| 1. |
- Chandramohan, Arun, et al.
(author)
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Design-Rules for Stapled Alpha-Helical Peptides with On-Target In Vivo Activity: Application to Mdm2/X dual antagonists
- 2023
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In: Nature Communications. - : Cold Spring Harbor Laboratory. - 2041-1723.
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Journal article (peer-reviewed)abstract
- Stapled α-helical peptides can bind to and modulate historically intractable targets while addressing the traditional liabilities associated with peptide therapeutics. However, their pipeline advancement has been impeded by the challenges of identifying peptides with sufficient cellular uptake to engage the target protein while lacking off-target toxicities. Here, we advance the field to arrive at a workflow for identifying advanced stapled peptide lead molecules with on-target in vivo activity with no off-target cell proliferation effects. Specifically, we generated a >350-member library based on ATSP-7041, a stapled peptide Mdm2(X) antagonist with validated on-target cellular effects but with significant off-target activity. Key insights from library analysis include 1) a clear correlation between lipophilicity and permeability, 2) removal of positive charge to avoid off-target toxicities, 3) judicious placement of anionic residues to enhance peptide solubility/behavior, 4) optimization of C-terminal length and helicity to enhance cell activity, 5) optimization of staple type/number to avoid polypharmacology. Incorporation of one or more of these attributes led to molecules with improved in vitro and in vivo activities (up to a >292x improved cell proliferation EC50). A subset of peptides were devoid of off-target cell proliferation effects in cell lines lacking wild-type p53 protein (up to a >3800x on-target index). This latter improvement contrasted with clinical Mdm2 antagonistic molecules. Application of these ‘design rules’ to a distinct Mdm2(X) peptide series resulted in rapid improvement in cellular activity (>150x) and removal of off-target toxicities. Overall, the detailed workflow outlined here should help researchers identify stapled α-helical peptides for therapeutic impact.
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| 2. |
- Chandramohan, Arun, et al.
(author)
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Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
- 2024
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- Although stapled α-helical peptides can address challenging targets, their advancement is impeded by poor understandings for making them cell permeable while avoiding off-target toxicities. By synthesizing >350 molecules, we present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects. Key insights include a clear correlation between lipophilicity and permeability, removal of positive charge to avoid off-target toxicities, judicious anionic residue placement to enhance solubility/behavior, optimization of C-terminal length/helicity to enhance potency, and optimization of staple type/number to avoid polypharmacology. Workflow application gives peptides with >292x improved cell proliferation potencies and no off-target cell proliferation effects ( > 3800x on-target index). Application of these ‘design rules’ to a distinct Mdm2(X) peptide series improves ( > 150x) cellular potencies and removes off-target toxicities. The outlined workflow should facilitate therapeutic impacts, especially for those targets such as Mdm2(X) that have hydrophobic interfaces and are targetable with a helical motif.
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| 3. |
- Feng, Zhenhua, et al.
(author)
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Multicore-Fiber-Enabled WSDM Optical Access Network With Centralized Carrier Delivery and RSOA-Based Adaptive Modulation
- 2015
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In: IEEE PHOTONICS JOURNAL. - : Institute of Electrical and Electronics Engineers (IEEE). - 1943-0655. ; 7:4
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Journal article (peer-reviewed)abstract
- We proposed and experimentally demonstrated a wavelength-space division multiplexing (WSDM) optical access network architecture with centralized optical carrier delivery utilizing multicore fibers (MCFs) and adaptive modulation based on reflective semiconductor amplifier (RSOA). In our experiment, five of the outer cores are used for undirectional downstream (DS) transmission only, whereas the remaining outer core is utilized as a dedicated channel to transmit upstream (US) signals. Optical carriers for US are delivered from the optical line terminal (OLT) to the optical network unit (ONU) via the inner core and then transmitted back to the OLT after amplification and modulation by the RSOA in the colorless ONU side. The mobile backhaul (MB) service is also supported by the inner core. Wavelengths used in US transmission should be different from that of the MB in order to avoid the Rayleigh backscattering effect in bidirectional transmission. With quadrature phase-shift keying-orthogonal frequency-division multiplexing (QPSK-OFDM) modulation format, the aggregation DS capacity reaches 250 Gb/s using five outer cores and ten wavelengths, and it can be further scaled to 1 Tb/s using 20 wavelengths modulated with 16 QAM-OFDM. For US transmission, 2.5 Gb/s QPSK-OFDM transmission can be achieved just using a low-bandwidth RSOA, and adaptive modulation is applied to the RSOA to further enhance the US data rate to 3.12 Gb/s. As an emulation of high-speed MB transmission, 48 Gb/s inphase and quadrature (IQ) modulated popularization division multiplexing (PDM)-QPSK signal is transmitted in the inner core of MCF and coherently detected in the OLT side. Both DS and US optical signals exhibit acceptable performance with sufficient power budget.
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| 5. |
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| 6. |
- Lin, Rui, et al.
(author)
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Real-time 100 Gbps/lambda/core NRZ and EDB IM/DD Transmission over 10 km Multicore Fiber
- 2018
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In: 2018 Optical Fiber Communications Conference and Exposition (OFC). - : Institute of Electrical and Electronics Engineers (IEEE). - 9781943580385 ; , s. 1-3
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Conference paper (peer-reviewed)abstract
- A BiCMOS chip-based real-time IM/DD spatial division multiplexing system is experimentally demonstrated for short-reach communications. 100 Gbps/λ/core NRZ and EDB transmission is achieved below 7%-overhead HD-FEC limit after 10km 7-core fiber with optical dispersion compensation.
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| 7. |
- Lin, Rui, et al.
(author)
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Real-time 100 Gbps/λ/core NRZ and EDB IM/DD transmission over multicore fiber for intra-datacenter communication networks
- 2018
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In: Optics Express. - : OSA - The Optical Society. - 1094-4087. ; 26:8, s. 10519-10526
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Journal article (peer-reviewed)abstract
- A BiCMOS chip-based real-time intensity modulation/direct detection spatial division multiplexing system is experimentally demonstrated for both optical interconnects. 100 Gbps/λ/core electrical duobinary (EDB) transmission over 1 km 7-core multicore fiber (MCF) is carried out, achieving KP4 forward error correction (FEC) limit (BER < 2E-4). Using optical dispersion compensation, 7 × 100 Gbps/λ/core transmission of both non-return-to-zero (NRZ) and EDB signals over 10 km MCF transmission is achieved with BER lower than 7% overhead hard-decision FEC limit (BER < 3.8E-3). The integrated low complexity transceiver IC and analog signal processing approach make such a system highly attractive for the high-speed intra-datacenter interconnects..
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| 8. |
- Lin, Rui, et al.
(author)
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Spatial division multiplexing for optical data center networks
- 2018
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In: 22ND INTERNATIONAL CONFERENCE ON OPTICAL NETWORK DESIGN AND MODELING (ONDM 2018). - : IEEE. ; , s. 239-241
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Conference paper (peer-reviewed)abstract
- Emerging mobile and cloud applications drive ever-increasing capacity demands, particularly for short-reach optical communications, where low-cost and low-power solutions are highly required. Spatial division multiplexing (SDM) techniques provide a promising way to scale up the lane count per fiber, while reducing the number of fiber connections and patch cords, and hence simplifying cabling complexity. This talk will address challenges on both system and network levels, and report our recent development on SDM techniques for optical data center networks.
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| 9. |
- Lin, Rui, 1988, et al.
(author)
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Telecommunication compatibility evaluation for co-existing quantum key distribution in homogenous multicore fiber
- 2020
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In: IEEE Access. - : Institute of Electrical and Electronics Engineers Inc.. - 2169-3536. ; 8, s. 78836-78846
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Journal article (peer-reviewed)abstract
- Quantum key distribution (QKD) is regarded as an alternative to traditional cryptography methods for securing data communication by quantum mechanics rather than computational complexity. Towards the massive deployment of QKD, embedding it with the telecommunication system is crucially important. Homogenous optical multi-core fibers (MCFs) compatible with spatial division multiplexing (SDM) are essential components for the next-generation optical communication infrastructure, which provides a big potential for co-existence of optical telecommunication systems and QKD. However, the QKD channel is extremely vulnerable due to the fact that the quantum states can be annihilated by noise during signal propagation. Thus, investigation of telecom compatibility for QKD co-existing with high-speed classical communication in SDM transmission media is needed. In this paper, we present analytical models of the noise sources in QKD links over heterogeneous MCFs. Spontaneous Raman scattering and inter-core crosstalk are experimentally characterized over spans of MCFs with different refractive index profiles, emulating shared telecom traffic conditions. Lower bounds for the secret key rates and quantum bit error rate (QBER) due to different core/wavelength allocation are obtained to validate intra- and inter-core co-existence of QKD and classical telecommunication
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| 10. |
- Ozolins, Oskars, et al.
(author)
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112 Gbps/λ PAM4 inter-DCI with continuous-fiber Bragg grating based dispersion compensators
- 2018
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In: Advanced Photonics 2018 (BGPP, IPR, NP, NOMA, Sensors, Networks, SPPCom, SOF) OSA Technical Digest (online) (Optical Society of America, 2018), paper NeTh3F.3. - : OSA - The Optical Society. - 9781557528209
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Conference paper (peer-reviewed)abstract
- We demonstrate 56 Gbaud/λ PAM4 inter - data center interconnects over 81 km single core single mode fiber and 33.6 km 7-core single mode fiber with continuous-fiber Bragg grating based chromatic dispersion compensators covering C-band.
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