabolite biosynthetic gene clusters (smBGCs) in actinomycetes. However, under standard laboratory culture conditions, many smBGCs are silent or cryptic. To activate these dormant smBGCs, several approaches, including culture-based or genetic engineering-based strategies, have been developed. Above all, coculture is a promising approach to induce novel secondary metabolite production from actinomycetes by mimicking an ecological habitat where cryptic smBGCs may be activated. In this review, we introduce coculture studies that aim to expand the chemical diversity of actinomycetes, by categorizing the cases by the type of coculture partner. Furthermore, we discuss the current challenges that need to be overcome to support the elicitation of novel bioactive compounds from actinomycetes.

Streptomyces species have attracted considerable interest as a reservoir of medically important secondary metabolites, which are even diverse and different between strains. Here, we reassess ten Streptomyces venezuelae strains by presenting the highly resolved classification, using 16S rRNA sequencing, MALDI-TOF MS protein profiling, and whole-genome sequencing. The results revealed that seven of the ten strains were misclassified as S. venezuelae species. Secondary metabolite biosynthetic gene cluster (smBGC) mining and targeted LC-MS/MS based metabolite screening of S. venezuelae and misclassified strains identified in total 59 secondary metabolites production. In addition, a comparison of pyrrolamide-type antibiotic BGCs of four misclassified strains, followed by functional genomics, revealed that athv28 is critical in the synthesis of the anthelvencin precursor, 5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate (ADPC). Our findings illustrate the importance of the accurate classification and better utilization of misclassified Streptomyces strains to discover smBGCs and their secondary metabolite products.

Heterologous production of recombinant proteins is gaining increasing interest in biotechnology with respect to productivity, scalability, and wide applicability. The members of genus Streptomyces have been proposed as remarkable hosts for heterologous production due to their versatile nature of expressing various secondary metabolite biosynthetic gene clusters and secretory enzymes. However, there are several issues that limit their use, including low yield, difficulty in genetic manipulation, and their complex cellular features. In this review, we summarize rational engineering approaches to optimizing the heterologous production of secondary metabolites and recombinant proteins in Streptomyces species in terms of genetic tool development and chassis construction. Further perspectives on the development of optimal Streptomyces chassis by the design-build-test-learn cycle in systems are suggested, which may increase the availability of secondary metabolites and recombinant proteins.

Covering: 2010 to 2020Over the last few decades, Streptomyces have been extensively investigated for their ability to produce diverse bioactive secondary metabolites. Recent advances in Streptomyces research have been largely supported by improvements in high-throughput technology 'omics'. From genomics, numerous secondary metabolite biosynthetic gene clusters were predicted, increasing their genomic potential for novel bioactive compound discovery. Additional omics, including transcriptomics, translatomics, interactomics, proteomics and metabolomics, have been applied to obtain a system-level understanding spanning entire bioprocesses of Streptomyces, revealing highly interconnected and multi-layered regulatory networks for secondary metabolism. The comprehensive understanding derived from this systematic information accelerates the rational engineering of Streptomyces to enhance secondary metabolite production, integrated with the exploitation of the highly efficient 'Design-Build-Test-Learn' cycle in synthetic biology. In this review, we describe the current status of omics applications in Streptomyces research to better understand the organism and exploit its genetic potential for higher production of valuable secondary metabolites and novel secondary metabolite discovery.

Pneumatically operated soft growing robots that extend via tip eversion are well-suited for navigation in confined spaces. Adding the ability to interact with the environment using sensors and tools attached to the robot tip would greatly enhance the usefulness of these robots for exploration in the field. However, because the material at the tip of the robot body continually changes as the robot grows and retracts, it is challenging to keep sensors and tools attached to the robot tip during actuation and environment interaction. In this paper, we analyze previous designs for mounting to the tip of soft growing robots, and we present a novel device that successfully remains attached to the robot tip while providing a mounting point for sensors and tools. Our tip mount incorporates and builds on our previous work on a device to retract the robot without undesired buckling of its body. Using our tip mount, we demonstrate two new soft growing robot capabilities: (1) pulling on the environment while retracting, and (2) retrieving and delivering objects. Finally, we discuss the limitations of our design and opportunities for improvement in future soft growing robot tip mounts., Comment: Video available at https://youtu.be/eBKRbu_LSYA

Biomaterials derived via programmable supramolecular protein assembly provide a viable means of constructing precisely defined structures. Here, we present programmed superstructures of AuPt nanoparticles (NPs) on carbon nanotubes (CNTs) that exhibit distinct electrocatalytic activities with respect to the nanoparticle positions via rationally modulated peptide-mediated assembly. De novo designed peptides assemble into six-helix bundles along the CNT axis to form a suprahelical structure. Surface cysteine residues of the peptides create AuPt-specific nucleation site, which allow for precise positioning of NPs onto helical geometries, as confirmed by 3-D reconstruction using electron tomography. The electrocatalytic model system, i.e., AuPt for oxygen reduction, yields electrochemical response signals that reflect the controlled arrangement of NPs in the intended assemblies. Our design approach can be expanded to versatile fields to build sophisticated functional assemblies. Keywords: supramolecular protein self-assembly; artificialy designed peptide; nanoparticle superstructure; electron tomography; peptide-based superstructure 3-D reconstruction; peptide-based catalyst; electrocatalytic oxygen reduction, National Research Foundation (U.S.) (NRF-2017M3D9A1073858), Korea. Institute of Basic Sciences (Grant IBS-R015-D1), Han'guk Kwahak Kisul Yŏn'guso. Institutional Program

Recommending personalized learning materials for online language learning is challenging because we typically lack data about the student's ability and the relative difficulty of learning materials. This makes it hard to recommend appropriate content that matches the student's prior knowledge. In this paper, we propose a refined hierarchical knowledge structure to model vocabulary knowledge, which enables us to automatically organize the authentic and up-to-date learning materials collected from the internet. Based on this knowledge structure, we then introduce a hybrid approach to recommend learning materials that adapts to a student's language level. We evaluate our work with an online Japanese learning tool and the results suggest adding adaptivity into material recommendation significantly increases student engagement., Comment: The short version of this paper is published at AIED 2019

Biomaterials derived via programmable supramolecular protein assembly provide a viable means of constructing precisely defined structures. Here, we present programmed superstructures of AuPt nanoparticles (NPs) on carbon nanotubes (CNTs) that exhibit distinct electrocatalytic activities with respect to the nanoparticle positions via rationally modulated peptide-mediated assembly. De novo designed peptides assemble into six-helix bundles along the CNT axis to form a suprahelical structure. Surface cysteine residues of the peptides create AuPt-specific nucleation site, which allow for precise positioning of NPs onto helical geometries, as confirmed by 3-D reconstruction using electron tomography. The electrocatalytic model system, i.e., AuPt for oxygen reduction, yields electrochemical response signals that reflect the controlled arrangement of NPs in the intended assemblies. Our design approach can be expanded to versatile fields to build sophisticated functional assemblies.

In spite of remarkable progress in machine learning techniques, the state-of-the-art machine learning algorithms often keep machines from real-time learning (online learning) due in part to computational complexity in parameter optimization. As an alternative, a learning algorithm to train a memory in real time is proposed, which is named as the Markov chain Hebbian learning algorithm. The algorithm pursues efficient memory use during training in that (i) the weight matrix has ternary elements (-1, 0, 1) and (ii) each update follows a Markov chain--the upcoming update does not need past weight memory. The algorithm was verified by two proof-of-concept tasks (handwritten digit recognition and multiplication table memorization) in which numbers were taken as symbols. Particularly, the latter bases multiplication arithmetic on memory, which may be analogous to humans' mental arithmetic. The memory-based multiplication arithmetic feasibly offers the basis of factorization, supporting novel insight into the arithmetic., Comment: 25 pages, 4 figures

The static power consumption became one of the key limiting factors on the shrinkage of feature size of VLSI circuit using CMOS technology. One major reason of high static power consumption is the off-state sub-threshold leakage current of the transistor. At room temperature, the possible steepest sub-threshold swing (SS) for turning off the transistor, is limited to 60 mV/decade due to a constant fundamental thermal dynamical limit (kBT/q) that is not scalable with reduced dimension. This limitation is inherent to CMOS because its off-state is governed by thermally activated diffusive current over a potential gate-controlled potential barrier. Completely different switching mechanism such as using the mechanical degree of freedom is necessary to break the SS limit. Previous studies using nano-electro-mechanical-system (NEMS) have shown suspended-gate MOSFET (SG-MOSFET) as logical switch, while we have previously proposed a suspended nanowire (NW) channel FET (NEMFET) with low pull-in voltage(Vpi) and high Ion/Ioff ratio due to the flexibility of nanowires. Here we report the first demonstration of a NEMFET device using suspended Ge/Si core/shell nanowire channel. The NEMFET channel is suspended over a local metal gate with the air gap thickness defined by the thickness of the supporting source/drain electrodes. DC transfer characteristics on multiple switching NEMFET demonstrates close-to-zero SS (<6mV) at room temperature with the slope only limited by measurement equipment resolution. Furthermore, we employed electrostatic actuation to study the AC mechanical response of the nanowire channel. Using the NEMFET as a signal mixer we characterized the resonant frequency and the speed of NEMFET device to be 125.9 MHz

Condensin is essential for the packaging of chromatin into condensed chromosomes in all eukaryotes. It is a multi-subunit protein complex consisting of two core subunits SMC2 and 4 and three auxiliary components CAP-H, CAP-D2, CAP-G for condensin I and CAP-H2, CAP-D3, CAP-G2 for condensin II. Condensin I associates with chromosomes after the nuclear envelope breaks down, and is required for the formation of higher order structure of condensed chromosomes, whereas, condensin II binds to DNA throughout the cell cycle and initiates prophase chromosome condensation. While its role in chromosome condensation is well-established, where condensin I binds in the vertebrate genome is a key outstanding question. This thesis illustrates the first genome-wide map of condensin I in vertebrate cells, which sheds light on the role of condensin I in chromosome condensation and will possibly assist to understand its increasing link to diseases. The genome-wide map suggests that condensin I is enriched at promoters of actively transcribed RNA polymerase II-driven genes, in addition to tRNA and rRNA genes. Furthermore, condensin I is enriched in discrete regions along the central axis, and high concentration of condensin I binding in centromeres and telomeres were observed which is thought to be required for the structural integrity of chromosomes for proper chromosome segregation during cell division. Importantly, this genomic localization pattern of condensin in vertebrates is also seen in bacteria and yeast, suggesting a conserved condensin binding in three kingdoms of life. Another key finding from this study is that condensin I regulates the gene expression through bookmarking. Although how condensin binds to these regions and regulates the genes is enigmatic, this finding is opening a window of new direction in the understanding of condensin and chromosome structure and their link to diseases.

We report nano-detection using a silica microtoroid with a reference interferometer. Single polystyrene nano-beads at a record 12.5nm radius are detected; Influenza-A virion binding events with signal-to-noise ratio exceeding 38:1 are observed.

The rest frame subjet algorithm is introduced to define the subjets for the SISCone jet. Using it, an IR and collinear safe jet shape observable N-subjettiness, $\tau_N^{j}$, is defined to discriminate the fat jet from a highly boosted color singlet particle decaying to N partons and the QCD jet. Using rest frame subjets and $\tau_2^{j}$ on dijets from highly boosted $\it H / W / Z$ bosons through $pp \to \it H W$, $\it H Z$, we found that statistical significance of the signal is about $2 \sigma$ at the LHC with $\mathcal{L} \sim 30 \mathrm{fb^{-1}}$ at $14 \tev$., Comment: 5 pages, 3 figures. v2: references added, minor corrections. Accepted by Phys. Rev. D

The rest frame subjet algorithm is introduced to define the subjets for the SISCone jet. Using it, an IR and collinear safe jet shape observable N-subjettiness, $\tau_N^{j}$, is defined to discriminate the fat jet from a highly boosted color singlet particle decaying to N partons and the QCD jet. Using rest frame subjets and $\tau_2^{j}$ on dijets from highly boosted $\it H / W / Z$ bosons through $pp \to \it H W$, $\it H Z$, we found that statistical significance of the signal is about $2 \sigma$ at the LHC with $\mathcal{L} \sim 30 \mathrm{fb^{-1}}$ at $14 \tev$., Comment: 5 pages, 3 figures. v2: references added, minor corrections. Accepted by Phys. Rev. D

In this Letter we consider very light Higgs fields in BMSSM(Beyond MSSM). The spectrum below TeV scale is the same as the MSSM but the Higgs potential is modified and is well described in terms of effective dimension five and six operators. A correction from the BMSSM operators allows us to consider new parameter space of Higgs sector which is not allowed in the MSSM. It can be regarded as a constrained version of general 2 Higgs doublet model (2HDM) as long as Higgs sector is concerned. We focus on the possibility that CP odd Higgs (A) mass is about 7 or 8 GeV and charged Higgs mass is comparable to W mass. At the same time one of the CP even Higgs (h) is light enough such that h and A production at the Z pole is kinematically allowed. The tension between forward backward asymmetry of bottom quark Ab_FB measured at LEP and the Standard Model prediction can be ameliorated if bottom quark pair produced from light CP even Higgs is taken into account., Comment: 18 pages, 5 figures

The rest frame subjet algorithm is introduced to define the subjets for the SISCone jet. Using it, an IR and collinear safe jet shape observable N-subjettiness, $\tau_N^{j}$, is defined to discriminate the fat jet from a highly boosted color singlet particle decaying to N partons and the QCD jet. Using rest frame subjets and $\tau_2^{j}$ on dijets from highly boosted $\it H / W / Z$ bosons through $pp \to \it H W$, $\it H Z$, we found that statistical significance of the signal is about $2 \sigma$ at the LHC with $\mathcal{L} \sim 30 \mathrm{fb^{-1}}$ at $14 \tev$., Comment: 5 pages, 3 figures. v2: references added, minor corrections. Accepted by Phys. Rev. D

We introduce a new collider variable, MCT2, named as constransverse mass. It is a mixture of `stransverse mass(MT2)' and `contransverse mass(MCT)' variables, where the usual endpoint structure of MT2 distribution can be amplified in the MCT2 basis by large Jacobian factor which is controlled by trial missing particle mass. Thus the MCT2 projection of events increases our observability to measure several important endpoints from new particle decays, which are usually expected to be buried by irreducible backgrounds with various systematic uncertainties at the LHC. In this paper we explain the phenomenology of endpoint amplification in MCT2 projection, and describe how one may employ this variable to measure several meaningful mass constraints of new particles., Comment: LaTeX file of 14 pages with 6 figures, small clarifications and more cuts on simulation, version to appear in Phys. Rev. D.

The light Higgs mass in the MSSM is highly constrained and is predicted to be close to M_Z which causes a tension between the LEP II Higgs mass bound 114 GeV and the natural electroweak symmetry breaking in the MSSM. The usual way to increase the light CP even Higgs mass was to increase the quartic coupling of the up type Higgs. We point out that the light Higgs mass can be increased by reducing the off-diagonal term in the mass matrix when tan beta is moderate, which is about 5 to 10. As a result no mixing and/or a Higgs mixing angle of the opposite sign arises and the branching ratio of Higgs decay is drastically changed. This is possible in scalar sequestering scenario in which mu parameter can be large independently of the electroweak symmetry breaking. We also discuss the same effect in the BMSSM., Comment: 20 pages, 6 figures

We introduce a new collider variable, MCT2, named as constransverse mass. It is a mixture of `stransverse mass(MT2)' and `contransverse mass(MCT)' variables, where the usual endpoint structure of MT2 distribution can be amplified in the MCT2 basis by large Jacobian factor which is controlled by trial missing particle mass. Thus the MCT2 projection of events increases our observability to measure several important endpoints from new particle decays, which are usually expected to be buried by irreducible backgrounds with various systematic uncertainties at the LHC. In this paper we explain the phenomenology of endpoint amplification in MCT2 projection, and describe how one may employ this variable to measure several meaningful mass constraints of new particles., Comment: LaTeX file of 14 pages with 6 figures, small clarifications and more cuts on simulation, version to appear in Phys. Rev. D.

We construct a supersymmetric standard model in the context of the Z_{12-I} orbifold compactification of the E_8 x E_8' heterotic string theory. The gauge group is SU(3)_c x SU(2)_L x U(1)_Y x U(1)^4 x [SO(10) x U(1)^3]' with sin^2\theta_W = 3/8. We obtain three families of SO(10) spinor-like chiral matter states, and Higgs doublets. All other extra states are exactly vector-like under the standard model gauge symmetry. There are numerous standard model singlets, many of which get VEVs such that only the standard model gauge symmetry survives and desired Yukawa couplings can be generated at lower energies. In particular, all vector-like exotic states achieve superheavy masses and the R-parity can be preserved., Comment: Submitted for the SUSY07 proceedings, 4 pages, LaTEX

We construct a supersymmetric standard model in the context of the $Z_{12-I}$ orbifold compactification of the heterotic string theory. The gauge group is $SU(3)_c\times SU(2)_L\times U(1)_Y\times U(1)^4\times[SO(10)\times U(1)^3]'$. We obtain three chiral families, $3\times\{Q,d^c,u^c,L,e^c,\nu^c\}$, and Higgs doublets. There are numerous neutral singlets many of which can have VEVs so that low energy phenomenology on Yukawa couplings can be satisfied. In one assignment (Model E) of the electroweak hypercharge, we obtain the string scale value of $sin^2\theta_W^0={3/8}$ and another exactly massless {\it exphoton} (in addition to the photon) coupling to exotic particles only. There are color triplet and anti-triplet exotics, $\alpha$ and $\bar{\alpha}$, $SU(2)_L$ doublet exotics, $\delta$ and $\bar{\delta}$, and $SU(3)_c\times SU(2)_L$ singlet but $Y={2/3},-{1/3},-{2/3},{1/3}$ exotics, $\xi,\eta,\bar{\xi}, \bar{\eta}$. We show that all these vector-like exotics achieve heavy masses by appropriate VEVs of neutral singlets. One can find an effective R-parity between light (electroweak scale) particles so that proton and the LSP can live sufficiently long. In another assignment (Model S) of the electroweak hypercharge, there does not appear any exotic particle but $sin^2\theta_W^0={3/14}$., Comment: 1+36 pages, JHEP3 class

We construct a supersymmetric standard model in the context of the Z_{12-I} orbifold compactification of the E_8 x E_8' heterotic string theory. The gauge group is SU(3)_c x SU(2)_L x U(1)_Y x U(1)^4 x [SO(10) x U(1)^3]' with sin^2\theta_W = 3/8. We obtain three families of SO(10) spinor-like chiral matter states, and Higgs doublets. All other extra states are exactly vector-like under the standard model gauge symmetry. There are numerous standard model singlets, many of which get VEVs such that only the standard model gauge symmetry survives and desired Yukawa couplings can be generated at lower energies. In particular, all vector-like exotic states achieve superheavy masses and the R-parity can be preserved., Comment: Submitted for the SUSY07 proceedings, 4 pages, LaTEX

We construct a supersymmetric standard model in the context of the $Z_{12-I}$ orbifold compactification of the heterotic string theory. The gauge group is $SU(3)_c\times SU(2)_L\times U(1)_Y\times U(1)^4\times[SO(10)\times U(1)^3]'$. We obtain three chiral families, $3\times\{Q,d^c,u^c,L,e^c,\nu^c\}$, and Higgs doublets. There are numerous neutral singlets many of which can have VEVs so that low energy phenomenology on Yukawa couplings can be satisfied. In one assignment (Model E) of the electroweak hypercharge, we obtain the string scale value of $sin^2\theta_W^0={3/8}$ and another exactly massless {\it exphoton} (in addition to the photon) coupling to exotic particles only. There are color triplet and anti-triplet exotics, $\alpha$ and $\bar{\alpha}$, $SU(2)_L$ doublet exotics, $\delta$ and $\bar{\delta}$, and $SU(3)_c\times SU(2)_L$ singlet but $Y={2/3},-{1/3},-{2/3},{1/3}$ exotics, $\xi,\eta,\bar{\xi}, \bar{\eta}$. We show that all these vector-like exotics achieve heavy masses by appropriate VEVs of neutral singlets. One can find an effective R-parity between light (electroweak scale) particles so that proton and the LSP can live sufficiently long. In another assignment (Model S) of the electroweak hypercharge, there does not appear any exotic particle but $sin^2\theta_W^0={3/14}$., Comment: 1+36 pages, JHEP3 class

We construct a supersymmetric standard model in the context of the Z_{12-I} orbifold compactification of the E_8 x E_8' heterotic string theory. The gauge group is SU(3)_c x SU(2)_L x U(1)_Y x U(1)^4 x [SO(10) x U(1)^3]' with sin^2\theta_W = 3/8. We obtain three families of SO(10) spinor-like chiral matter states, and Higgs doublets. All other extra states are exactly vector-like under the standard model gauge symmetry. There are numerous standard model singlets, many of which get VEVs such that only the standard model gauge symmetry survives and desired Yukawa couplings can be generated at lower energies. In particular, all vector-like exotic states achieve superheavy masses and the R-parity can be preserved., Comment: Submitted for the SUSY07 proceedings, 4 pages, LaTEX