Native collagen VI delays early muscle stem cell differentiation.

Adult muscle stem cells (MuSCs) are critical for muscle homeostasis and regeneration, and their behavior relies on a finely regulated niche made of specific extracellular matrix (ECM) components and soluble factors. Among ECM proteins, collagen VI (Col6) influences the mechanical properties of the niche and, in turn, MuSC self-renewal capabilities. Here, we investigated whether Col6 can exert a direct function as a biochemical signal for regulating the stemness and differentiation of murine MuSCs and myoblasts. Native Col6, but not its pepsin-resistant fragment, counteracts the early differentiation of myogenic cells by reducing the expression of differentiation marker genes and preserving stemness features, with inhibition of the canonical Wnt pathway. Our data indicate that extracellular Col6 acts as a soluble ligand in delaying early myogenic differentiation by regulating intracellular signals involved in adult myogenesis.

Targeting Interleukin-1ß Protects from Aortic Aneurysms Induced by Disrupted Transforming Growth Factor ß Signaling.

Aortic aneurysms are life-threatening conditions with effective treatments mainly limited to emergency surgery or trans-arterial endovascular stent grafts, thus calling for the identification of specific molecular targets. Genetic studies have highlighted controversial roles of transforming growth factor ß (TGF-ß) signaling in aneurysm development. Here, we report on aneurysms developing in adult mice after smooth muscle cell (SMC)-specific inactivation of Smad4, an intracellular transducer of TGF-ß. The results revealed that Smad4 inhibition activated interleukin-1ß (IL-1ß) in SMCs. This danger signal later recruited innate immunity in the adventitia through chemokine (C-C motif) ligand 2 (CCL2) and modified the mechanical properties of the aortic wall, thus favoring vessel dilation. SMC-specific Smad4 deletion in Il1r1- or Ccr2-null mice resulted in milder aortic pathology. A chronic treatment with anti-IL-1ß antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF-ß signaling, such as those driven by SMAD4 mutations.

Effects of cavity nonlinearities and linear losses on silicon microring-based reservoir computing.

Microring resonators (MRRs) are promising devices for time-delay photonic reservoir computing, but the impact of the different physical effects taking place in the MRRs on the reservoir computing performance is yet to be fully understood. We numerically analyze the impact of linear losses as well as thermo-optic and free-carrier effects relaxation times on the prediction error of the time-series task NARMA-10. We demonstrate the existence of three regions, defined by the input power and the frequency detuning between the optical source and the microring resonance, that reveal the cavity transition from linear to nonlinear regimes. One of these regions offers very low error in time-series prediction under relatively low input power and number of nodes while the other regions either lack nonlinearity or become unstable. This study provides insight into the design of the MRR and the optimization of its physical properties for improving the prediction performance of time-delay reservoir computing.

Collagen VI sustains cell stemness and chemotherapy resistance in glioblastoma.

Microenvironmental factors are known fundamental regulators of the phenotype and aggressiveness of glioblastoma (GBM), the most lethal brain tumor, characterized by fast progression and marked resistance to treatments. In this context, the extracellular matrix (ECM) is known to heavily influence the behavior of cancer cells from several origins, contributing to stem cell niches, influencing tumor invasiveness and response to chemotherapy, mediating survival signaling cascades, and modulating inflammatory cell recruitment. Here, we show that collagen VI (COL6), an ECM protein widely expressed in both normal and pathological tissues, has a distinctive distribution within the GBM mass, strongly correlated with the most aggressive and phenotypically immature cells. Our data demonstrate that COL6 sustains the stem-like properties of GBM cells and supports the maintenance of an aggressive transcriptional program promoting cancer cell proliferation and survival. In particular, we identified a specific subset of COL6-transcriptionally co-regulated genes, required for the response of cells to replicative stress and DNA damage, supporting the concept that COL6 is an essential stimulus for the activation of GBM cell response and resistance to chemotherapy, through the ATM/ATR axis. Altogether, these findings indicate that COL6 plays a pivotal role in GBM tumor biology, exerting a pleiotropic action across different GBM hallmarks, including phenotypic identity and gene transcription, as well as response to treatments, thus providing valuable information for the understanding of the complex microenvironmental cues underlying GBM malignancy.

Addressing data scarcity in optical matrix multiplier modeling using transfer learning.

We present and experimentally evaluate the use of transfer learning to address experimental data scarcity when training neural network (NN) models for Mach-Zehnder interferometer mesh-based optical matrix multipliers. Our approach involves pretraining the model using synthetic data generated from a less accurate analytical model and fine-tuning it with experimental data. Our investigation demonstrates that this method yields significant reductions in modeling errors compared to using an analytical model or a standalone NN model when training data is limited. Utilizing regularization techniques and ensemble averaging, we achieve <1 dB root-mean-square error on the 3×3 matrix weights implemented by a photonic chip while using only 25% of the available data.

Experimental validation of machine-learning based spectral-spatial power evolution shaping using Raman amplifiers.

We experimentally validate a real-time machine learning framework, capable of controlling the pump power values of Raman amplifiers to shape the signal power evolution in two-dimensions (2D): frequency and fiber distance. In our setup, power values of four first-order counter-propagating pumps are optimized to achieve the desired 2D power profile. The pump power optimization framework includes a convolutional neural network (CNN) followed by differential evolution (DE) technique, applied online to the amplifier setup to automatically achieve the target 2D power profiles. The results on achievable 2D profiles show that the framework is able to guarantee very low maximum absolute error (MAE) (<0.5 dB) between the obtained and the target 2D profiles. Moreover, the framework is tested in a multi-objective design scenario where the goal is to achieve the 2D profiles with flat gain levels at the end of the span, jointly with minimum spectral excursion over the entire fiber length. In this case, the experimental results assert that for 2D profiles with the target flat gain levels, the DE obtains less than 1 dB maximum gain deviation, when the setup is not physically limited in the pump power values. The simulation results also prove that with enough pump power available, better gain deviation (less than 0.6 dB) for higher target gain levels is achievable.

Optimization of frequency combs spectral-flatness using evolutionary algorithm.

We demonstrate the use of meta-heuristics algorithms for flatness optimization of optical frequency combs (OFCs). Without any additional component for flatness compensation, the laser alone is explored when driven by optimized bias current and radio frequency (RF) driving signals composed by multiple harmonics. The bias current amplitude and RF harmonic amplitudes and relative phases are optimized using particle swarm optimization (PSO) and differential evolution (DE) algorithms. The numerical results lead to a 9 lines-GS-laser-based OFC spectrum with 2.9 dB flatness. An online experimental optimization using the DE algorithm results in a 7-line-GS-laser-based OFC with 2 dB flatness.

Inverse design of a Raman amplifier in frequency and distance domains using convolutional neural networks.

We present a convolutional neural network architecture for inverse Raman amplifier design. This model aims at finding the pump powers and wavelengths required for a target signal power evolution in both distance along the fiber and in frequency. Using the proposed framework, the prediction of the pump configuration required to achieve a target power profile is demonstrated numerically with high accuracy in C-band considering both counter-propagating and bidirectional pumping schemes. For a distributed Raman amplifier based on a 100 km single-mode fiber, a low mean set (0.51, 0.54, and 0.64 dB) and standard deviation set (0.62, 0.43, and 0.38 dB) of the maximum test error are obtained numerically employing two and three counter-, and four bidirectional propagating pumps, respectively.

Simultaneous gain profile design and noise figure prediction for Raman amplifiers using machine learning.

A machine learning framework predicting pump powers and noise figure profile for a target distributed Raman amplifier gain profile is experimentally demonstrated. We employ a single-layer neural network to learn the mapping from the gain profiles to the pump powers and noise figures. The obtained results show highly accurate gain profile designs and noise figure predictions, with a maximum error on average of ∼0.3dB. This framework provides a comprehensive characterization of the Raman amplifier and thus is a valuable tool for predicting the performance of next-generation optical communication systems, expected to employ Raman amplification.

All-optical OFDM demultiplexing with optical partial Fourier transform and coherent sampling.

We propose a novel scheme with a "time-lens"-based partial optical Fourier transform (OFT) and coherent sampling for high-speed complex orthogonal frequency-division multiplexing (OFDM) signal detection. Compared with all-optical OFDM demultiplexing with a matched optical filter, our proposed method replaces specialized optical filters with commercially available equipment, which relaxes stringent manufacturing and operational requirements. Our simulation shows that even with a partial OFT, theoretically, close to inter-channel interference-free performance is possible. In addition, we performed a proof-of-concept experiment of 16×10 Gbaud quadrature phase-shift keying (QPSK) all-optical OFDM detection, with all the bit error rates far below the 7% hard-overhead forward error correction limit.

Loss of EMILIN-1 Enhances Arteriolar Myogenic Tone Through TGF-ß (Transforming Growth Factor-ß)-Dependent Transactivation of EGFR (Epidermal Growth Factor Receptor) and Is Relevant for Hypertension in Mice and Humans.

Objective- EMILIN-1 (elastin microfibrils interface located protein-1) protein inhibits pro-TGF-ß (transforming growth factor-ß) proteolysis and limits TGF-ß bioavailability in vascular extracellular matrix. Emilin1-/- null mice display increased vascular TGF-ß signaling and are hypertensive. Because EMILIN-1 is expressed in vessels from embryonic life to adulthood, we aimed at unravelling whether the hypertensive phenotype of Emilin1-/- null mice results from a developmental defect or lack of homeostatic role in the adult. Approach and Results- By using a conditional gene targeting inactivating EMILIN-1 in smooth muscle cells of adult mice, we show that increased blood pressure in mice with selective smooth muscle cell ablation of EMILIN-1 depends on enhanced myogenic tone. Mechanistically, we unveil that higher TGF-ß signaling in smooth muscle cells stimulates HB-EGF (heparin-binding epidermal growth factor) expression and subsequent transactivation of EGFR (epidermal growth factor receptor). With increasing intraluminal pressure in resistance arteries, the cross talk established by TGF-ß and EGFR signals recruits TRPC6 (TRP [transient receptor potential] classical type 6) and TRPM4 (TRP melastatin type 4) channels, lastly stimulating voltage-dependent calcium channels and potentiating myogenic tone. We found reduced EMILIN-1 and enhanced myogenic tone, dependent on increased TGF-ß-EGFR signaling, in resistance arteries from hypertensive patients. Conclusions- Taken together, our findings implicate an unexpected role of the TGF-ß-EGFR pathway in hypertension with current translational perspectives.

12 mode, WDM, MIMO-free orbital angular momentum transmission.

Simultaneous MIMO-free transmission of 12 orbital angular momentum (OAM) modes over a 1.2 km air-core fiber is demonstrated. WDM compatibility of the system is shown by using 60, 25 GHz spaced WDM channels with 10 GBaud QPSK signals. System performance is evaluated by measuring bit error rates, which are found to be below the soft FEC limit, and limited by inter-modal crosstalk. The crosstalk in the system is analyzed, and it is concluded that it can be significantly reduced with an improved multiplexer and de-multiplexer.

THz photonic wireless links with 16-QAM modulation in the 375-450 GHz band.

We propose and experimentally demonstrate THz photonic wireless communication systems with 16-QAM modulation in the 375-450 GHz band. The overall throughput reaches as high as 80 Gbit/s by exploiting four THz channels with 5 Gbaud 16-QAM baseband modulation per channel. We create a coherent optical frequency comb (OFC) for photonic generation of multiple THz carriers based on photo-mixing in a uni-travelling carrier photodiode (UTC-PD). The OFC configuration also allows us to generate reconfigurable THz carriers with low phase noise. The multiple-channel THz radiation is received by using a Schottky mixer based electrical receiver after 0.5 m free-space wireless propagation. 2-channel (40 Gbit/s) and 4-channel (80 Gbit/s) THz photonic wireless links with 16-QAM modulation are reported in this paper, and the bit error rate (BER) performance for all channels in both cases is below the hard decision forward error correction (HD-FEC) threshold of 3.8e-3 with 7% overhead. In addition, we also successfully demonstrate hybrid photonic wireless transmission of 40 Gbit/s 16-QAM signal at carrier frequencies of 400 GHz and 425 GHz over 30 km standard single mode fiber (SSMF) between the optical baseband signal transmitter and the THz wireless transmitter with negligible induced power penalty.

Multichannel nonlinear distortion compensation using optical phase conjugation in a silicon nanowire.

We experimentally demonstrate compensation of nonlinear distortion caused by the Kerr effect in a 3 × 32-Gbaud quadrature phase-shift keying (QPSK) wavelength-division multiplexing (WDM) transmission system. We use optical phase conjugation (OPC) produced by four-wave mixing (FWM) in a 7-mm long silicon nanowire. A clear improvement in Q-factor is shown after 800-km transmission with high span input power when comparing the system with and without the optical phase conjugation module. The influence of OSNR degradation introduced by the silicon nanowire is analysed by comparing transmission systems of three different lengths. This is the first demonstration of nonlinear compensation using a silicon nanowire.

Kerr nonlinearity mitigation in 5 × 28-GBd PDM 16-QAM signal transmission over a dispersion-uncompensated link with backward-pumped distributed Raman amplification.

We present experimental and numerical investigations of Kerr nonlinearity compensation in a 400-km standard single-mode fiber link with distributed Raman amplification with backward pumping. A dual-pump polarization-independent fiber-based optical parametric amplifier is used for mid-link spectral inversion of 5 × 28-GBd polarization-multiplexed 16-QAM signals. Signal quality factor (Q-factor) improvements of 1.1 dB and 0.8 dB were obtained in the cases of a single-channel and a five-channel wavelength-division multiplexing (WDM) system, respectively. The experimental results are compared to numerical simulations with good agreement. It is also shown with simulations that a maximum transmission reach of 2400 km enabled by the optical phase conjugator is possible for the WDM signal.

Phase regeneration of DPSK signals in a silicon waveguide with reverse-biased p-i-n junction.

Phase regeneration of differential phase-shift keying (DPSK) signals is demonstrated using a silicon waveguide as nonlinear medium for the first time. A p-i-n junction across the waveguide enables decreasing the nonlinear losses introduced by free-carrier absorption (FCA), thus allowing phase-sensitive extinction ratios as high as 20 dB to be reached under continuous-wave (CW) pumping operation. Furthermore the regeneration properties are investigated under dynamic operation for a 10-Gb/s DPSK signal degraded by phase noise, showing receiver sensitivity improvements above 14 dB. Different phase noise frequencies and amplitudes are examined, resulting in an improvement of the performance of the regenerated signal in all the considered cases.

Modeling Doxorubicin Pharmacokinetics in Multiple Myeloma Suggests Mechanism of Drug Resistance.

OBJECTIVE: Multiple myeloma (MM) is a plasma cell malignancy often treated with chemotherapy drugs. Among these, doxorubicin (DOXO) is commonly employed, sometimes in combined-drug therapies, but it has to be optimally administered in order to maximize its efficacy and reduce possible side effects. To support DOXO studies and treatment optimization, here we propose an experimental/modeling approach to establish a model describing DOXO pharmacokinetics (PK) in MM cells. METHODS: A series of in vitro experiments were performed in MM1R and MOLP-2 cells. DOXO was administered at two dosages (200 nM, 450 nM) at [Formula: see text] = 0 and removed at [Formula: see text] = 3 hrs. Intracellular DOXO concentration was measured via fluorescence microscopy during both drug uptake ([Formula: see text] = 0-3 hrs) and release phases ([Formula: see text] = 3-8 hrs). Four PK candidate models were identified, and were compared and selected based on their ability to describe DOXO data and numerical parameter identification. RESULTS: The most parsimonious model consists of three compartments describing DOXO distribution between the extracellular space, the cell cytoplasm and the nucleus, and defines the intracellular DOXO efflux rate through a Hill function, simulating a threshold/saturation drug resistance mechanism. This model predicted DOXO data well in all the experiments and provided precise parameter estimates (mean ± standard deviation coefficient of variation: 15.8 ± 12.2%). CONCLUSIONS: A reliable PK model describing DOXO uptake and release in MM cells has been successfully developed. SIGNIFICANCE: The proposed PK model, once integrated with DOXO pharmacodynamics, has the potential of allowing the study and the optimization of DOXO treatment strategies in MM.

Ex vivo expansion in a clinical grade medium, containing growth factors from human platelets, enhances migration capacity of adipose stem cells.

Introduction: Adipose tissue mesenchymal stem/stromal cells (ASC) can be used as advanced therapy medicinal product in regenerative and cancer medicine. We previously demonstrated Supernatant Rich in Growth Factors (SRGF) can replace fetal bovine serum (FBS) to expand ASC by a clinical grade compliant protocol. The therapeutic potential of ASC is based also on their homing capacity toward inflammatory/cancer sites: oriented cell migration is a fundamental process in this scenario. We investigated the impact of SRGF on ASC migration properties. Methods: The motility/migration potential of ASC expanded in 5% SRGF was analyzed, in comparison to 10% FBS, by standard wound healing, bidimensional chemotaxis and transwell assays, and by millifluidic transwell tests. Mechanisms involved in the migration process were investigated by transient protein overexpression. Results: In comparison to standard 10% FBS, supplementation of the cell culture medium with 5% SRGF, strongly increased migration properties of ASC along the chemotactic gradient and toward cancer cell derived soluble factors, both in static and millifluidic conditions. We showed that, independently from applied migratory stimulus, SRGF expanded ASC were characterized by far lower expression of α-smooth muscle actin (αSMA), a protein involved in the cell migration machinery. Overexpression of αSMA induced a significant and marked decrease in migration capacity of SRGF expanded ASC. Discussion: In conclusion, 5% SRGF addition in the cell culture medium increases the migration potential of ASC, reasonably through appropriate downregulation of αSMA. Thus, SRGF could potentially improve the therapeutic impact of ASC, both as modulators of the immune microenviroment or as targeted drug delivery vehicles in oncology.

Polarization diversity DPSK demodulator on the silicon-on-insulator platform with simple fabrication.

We demonstrate a novel polarization diversity differential phase-shift keying (DPSK) demodulator on the SOI platform, which is fabricated in a single lithography and etching step. The polarization diversity DPSK demodulator is based on a novel polarization splitter and rotator, which consists of a tapered waveguide followed by a 2 × 2 multimode interferometer. A lowest insertion loss of 0.5 dB with low polarization dependent loss of 1.6 dB and low polarization dependent extinction ratio smaller than 3 dB are measured for the polarization diversity circuit. Clear eye-diagrams and a finite power penalty of only 3 dB when the input state of polarization is scrambled are obtained for 40 Gbit/s non return-to-zero DPSK (NRZ-DPSK) demodulation.

QPSK-to-2×BPSK wavelength and modulation format conversion through phase-sensitive four-wave mixing in a highly nonlinear optical fiber.

A phase-sensitive four-wave mixing (FWM) scheme enabling the simultaneous conversion of the two orthogonal quadratures of an optical signal to different wavelengths is demonstrated for the first time under dynamic operation using a highly nonlinear optical fiber (HNLF) as the nonlinear medium. The scheme is first optimized with respect to the power levels and phases of the four phase-coherent pumps. The successful modulation and wavelength conversion of the two complex quadratures of a quadrature phase-shift keying (QPSK) signal to two binary phase-shift keying (BPSK) signals is then demonstrated experimentally with no power penalty at a bit-error-ratio (BER) of 10(-9) compared to direct interferometric demodulation of the QPSK signal.