Extending the coverage of user-diversified IM-DD PON by FDM: a mathematical model with experimental verification.

Future passive optical networks (PONs) call for more flexibility to support diversified users with various rate demands and link qualities. Using traditional time-division multiplexing (TDM), the concept of a flexible rate PON was proposed to accommodate more users with link diversity by rate adaptation. In this Letter, we reveal the PON coverage can be further extended through frequency-division multiplexing (FDM) in the presence of multiuser diversity, namely, (i) there exist users with frequency-dependent link conditions and (ii) the link conditions exhibit disparity among users. We build a mathematical model and propose an optimization algorithm based on the binary tree search to optimize diversity gain. We experimentally verify its feasibility by studying the diversity gain concerning chromatic dispersion, optical path loss, and signal-to-noise ratio (SNR) variation in a 200G-class intensity-modulation direct-detection (IM-DD) system.

Cryo-EM structures of Escherichia coli cytochrome bo3 reveal bound phospholipids and ubiquinone-8 in a dynamic substrate binding site.

Two independent structures of the proton-pumping, respiratory cytochrome bo3 ubiquinol oxidase (cyt bo3 ) have been determined by cryogenic electron microscopy (cryo-EM) in styrene-maleic acid (SMA) copolymer nanodiscs and in membrane scaffold protein (MSP) nanodiscs to 2.55- and 2.19-Å resolution, respectively. The structures include the metal redox centers (heme b, heme o3 , and CuB), the redox-active cross-linked histidine-tyrosine cofactor, and the internal water molecules in the proton-conducting D channel. Each structure also contains one equivalent of ubiquinone-8 (UQ8) in the substrate binding site as well as several phospholipid molecules. The isoprene side chain of UQ8 is clamped within a hydrophobic groove in subunit I by transmembrane helix TM0, which is only present in quinol oxidases and not in the closely related cytochrome c oxidases. Both structures show carbonyl O1 of the UQ8 headgroup hydrogen bonded to D75I and R71I In both structures, residue H98I occupies two conformations. In conformation 1, H98I forms a hydrogen bond with carbonyl O4 of the UQ8 headgroup, but in conformation 2, the imidazole side chain of H98I has flipped to form a hydrogen bond with E14I at the N-terminal end of TM0. We propose that H98I dynamics facilitate proton transfer from ubiquinol to the periplasmic aqueous phase during oxidation of the substrate. Computational studies show that TM0 creates a channel, allowing access of water to the ubiquinol headgroup and to H98I.

JAK inhibitors and the risk of malignancy: a meta-analysis across disease indications.

OBJECTIVES: To estimate the association of Janus kinase inhibitors (JAKi) with the incidence of malignancy, compared with placebo, tumour necrosis factor (TNF)-α inhibitors (TNFi) and methotrexate. METHODS: Systematic searches of databases were performed, to December 2022, to identify phase II/III/IV randomised clinical trials (RCTs) and long-term extension (LTE) studies of JAKi (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib) compared with placebo, TNFi or methotrexate, in adults with rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease or atopic dermatitis. Network and pairwise meta-analyses were performed to estimate incidence rate ratios (IRRs) for malignancy between JAKi and comparators. Bias was assessed using the Cochrane Risk of Bias-2 tool. RESULTS: In 62 eligible RCTs and 16 LTE studies, there were 82 366 person-years of exposure to JAKi, 2924 to placebo, 7909 to TNFi and 1074 to methotrexate. The overall malignancy incidence rate was 1.15 per 100 person-years in RCTs, and 1.26 per 100 person-years across combined RCT and LTE data. In network meta-analyses, the incidence of all malignancies including non-melanomatous skin cancers (NMSCs) was not significantly different between JAKi and placebo (IRR 0.71; 95% CI 0.44 to 1.15) or between JAKi and methotrexate (IRR 0.77; 95% CI 0.35 to 1.68). Compared with TNFi, however, JAKi were associated with an increased incidence of malignancy (IRR 1.50; 95% CI 1.16 to 1.94). Findings were consistent when analysing NMSC only and when analysing combined RCT/LTE data. CONCLUSIONS: JAKi were associated with a higher incidence of malignancy compared with TNFi but not placebo or methotrexate. Cancers were rare events in all comparisons. PROSPERO REGISTRATION NUMBER: CRD42022362630.

Peak-tracking BOTDA with dynamic ternary search.

We propose a peak-tracking BOTDA (PT-BOTDA) equipped with an efficient dynamic Brillouin frequency shift (BFS) searching scheme based on ternary search. The proposed scheme establishes a feedback loop between the selected frequency and the corresponding Brillouin gain to reduce the required number of scanning frequencies in one measurement. We also demonstrate the performance evaluation of the proposed scheme under scenarios with different searching granularities and dynamic sensing ranges. Experimental results indicate that in all situations, the proposed PT-BOTDA can achieve at least 85% and 97% reduction in the number of scanning frequencies for 1-MHz and 0.1-MHz frequency steps, respectively, with a 3-meter spatial resolution, while maintaining a convincing BFS searching accuracy under sufficient SNR condition using a smaller searching interval.

Nonlinear distortion mitigation of DML-based OFDM optical systems with non-orthogonal DFT-precoding.

We propose a non-orthogonal discrete Fourier transform (DFT) matrix precoding scheme for the mitigation of nonlinear distortion induced by the interaction between laser chirp and fiber dispersion in a directly modulated laser (DML)-based orthogonal frequency division multiplexing (OFDM) transmission system. Compared with conventional OFDM, the proposed method can decrease the peak-to-average power ratio (PAPR) and significantly reduce the nonlinear distortion without sacrificing spectral efficiency (SE). The cascaded binary-phase-shift-keying iterative detection (CBID) algorithm is used to eliminate the inter-carrier interference (ICI) that is purposely induced by the non-orthogonal precoding. The performance of the proposed scheme is experimentally evaluated, achieving ∼0.4-dB sensitivity improvement at the KP4-forward error correction (FEC) threshold over the T/2-spaced third-order Volterra nonlinear equalizer (VNLE). Meanwhile, compared to the VNLE, the reduction in computational complexity of one OFDM frame is 90% for multiplication and 88.32% for addition in this work.

Anionic Lipids Confine Cytochrome c2 to the Surface of Bioenergetic Membranes without Compromising Its Interaction with Redox Partners.

Cytochrome c2 (cyt. c2) is a major element in electron transfer between redox proteins in bioenergetic membranes. While the interaction between cyt. c2 and anionic lipids abundant in bioenergetic membranes has been reported, their effect on the shuttling activity of cyt. c2 remains elusive. Here, the effect of anionic lipids on the interaction and binding of cyt. c2 to the cytochrome bc1 complex (bc1) is investigated using a combination of molecular dynamics (MD) and Brownian dynamics (BD) simulations. MD is used to generate thermally accessible conformations of cyt. c2 and membrane-embedded bc1, which were subsequently used in multireplica BD simulations of diffusion of cyt. c2 from solution to bc1, in the presence of various lipids. We show that, counterintuitively, anionic lipids facilitate association of cyt. c2 with bc1 by localizing its diffusion to the membrane surface. The observed lipid-mediated bc1 association is further enhanced by the oxidized state of cyt. c2, in line with its physiological function. This lipid-mediated enhancement is salinity-dependent, and anionic lipids can disrupt cyt. c2-bc1 interaction at nonphysiological salt levels. Our data highlight the importance of the redox state of cyt. c2, the lipid composition of the chromatophore membrane, and the salinity of the chromatophore in regulating the efficiency of the electron shuttling process mediated by cyt. c2. The conclusions can be extrapolated to mitochondrial systems and processes, or any bioenergetic membrane, given the structural similarity between cyt. c2 and bc1 and their mitochondrial counterparts.

Dynamic polarization-insensitive BOTDA in direct-detection OFDM with CNN-based BFS extraction.

We propose a dynamic polarization-insensitive Brillouin optical time domain analyzer (D/PI-BOTDA) with orthogonal frequency division multiplexing (OFDM) based on intensity-modulated direct-detection (IM-DD). A polarization-division-multiplexed (PDM) pump signal enables polarization diversity of the stimulated Brillouin scattering while a multi-frequency OFDM probe signal realizes dynamic sensing with single-shot transmission. We experimentally demonstrated distributed temperature sensing along a total 940-meter fiber with a temperature sensing coefficient of 1.2°C/MHz. The experimental results indicated a remarkable suppression of Brillouin gain fluctuation up to 4.38 times compared to the case without polarization diversity. To facilitate the Brillouin frequency shift (BFS) extraction process, we also implement a CNN-based BFS extraction method with SE-Res2Net block. The adopted algorithm achieves a higher accuracy than conventional curve fitting method, with a 10-time enhancement in the time efficiency.

Charge Transfer and Chemo-Mechanical Coupling in Respiratory Complex I.

The mitochondrial respiratory chain, formed by five protein complexes, utilizes energy from catabolic processes to synthesize ATP. Complex I, the first and the largest protein complex of the chain, harvests electrons from NADH to reduce quinone, while pumping protons across the mitochondrial membrane. Detailed knowledge of the working principle of such coupled charge-transfer processes remains, however, fragmentary due to bottlenecks in understanding redox-driven conformational transitions and their interplay with the hydrated proton pathways. Complex I from Thermus thermophilus encases 16 subunits with nine iron-sulfur clusters, reduced by electrons from NADH. Here, employing the latest crystal structure of T. thermophilus complex I, we have used microsecond-scale molecular dynamics simulations to study the chemo-mechanical coupling between redox changes of the iron-sulfur clusters and conformational transitions across complex I. First, we identify the redox switches within complex I, which allosterically couple the dynamics of the quinone binding pocket to the site of NADH reduction. Second, our free-energy calculations reveal that the affinity of the quinone, specifically menaquinone, for the binding-site is higher than that of its reduced, menaquinol form-a design essential for menaquinol release. Remarkably, the barriers to diffusive menaquinone dynamics are lesser than that of the more ubiquitous ubiquinone, and the naphthoquinone headgroup of the former furnishes stronger binding interactions with the pocket, favoring menaquinone for charge transport in T. thermophilus. Our computations are consistent with experimentally validated mutations and hierarchize the key residues into three functional classes, identifying new mutation targets. Third, long-range hydrogen-bond networks connecting the quinone-binding site to the transmembrane subunits are found to be responsible for proton pumping. Put together, the simulations reveal the molecular design principles linking redox reactions to quinone turnover to proton translocation in complex I.

Channel interference study and power ratio optimization on two optical Nyquist-PM-QPSK signals with spectral overlap.

Recent signal processing of optical signals has involved possible overlapping of the spectra from the adjacent optical channels for channel multiplexing and improving system throughput. However, the incurred channel interference performance has not yet been carefully characterized. In this paper, we carry out simulations and experiments to investigate various system parameters that determine such adjacent channel interference performance and further optimize the channel power ratio when two optical channels, each carrying a Nyquist shaped and polarization multiplexed quadrature phase-shift keying (Nyquist-PM-QPSK) signal, are being multiplexed with optical spectral overlap. With a properly designed successive interference cancellation (SIC) algorithm, both channels can be successfully separated and decoded individually. The OSNR penalties due to possible time offset, polarization rotation, and frequency offset between the two adjacent optical channels are investigated. The power ratio between the two adjacent optical channels are further optimized with respect to the OSNR penalties.

Experimental demonstration of 111.1-Gb/s net information rate using IM/DD probabilistically shaped orthogonal chirp-division multiplexing with a 10-GHz-class modulator.

We propose probabilistically shaped quadrature amplitude modulation (PS-QAM) formats to maximize the capacity in fiber transmission systems using orthogonal chirp-division multiplexing (OCDM). OCDM possesses the property of chirp spread spectrum (CSS), leading to improved resilience to system impairments. We further investigate the recently proposed robust channel estimator based on pulse compression and noise rejection and experimentally demonstrate its feasibility in an intensity-modulated/direction-detection (IM/DD) OCDM system. By applying the proposed PS-QAM based OCDM to an IM/DD optical system, a net information rate of 111.1 Gb/s has been successfully achieved using a 10-GHz class Mach-Zehnder modulator (MZM) and has also shown improved performance compared to the conventional PS-QAM based orthogonal frequency-division multiplexing (OFDM) systems. Moreover, due to the superior characteristics of OCDM, there is no need for additional feedback to obtain the prior knowledge of channel state information in the proposed system, leading to reduced complexity and cost.

Experimental characterization of the radio over fiber aided twin-antenna spatial modulation downlink.

In this paper, we present the design and the experimental demonstration of a radio over fiber (RoF) network relying on state-of-the-art spatial modulation (SM), that activates one out of multiple antennas. We propose a novel RoF-aided SM encoding scheme, where the optical single side-band signal generated by a Mach-Zehnder modulator (MZM) is used for both the antenna selection and for the classic modulated symbol selection. The SM encoding is optically processed in a centralized fashion, aiming for the reduction of power consumption and for enabling cost-effective maintenance and management, which can be employed in the context of a cloud radio access network (C-RAN) and a small-cell front-haul. Furthermore, an experimental demonstration of the proposed system is discussed and analyzed, where a 20 km standard single mode fiber (SSMF) is used for transmission. In this experiment, a 2 Gbps transmission relying on two transmit and two receive antennas is achieved with less than 1 dB SNR degradation compared to those operating without RoF.

Adaptively loaded SP-offset-QAM OFDM for IM/DD communication systems.

In this paper, we propose adaptively loaded set-partitioned offset quadrature amplitude modulation (SP-offset-QAM) orthogonal frequency division multiplexing (OFDM) for low-cost intensity-modulation direct-detection (IM/DD) communication systems. We compare this scheme with multi-band carrier-less amplitude phase modulation (CAP) and conventional OFDM, and demonstrate >40 Gbit/s transmission over 50-km single-mode fiber. It is shown that the use of SP-QAM formats, together with the adaptive loading algorithm specifically designed to this group of formats, results in significant performance improvement for all these three schemes. SP-offset-QAM OFDM exhibits greatly reduced complexity compared to SP-QAM based multi-band CAP, via parallelized implementation and minimized memory length for spectral shaping. On the other hand, this scheme shows better performance than SP-QAM based conventional OFDM at both back-to-back and after transmission. We also characterize the proposed scheme in terms of enhanced tolerance to fiber intra-channel nonlinearity and the potential to increase the communication security. The studies show that adaptive SP-offset-QAM OFDM is a promising IM/DD solution for medium- and long-reach optical access networks and data center connections.

Physical-layer network coding for passive optical interconnect in datacenter networks.

We introduce physical-layer network coding (PLNC) technique in a passive optical interconnect (POI) architecture for datacenter networks. The implementation of the PLNC in the POI at 2.5 Gb/s and 10Gb/s have been experimentally validated while the gains in terms of network layer performances have been investigated by simulation. The results reveal that in order to realize negligible packet drop, the wavelengths usage can be reduced by half while a significant improvement in packet delay especially under high traffic load can be achieved by employing PLNC over POI.

Common phase error estimation in coherent optical OFDM systems using best-fit bounding box.

In this paper, we investigate and characterize a new approach of adopting best-fit bounding box method for common phase error estimation in coherent optical OFDM systems. The method is based on the calculation of the 2-D convex hull of the received signal constellation, which is generally adopted in image processing area to correct the skew of images. We further perform detailed characterizations including root mean square error analysis, laser linewidth tolerance, noise tolerance, and computation complexity analysis, via numerical simulations and experiments. The results show the proposed method achieves much improved spectral efficiency and comparable system performance than the pilot-aided method, while it exhibits good estimation accuracy and reduced complexity than the blind phase searching method.

Physical-layer network coding in coherent optical OFDM systems.

We present the first experimental demonstration and characterization of the application of optical physical-layer network coding in coherent optical OFDM systems. It combines two optical OFDM frames to share the same link so as to enhance system throughput, while individual OFDM frames can be recovered with digital signal processing at the destined node.

Coded-subcarrier-aided chromatic dispersion monitoring scheme for flexible optical OFDM networks.

A simple coded-subcarrier aided scheme is proposed to perform chromatic dispersion monitoring in flexible optical OFDM networks. A pair of coded label subcarriers is added to both edges of the optical OFDM signal spectrum at the edge transmitter node. Upon reception at any intermediate or the receiver node, chromatic dispersion estimation is performed, via simple direct detection, followed by electronic correlation procedures with the designated code sequences. The feasibility and the performance of the proposed scheme have been experimentally characterized. It provides a cost-effective monitoring solution for the optical OFDM signals across intermediate nodes in flexible OFDM networks.

Enhancing nursing students' clinical competency using a multi-patient simulation learning model: A randomized controlled study.

BACKGROUND: For nurses, clinical competency is paramount in ensuring that patients receive safe, high-quality care. Multi-patient simulation (MPS) in nursing education is gaining attention, and evidence shows its suitability for real-life situations. MPS can be an effective solution for nurses' continuing clinical education. OBJECTIVES: This project compares the effectiveness of MPS (involving both a standardized patient and a high fidelity simulator) and a single high-fidelity simulation (single HFS; only involving a high fidelity simulator) for enhancing the clinical competency of nursing students. DESIGN: A stratified, permuted, block randomized controlled study design was used. SETTINGS AND PARTICIPANTS: Sixty undergraduate nursing students in years 3, 4, and 5 were selected to participate. Subgroups with each comprising three undergraduate nursing students from different years were formed. METHODS: The participants were randomized to receive either an MPS (intervention group) or single HFS (control group) for 1 day; they later received the same intervention after a 30-day washout period. One objectively measured questionnaire and two self-reported questionnaires were used to measure clinical competency: the Creighton Competency Evaluation Instrument (CCEI), Clinical Competence Questionnaire (CCQ), and Simulation Effectiveness Tool - Modified Questionnaire (SET-M). RESULTS: The results revealed significant between-group differences. Specifically, the intervention group showed greater improvement than the control group in both the CCQ (linear contrast [d] = 71.4; 95 % confidence interval [CI] = 53.407, 89.393; P < 0.001) and CCEI total scores (d = 7.17; 95 % CI = 5.837, 8.503; P < 0.001). The SET-M results indicated that 85 % of the participants (n = 51) strongly agreed that they felt more confident about performing a patient handover to the healthcare team after the simulation. CONCLUSIONS: The study findings indicated that both the MPS and single HFS effectively enhanced students' clinical competency. However, MPSs have superior educational outcomes relative to traditional single HFSs.

Revealing a Hidden Intermediate of Rotatory Catalysis with X-ray Crystallography and Molecular Simulations.

The mechanism of rotatory catalysis in ATP-hydrolyzing molecular motors remains an unresolved puzzle in biological energy transfer. Notwithstanding the wealth of available biochemical and structural information inferred from years of experiments, knowledge on how the coupling between the chemical and mechanical steps within motors enforces directional rotatory movements remains fragmentary. Even more contentious is to pinpoint the rate-limiting step of a multistep rotation process. Here, using vacuolar or V1-type hexameric ATPase as an exemplary rotational motor, we present a model of the complete 4-step conformational cycle involved in rotatory catalysis. First, using X-ray crystallography, a new intermediate or "dwell" is identified, which enables the release of an inorganic phosphate (or Pi) after ATP hydrolysis. Using molecular dynamics simulations, this new dwell is placed in a sequence with three other crystal structures to derive a putative cyclic rotation path. Free-energy simulations are employed to estimate the rate of the hexameric protein transformations and delineate allosteric effects that allow new reactant ATP entry only after hydrolysis product exit. An analysis of transfer entropy brings to light how the side-chain-level interactions transcend into larger-scale reorganizations, highlighting the role of the ubiquitous arginine-finger residues in coupling chemical and mechanical information. An inspection of all known rates encompassing the 4-step rotation mechanism implicates the overcoming of the ADP interactions with V1-ATPase to be the rate-limiting step of motor action.

ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome.

Vaccines derived from chimpanzee adenovirus Y25 (ChAdOx1), human adenovirus type 26 (HAdV-D26), and human adenovirus type 5 (HAdV-C5) are critical in combatting the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic. As part of the largest vaccination campaign in history, ultrarare side effects not seen in phase 3 trials, including thrombosis with thrombocytopenia syndrome (TTS), a rare condition resembling heparin-induced thrombocytopenia (HIT), have been observed. This study demonstrates that all three adenoviruses deployed as vaccination vectors versus SARS-CoV-2 bind to platelet factor 4 (PF4), a protein implicated in the pathogenesis of HIT. We have determined the structure of the ChAdOx1 viral vector and used it in state-of-the-art computational simulations to demonstrate an electrostatic interaction mechanism with PF4, which was confirmed experimentally by surface plasmon resonance. These data confirm that PF4 is capable of forming stable complexes with clinically relevant adenoviruses, an important step in unraveling the mechanisms underlying TTS.

Microscopic view of lipids and their diverse biological functions.

Biological membranes and their diverse lipid constituents play key roles in a broad spectrum of cellular and physiological processes. Characterization of membrane-associated phenomena at a microscopic level is therefore essential to our fundamental understanding of such processes. Due to the semi-fluid and dynamic nature of lipid bilayers, and their complex compositions, detailed characterization of biological membranes at an atomic scale has been refractory to experimental approaches. Computational modeling and simulation offer a highly complementary toolset with sufficient spatial and temporal resolutions to fill this gap. Here, we review recent molecular dynamics studies focusing on the diversity of lipid composition of biological membranes, or aiming at the characterization of lipid-protein interaction, with the overall goal of dissecting how lipids impact biological roles of the cellular membranes.