100 Gbps PAM4 ultra-thin photodetectors integrated on SOI platform by micro transfer printing.

The integration of compact high-bandwidth III-V active devices in a scalable manner is highly significant for Silicon-on-insulator (SOI) photonic integrated circuits. To address this, we demonstrate the integration of pre-fabricated 21 × 57 µm2 InGaAs photodetector (PD) coupons with a thickness of 675 nm to a 500 nm SOI platform using a direct bonding micro-transfer printing process. The common devices are coupled to the Si waveguides via butt, grating and evanescent coupling schemes with responsivities of 0.13, 0.3 and 0.6 A/W respectively, in line with simulations. The thin device facilitates simplified high-speed connections without the need for an interlayer dielectric. A back-to-back data communication rate of 50 Gb/s is achieved with on-off keying and with post processing of four-level pulse-amplitude modulation (PAM4) 100 Gb/s is realized. Potentially, around 1 million devices per 75 mm InP wafer can be attained. The integration of compact PDs exhibited in this work can be extended to modulators and lasers in the future.

Nanocapillary sampling coupled to liquid chromatography mass spectrometry delivers single cell drug measurement and lipid fingerprints.

This work describes the development of a new approach to measure drug levels and lipid fingerprints in single living mammalian cells. Nanocapillary sampling is an approach that enables the selection and isolation of single living cells under microscope observation. Here, live single cell nanocapillary sampling is coupled to liquid chromatography for the first time. This allows molecular species to be separated prior to ionisation and improves measurement precision of drug analytes. The efficiency of transferring analytes from the sampling capillary into a vial was optimised in this work. The analysis was carried out using standard flow liquid chromatography coupled to widely available mass spectrometry instrumentation, highlighting opportunities for widespread adoption. The method was applied to 30 living cells, revealing cell-to-cell heterogeneity in the uptake of different drug molecules. Using this system, we detected 14-158 lipid features per single cell, revealing the association between bedaquiline uptake and lipid fingerprints.

Pro-MAP: a robust pipeline for the pre-processing of single channel protein microarray data.

BACKGROUND: The central role of proteins in diseases has made them increasingly attractive as therapeutic targets and indicators of cellular processes. Protein microarrays are emerging as an important means of characterising protein activity. Their accurate downstream analysis to produce biologically significant conclusions is largely dependent on proper pre-processing of extracted signal intensities. However, existing computational tools are not specifically tailored to the nature of these data and lack unanimity. RESULTS: Here, we present the single-channel Protein Microarray Analysis Pipeline, a tailored computational tool for analysis of single-channel protein microarrays enabling biomarker identification, implemented in R, and as an interactive web application. We compared four existing background correction and normalization methods as well as three array filtering techniques, applied to four real datasets with two microarray designs, extracted using two software programs. The normexp, cyclic loess, and array weighting methods were most effective for background correction, normalization, and filtering respectively. CONCLUSIONS: Thus, here we provided a versatile and effective pre-processing and differential analysis workflow for single-channel protein microarray data in form of an R script and web application ( https://metaomics.uct.ac.za/shinyapps/Pro-MAP/ .) for those not well versed in the R programming language.

High Throughput LC-MS Platform for Large Scale Screening of Bioactive Polar Lipids in Human Plasma and Serum.

Lipids play a key role in many biological processes, and their accurate measurement is critical to unraveling the biology of diseases and human health. A high throughput HILIC-based (LC-MS) method for the semiquantitative screening of over 2000 lipids, based on over 4000 MRM transitions, was devised to produce an accessible and robust lipidomic screen for phospholipids in human plasma/serum. This methodology integrates many of the advantages of global lipid analysis with those of targeted approaches. Having used the method as an initial "wide class" screen, it can then be easily adapted for a more targeted analysis and quantification of key, dysregulated lipids. Robustness was assessed using 1550 continuous injections of plasma extracts onto a single column and via the evaluation of columns from 5 different batches of stationary phase. Initial screens in positive (239 lipids, 431 MRM transitions) and negative electrospray ionization (ESI) mode (232 lipids, 446 MRM transitions) were assessed for reproducibility, sensitivity, and dynamic range using analysis times of 8 min. The total number of lipids monitored using these screening methods was 433 with an overlap of 38 lipids in both modes. A polarity switching method for accurate quantification, using the same LC conditions, was assessed for intra- and interday reproducibility, accuracy, dynamic range, stability, carryover, dilution integrity, and matrix interferences and found to be acceptable. This polarity switching method was then applied to lipids important in the stratification of human prostate cancer samples.

Aether, dark energy and string compactifications.

The nineteenth-century aether died with special relativity but was resurrected by general relativity in the form of dark energy; a tensile material with tension equal to its energy density. Such a material is provided by the D-branes of string-theory; these can support the fields of supersymmetric particle-physics, although their energy density is cancelled by orientifold singularities upon compactification. Dark energy can still arise from supersymmetry-breaking anti-D-branes but it is probably time-dependent. Recent results on time-dependent compactifications to an FLRW universe with late-time accelerated expansion are reviewed. This article is part of the theme issue 'The future of mathematical cosmology, Volume 2'.

Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1.

Post-traumatic OA (PTOA) is often triggered by injurious, high-impact loading events which result in rapid, excessive chondrocyte cell death and a phenotypic shift in residual cells toward a more catabolic state. As such, the identification of a disease-modifying OA drug (DMOAD) that can protect chondrocytes from death following impact injury, and thereby prevent cartilage degradation and progression to PTOA, would offer a novel intervention. We have previously shown that urocortin-1 (Ucn) is an essential endogenous pro-survival factor that protects chondrocytes from OA-associated pro-apoptotic stimuli. Here, using a drop tower PTOA-induction model, we demonstrate the extent of Ucn's chondroprotective role in cartilage explants exposed to excessive impact load. Using pathway-specific agonists and antagonists, we show that Ucn acts to block load-induced intracellular calcium accumulation through blockade of the non-selective cation channel Piezo1 rather than TRPV4. This protective effect is mediated primarily through the Ucn receptor CRF-R1 rather than CRF-R2. Crucially, we demonstrate that the chondroprotective effect of Ucn is maintained whether it is applied pre-impact or post-impact, highlighting the potential of Ucn as a novel DMOAD for the prevention of injurious impact overload-induced PTOA.

High-Throughput Microbore Ultrahigh-Performance Liquid Chromatography-Ion Mobility-Enabled-Mass Spectrometry-Based Proteomics Methodology for the Exploratory Analysis of Serum Samples from Large Cohort Studies.

The deployment of proteomic analysis in clinical studies represents a significant opportunity to detect and validate biomarkers in translational medicine, improve disease understanding, and provide baseline information on population health. However, comprehensive proteome studies usually employ nanoscale chromatography and often require several hours of analysis/sample. Here, we describe a high-throughput liquid chromatography tandem mass spectrometry (LC/MS/MS) methodology using 1 mm scale chromatography requiring only 15 min/sample, coupled to ion mobility-enabled mass spectrometry. The short run time effected a 6-fold increase in productivity compared with nanoscale LC/MS. The method demonstrated excellent reproducibility with retention time coefficient of variations of less than 0.05% and peak area reproducibility ranging from 5 to 15%. The 1 mm system produced similar chromatographic peak capacity values to the nanoscale miniaturized system, detecting 90% of the Escherichia coli proteins identified by the 75 µm LC/MS system (albeit based on only 75% of the peptides found by the latter). Application to the analysis of serum samples from a human prostate cancer study group resulted in the identification of a total of 533 proteins revealing the differential expression of proteins linked to patients receiving hormone-radiotherapy or undergoing surgery.

Intrinsically Connected: Therapeutically Targeting the Cathepsin Proteases and the Bcl-2 Family of Protein Substrates as Co-regulators of Apoptosis.

Taken with the growing importance of cathepsin-mediated substrate proteolysis in tumor biology and progression, the focus and emphasis placed on therapeutic design and development is coming into fruition. Underpinning this approach is the invariable progression from the direction of fully characterizing cathepsin protease members and their substrate targets, towards targeting such an interaction with tangible therapeutics. The two groups of such substrates that have gained much attention over the years are the pro- and anti- apoptotic protein intermediates from the extrinsic and intrinsic signaling arms of the apoptosis pathway. As proteins that are central to determining cellular fate, some of them present themselves as very favorable candidates for therapeutic targeting. However, considering that both anti- and pro- apoptotic signaling intermediates have been reported to be downstream substrates for certain activated cathepsin proteases, therapeutic targeting approaches based on greater selectivity do need to be given greater consideration. Herein, we review the relationships shared by the cathepsin proteases and the Bcl-2 homology domain proteins, in the context of how the topical approach of adopting 'BH3-mimetics' can be explored further in modulating the relationship between the anti- and pro- apoptotic signaling intermediates from the intrinsic apoptosis pathway and their upstream cathepsin protease regulators. Based on this, we highlight important future considerations for improved therapeutic design.

Cdc6 as a novel target in cancer: Oncogenic potential, senescence and subcellular localisation.

Cdc6 is a key replication licencing factor with a pivotal role in regulating the process of DNA replication, rendering it an important investigatory focus in tumourigenesis. Indeed, Cdc6 overexpression has been found to be a feature in certain tumours and has been associated as an early event in malignancies. With a focus on pancreatic cancer, there are evidence of its convergence in downstream pathways implicated in major genetic alterations found in pancreatic cancer, primarily KRAS. There is also data of its direct influence on protumourigenic processes as a transcriptional regulator, repressing the key tumour suppressor loci CDH1 (E-Cadherin) and influencing epithelial to mesenchymal transition (EMT). Moreover, gene amplification of Cdc6 as well as of E2F (an upstream regulator of Cdc6) have also been found to be a key feature in tumours overexpressing Cdc6, further highlighting this event as a potential driver of tumourigenesis. In this review, we summarise the evidence for the role of Cdc6 overexpression in cancer, specifically that of pancreatic cancer. More importantly, we recapitulate the role of Cdc6 as part of the DNA damage response and on senescence-an important antitumour barrier-in the context of pancreatic cancer. Finally, recent emerging observations suggest that the potential of the subcellular localisation of Cdc6 in inducing senescence. In this regard, we speculate and hypothesise potentially exploitable mechanisms in the context of inducing senescence via a novel pathway involving cytoplasmic retention of Cdc6 and Cyclin E.

Manifestly Lorentz Invariant Chiral Boson Action.

A manifestly Lorentz invariant action is found for the Floreanini-Jackiw chiral boson. The method involves a novel chiral reduction of the phase-space action for a string and can be adapted to describe chiral bosons on the heterotic string worldsheet. A similar manifestly Lorentz invariant action is found for an entire class of conformal chiral 2k-form electrodynamics in (4k+2) dimensions which includes the Floreanini-Jackiw theory as the k=0 case.

Fast channel estimation and equalization scheme for offset-QAM OFDM systems.

We show that the orthogonality between signal and intrinsic imaginary interference (IMI) in offset quadrature amplitude modulation (offset-QAM) orthogonal frequency division multiplexing (OFDM) can still be maintained under a certain condition even when the timing slots of different subcarriers are misaligned. We show that the phase and velocity differences over subcarriers induced by fiber dispersion satisfy this condition. Based on this, we propose a fast channel estimation and equalization scheme without prior channel information including coarse dispersion. We investigate the proposed scheme in a 40-Gbit/s offset-16QAM OFDM experiment and 240-Gbit/s polarization-division-multiplexed offset-16QAM OFDM simulations, both over 1200-km single-mode fiber. It is shown that the proposed scheme gives better performance, reduced overhead for the training sequence, and/or lower complexity than other schemes. We also compare offset-QAM OFDM with the proposed scheme and conventional OFDM, and show that in addition to the elimination of cyclic prefix overhead, offset-QAM OFDM gives better performance and longer transmission reach for a moderate/small number of subcarriers.

Orthogonal chirp-division multiplexing for IM/DD-based short-reach systems.

Orthogonal chirp-division multiplexing (OCDM) has been recently proposed as an attractive modulation technique for realizing high-speed coherent lightwave systems in virtue of its resilience against system impairments. However, the complex-valued OCDM signal is not directly viable for optical intensity modulation and direct detection (IM/DD) systems. In this paper, a double-sideband (DSB)-modulated OCDM scheme is proposed for short-reach, high-speed IM/DD systems. In the proposed scheme, the real-valued OCDM signal is generated by a simple digital up-conversion technique, which converts the complex-baseband signal to a passband to avoid the aliasing for DSB modulation. At the receiver, inverse operations revert the signal back to the baseband for demodulation. Experiments were carried out to validate the feasibility and advantages of the proposed scheme, and OCDM signals with data rates up to 174.5 Gbit/s were successfully demonstrated. The results confirm that the proposed IM/DD-OCDM system is more robust to impairments and thus achieves better performance than a discrete multi-tone system.

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.

Integrated Cellular and Plasma Proteomics of Contrasting B-cell Cancers Reveals Common, Unique and Systemic Signatures.

Approximately 800,000 leukemia and lymphoma cases are diagnosed worldwide each year. Burkitt's lymphoma (BL) and chronic lymphocytic leukemia (CLL) are examples of contrasting B-cell cancers; BL is a highly aggressive lymphoid tumor, frequently affecting children, whereas CLL typically presents as an indolent, slow-progressing leukemia affecting the elderly. The B-cell-specific overexpression of the myc and TCL1 oncogenes in mice induce spontaneous malignancies modeling BL and CLL, respectively. Quantitative mass spectrometry proteomics and isobaric labeling were employed to examine the biology underpinning contrasting Eµ-myc and Eµ-TCL1 B-cell tumors. Additionally, the plasma proteome was evaluated using subproteome enrichment to interrogate biomarker emergence and the systemic effects of tumor burden. Over 10,000 proteins were identified (q<0.01) of which 8270 cellular and 2095 plasma proteins were quantitatively profiled. A common B-cell tumor signature of 695 overexpressed proteins highlighted ribosome biogenesis, cell-cycle promotion and chromosome segregation. Eµ-myc tumors overexpressed several methylating enzymes and underexpressed many cytoskeletal components. Eµ-TCL1 tumors specifically overexpressed ER stress response proteins and signaling components in addition to both subunits of the interleukin-5 (IL5) receptor. IL5 treatment promoted Eµ-TCL1 tumor proliferation, suggesting an amplification of IL5-induced AKT signaling by TCL1. Tumor plasma contained a substantial tumor lysis signature, most prominent in Eµ-myc plasma, whereas Eµ-TCL1 plasma contained signatures of immune-response, inflammation and microenvironment interactions, with putative biomarkers in early-stage cancer. These findings provide a detailed characterization of contrasting B-cell tumor models, identifying common and specific tumor mechanisms. Integrated plasma proteomics allowed the dissection of a systemic response and a tumor lysis signature present in early- and late-stage cancers, respectively. Overall, this study suggests common B-cell cancer signatures exist and illustrates the potential of the further evaluation of B-cell cancer subtypes by integrative proteomics.

Increased circulating resistin levels in early-onset breast cancer patients of normal body mass index correlate with lymph node negative involvement and longer disease free survival: a multi-center POSH cohort serum proteomics study.

BACKGROUND: Early-onset breast cancer (EOBC) affects about one in 300 women aged 40 years or younger and is associated with worse outcomes than later onset breast cancer. This study explored novel serum proteins as surrogate markers of prognosis in patients with EOBC. METHODS: Serum samples from EOBC patients (stages 1-3) were analysed using agnostic high-precision quantitative proteomics. Patients received anthracycline-based chemotherapy. The discovery cohort (n = 399) either had more than 5-year disease-free survival (DFS) (good outcome group, n = 203) or DFS of less than 2 years (poor outcome group, n = 196). Expressed proteins were assessed for differential expression between the two groups. Bioinformatics pathway and network analysis in combination with literature research were used to determine clinically relevant proteins. ELISA analysis against an independent sample set from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort (n = 181) was used to validate expression levels of the selected target. Linear and generalized linear modelling was applied to determine the effect of target markers, body mass index (BMI), lymph node involvement (LN), oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 status on patients' outcome. RESULTS: A total of 5346 unique proteins were analysed (peptide FDR p ≤ 0.05). Of these, 812 were differentially expressed in the good vs poor outcome groups and showed significant enrichment for the insulin signalling (p = 0.01) and the glycolysis/gluconeogenesis (p = 0.01) pathways. These proteins further correlated with interaction networks involving glucose and fatty acid metabolism. A consistent nodal protein to these metabolic networks was resistin (upregulated in the good outcome group, p = 0.009). ELISA validation demonstrated resistin to be upregulated in the good outcome group (p = 0.04), irrespective of BMI and ER status. LN involvement was the only covariate with a significant association with resistin measurements (p = 0.004). An ancillary in-silico observation was the induction of the inflammatory response, leucocyte infiltration, lymphocyte migration and recruitment of phagocytes (p < 0.0001, z-score > 2). Survival analysis showed that resistin overexpression was associated with improved DFS. CONCLUSIONS: Higher circulating resistin correlated with node-negative patients and longer DFS independent of BMI and ER status in women with EOBC. Overexpression of serum resistin in EOBC may be a surrogate indicator of improved prognosis.

Point-to-point overlay of a 100Gb/s DP-QPSK channel in LR-PONs for urban and rural areas.

The continuing growth in information demand from fixed and mobile end-users, coupled with the need to deliver this content in an economically viable manner, is driving new innovations in access networks. In particular, it is becoming increasingly important to find new ways to enable the coexistence of heterogeneous services types which may require different signal modulation formats over the same fiber infrastructure. For example, the same physical layer can potentially be used to deliver shared 10Gb/s services to residential customers, dedicated point-to-point (P2P) 100Gb/s services to business customers, and wireless fronthaul, in a highly cost-effective manner. In this converged scenario, the performance of phase modulated signals can be heavily affected by nonlinear crosstalk from co-propagating on-off-keying (OOK) channels. In this paper, the overlay of a 100G P2P dual-polarization quadrature phase-shift keying (DP-QPSK) channel in a long-reach passive optical network (LR-PON) in the presence of co-propagating 10Gb/s OOK neighboring channels is studied for two different PON topologies. The first LR-PON topology is particularly suited for densely populated areas while the second is aimed at rural, sparsely populated areas. The experimental results indicate that with an emulated load of 40 channels the urban architecture can support up to 100km span and 512 users, while the rural architecture can support up to 120km span and 1024 users. Finally, a system model is developed to predict the system performance and system margins for configurations different from the experimental setups and to carry out design optimization that could in principle lead to even more efficient and robust schemes.

Gravity and the Spin-2 Planar Schrödinger Equation.

A Schrödinger equation proposed for the Girvin-MacDonald-Platzman gapped spin-2 mode of fractional quantum Hall states is found from a novel nonrelativistic limit, applicable only in 2+1 dimensions, of the massive spin-2 Fierz-Pauli field equations. It is also found from a novel null reduction of the linearized Einstein field equations in 3+1 dimensions, and in this context a uniform distribution of spin-2 particles implies, via a Brinkmann-wave solution of the nonlinear Einstein equations, a confining harmonic oscillator potential for the individual particles.

Exploring and exploiting the systemic effects of deregulated replication licensing.

Maintenance and accurate propagation of the genetic material are key features for physiological development and wellbeing. The replication licensing machinery is crucial for replication precision as it ensures that replication takes place once per cell cycle. Thus, the expression status of the components comprising the replication licensing apparatus is tightly regulated to avoid re-replication; a form of replication stress that leads to genomic instability, a hallmark of cancer. In the present review we discuss the mechanistic basis of replication licensing deregulation, which leads to systemic effects, exemplified by its role in carcinogenesis and a variety of genetic syndromes. In addition, new insights demonstrate that above a particular threshold, the replication licensing factor Cdc6 acts as global transcriptional regulator, outlining new lines of exploration. The role of the putative replication licensing factor ChlR1/DDX11, mutated in the Warsaw Breakage Syndrome, in cancer is also considered. Finally, future perspectives focused on the potential therapeutic advantage by targeting replication licensing factors, and particularly Cdc6, are discussed.

Optimization of PAM-4 transmitters based on lumped silicon photonic MZMs for high-speed short-reach optical links.

We demonstrate how to optimize the performance of PAM-4 transmitters based on lumped Silicon Photonic Mach-Zehnder Modulators (MZMs) for short-reach optical links. Firstly, we analyze the trade-off that occurs between extinction ratio and modulation loss when driving an MZM with a voltage swing less than the MZM's Vπ. This is important when driver circuits are realized in deep submicron CMOS process nodes. Next, a driving scheme based upon a switched capacitor approach is proposed to maximize the achievable bandwidth of the combined lumped MZM and CMOS driver chip. This scheme allows the use of lumped MZM for high speed optical links with reduced RF driver power consumption compared to the conventional approach of driving MZMs (with transmission line based electrodes) with a power amplifier. This is critical for upcoming short-reach link standards such as 400Gb/s 802.3 Ethernet. The driver chip was fabricated using a 65nm CMOS technology and flip-chipped on top of the Silicon Photonic chip (fabricated using IMEC's ISIPP25G technology) that contains the MZM. Open eyes with 4dB extinction ratio for a 36Gb/s (18Gbaud) PAM-4 signal are experimentally demonstrated. The electronic driver chip has a core area of only 0.11mm2 and consumes 236mW from 1.2V and 2.4V supply voltages. This corresponds to an energy efficiency of 6.55pJ/bit including Gray encoder and retiming, or 5.37pJ/bit for the driver circuit only.

Anti-de Sitter Particles and Manifest (Super)Isometries.

Starting from the classical action for a spin-zero particle in a D-dimensional anti-de Sitter (AdS) spacetime, we recover the Breitenlohner-Freedman bound by quantization. For D=4, 5, 7 and using an Sl(2;K) spinor notation for K=R,C,H, we find a bitwistor form of the action for which the AdS isometry group is linearly realized, although only for zero mass when D=4, 7 in agreement with previous constructions. For zero mass and D=4 the conformal isometry group is linearly realized. We extend these results to the superparticle in the maximally supersymmetric "AdS×S" string or M-theory vacua, showing that quantization yields a 128+128 component supermultiplet. We also extend them to the null string.