Motor neuron-derived Thsd7a is essential for zebrafish vascular development via the Notch-dll4 signaling pathway.

BackgroundDevelopment of neural and vascular systems displays astonishing similarities among vertebrates. This parallelism is under a precise control of complex guidance signals and neurovascular interactions. Previously, our group identified a highly conserved neural protein called thrombospondin type I domain containing 7A (THSD7A). Soluble THSD7A promoted and guided endothelial cell migration, tube formation and sprouting. In addition, we showed that thsd7a could be detected in the nervous system and was required for intersegmental vessels (ISV) patterning during zebrafish development. However, the exact origin of THSD7A and its effect on neurovascular interaction remains unclear.ResultsIn this study, we discovered that zebrafish thsd7a was expressed in the primary motor neurons. Knockdown of Thsd7a disrupted normal primary motor neuron formation and ISV sprouting in the Tg(kdr:EGFP/mnx1:TagRFP) double transgenic zebrafish. Interestingly, we found that Thsd7a morphants displayed distinct phenotypes that are very similar to the loss of Notch-delta like 4 (dll4) signaling. Transcript profiling further revealed that expression levels of notch1b and its downstream targets, vegfr2/3 and nrarpb, were down-regulated in the Thsd7a morphants. These data supported that zebrafish Thsd7a could regulate angiogenic sprouting via Notch-dll4 signaling during development.ConclusionsOur results suggested that motor neuron-derived Thsd7a plays a significant role in neurovascular interactions. Thsd7a could regulate ISV angiogenesis via Notch-dll4 signaling. Thus, Thsd7a is a potent angioneurin involved in the development of both neural and vascular systems

How to Estimate Model Transferability of Pre-Trained Speech Models?

In this work, we introduce a ``score-based assessment'' framework for estimating the transferability of pre-trained speech models (PSMs) for fine-tuning target tasks. We leverage upon two representation theories, Bayesian likelihood estimation and optimal transport, to generate rank scores for the PSM candidates using the extracted representations. Our framework efficiently computes transferability scores without actual fine-tuning of candidate models or layers by making a temporal independent hypothesis. We evaluate some popular supervised speech models (e.g., Conformer RNN-Transducer) and self-supervised speech models (e.g., HuBERT) in cross-layer and cross-model settings using public data. Experimental results show a high Spearman's rank correlation and low $p$-value between our estimation framework and fine-tuning ground truth. Our proposed transferability framework requires less computational time and resources, making it a resource-saving and time-efficient approach for tuning speech foundation models.Comment: Accepted to Interspeech. Code will be release

GRP78 Knockdown Enhances Apoptosis via the Down-Regulation of Oxidative Stress and Akt Pathway after Epirubicin Treatment in Colon Cancer DLD-1 Cells

INTRODUCTION: The 78-kDa glucose-regulated protein (GRP78) is induced in the cancer microenvironment and can be considered as a novel predictor of responsiveness to chemotherapy in many cancers. In this study, we found that intracellular reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation were higher in GRP78 knockdown DLD-1 colon cancer cells compared with scrambled control cells. METHODOLOGY/PRINCIPAL FINDINGS: Treatment with epirubicin in GRP78 knockdown DLD-1 cells enhanced apoptosis and was associated with decreased production of intracellular ROS. In addition, apoptosis was increased by the antioxidants propyl gallate (PG) and dithiothreitol (DTT) in epirubicin-treated scrambled control cells. Epirubicin-treated GRP78 knockdown cells resulted in more inactivated Akt pathway members, such as phosphorylated Akt and GSK-3β, as well as downstream targets of β-catenin expression. Knockdown of Nrf2 with small interfering RNA (siRNA) increased apoptosis in epirubicin-treated GRP78 knockdown cells, which suggested that Nrf2 may be a primary defense mechanism in GRP78 knockdown cells. We also demonstrated that epirubicin-treated GRP78 knockdown cells could decrease survival pathway signaling through the redox activation of protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase that negatively regulates the Akt pathway. CONCLUSIONS: Our results indicate that epirubicin decreased the intracellular ROS in GRP78 knockdown cells, which decreased survival signaling through both the Akt pathway and the activation of PP2A. Together, these mechanisms contributed to the enhanced level of epirubicin-induced apoptosis that was observed in the GRP78 knockdown cells

Rapid Cdc13 turnover and telomere length homeostasis are controlled by Cdk1-mediated phosphorylation of Cdc13

Budding yeast telomerase is mainly activated by Tel1/Mec1 (yeast ATM/ATR) on Cdc13 from late S to G2 phase of the cell cycle. Here, we demonstrated that the telomerase-recruitment domain of Cdc13 is also phosphorylated by Cdk1 at the same cell cycle stage as the Tel1/Mec1-dependent regulation. Phosphor-specific gel analysis demonstrated that Cdk1 phosphorylates residues 308 and 336 of Cdc13. The residue T308 of Cdc13 is critical for efficient Mec1-mediated S306 phosphorylation in vitro. Phenotypic analysis in vivo revealed that the mutations in the Cdc13 S/TP motifs phosphorylated by Cdk1 caused cell cycle delay and telomere shortening and these phenotypes could be partially restored by the replacement with a negative charge residue. In the absence of Ku or Tel1, Cdk1-mediated phosphorylation of Cdc13 showed no effect on telomere length maintenance. Moreover, this Cdk1-mediated phosphorylation was required to promote the regular turnover of Cdc13. Together these results demonstrate that Cdk1 phosphorylates the telomerase recruitment domain of Cdc13, thereby preserves optimal function and expression level of Cdc13 for precise telomere replication and cell cycle progression

Anti-UVC Irradiation and Metal Chelation Properties of 6-Benzoyl-5,7-dihydroxy-4-phenyl-chromen-2-one: An Implications for Anti-Cataract Agent

Coumarin derivative 1, 5,7-dihydroxy-6-(3-methyl-1-butyryl)-4-phenyl-chromen- 2-one, has been reported to possess radical scavenging activity and DNA protection. We have synthesized a series of coumarins with structural modifications at positions C4, C5, C6 and C7 and evaluated them for their anti-UVC properties. Coumarin 7, 6-benzoyl-5,6-dihydroxy-4-phenyl-chromen-2-one, was found to have the most potent activity in protecting porcine γ-crystallin against UVC insults. Results of fluorescence assays indicated that compound 7 was capable of decreasing the loss of intensity while lens crystallins and DNA PUC19 were irradiated with UVC. Presence of compound 7 decreased hydroxyl radical levels determined by probe 1b and the free iron concentrations determined by Ferrozine reagent. The chelation assay showed that compound 7 was chelated to metal via 6-CO and 5-OH on the benzopyrone ring. The observed protective effects of compound 7 towards crystallins from insults of UVC and free radicals may be due to its iron-chelating activity and its peak absorption at 254 nm

Hybrid Ring- and Tree-Topology RoF Transmission System with Disconnection Protection

This paper proposes a hybrid ring- and tree-topology radio over fiber (RoF) transmission system with self-disconnection protection that can support the high distribution density of base stations (BSs) in a metropolitan area and strengthen the network quality of service through self-disconnection protection. The number of supportable BS in the system can be increased significantly by integrating the time- and wavelength-division multiplexing techniques and properly utilizing a new-generation single-line bidirectional add/drop multiplexer (SBOADM) into the proposed system. Moreover, when the ring–fiber link of the system is interrupted for any reason, the system operator can recover the broken connections quickly only by transforming an optical switch state at the CO end to allow the downlink optical signals to transmit along the clockwise and counterclockwise directions of the ring–fiber link simultaneously. In this case, the downstream optical signals can be delivered to each set of BS-groups through the two-way transmission characteristics of the SBOADM automatically, and the uplink optical signals, originally, from each set of BS-groups can be transmitted back to the CO end along the opposite direction of the downlink signal-routing path. In this way, the interference caused by fiber breakage can be avoided immediately, and the entire transport system can be reconnected to ensure the quality of network services. Our experimental results prove that the overall transmission performances are similar to those under normal circumstances

Single-Line Bidirectional Optical Add/Drop Multiplexer for Ring Topology Optical Fiber Networks

A new type of passive single-line bidirectional optical add/drop multiplexer (SBOADM) is proposed and experimentally demonstrated. When the proposed SBOADM is placed as a node of a ring topology optical fiber network, the special routing function of the SBOADM can always drop down the desired downstream signals whether the signals are injected into the SBOADM in either the clockwise (CW) or counterclockwise (CCW) direction and can upload and send back the upstream signals via the reversed optical pathway of the downstream signals. Once fiber link failure occurs in the optical network, the blocked network connections can be recovered immediately by sending out the downstream signals in both the CW and CCW directions of the fiber ring. As in all passive devices, the SBOADM needs no power supply or complicated network management to achieve the bidirectional function. Thus, the proposed device is an optimal solution to enhance the stability and reliability of rapidly developed optical fiber networks

Hybrid Ring- and Tree-Topology RoF Transmission System with Disconnection Protection

This paper proposes a hybrid ring- and tree-topology radio over fiber (RoF) transmission system with self-disconnection protection that can support the high distribution density of base stations (BSs) in a metropolitan area and strengthen the network quality of service through self-disconnection protection. The number of supportable BS in the system can be increased significantly by integrating the time- and wavelength-division multiplexing techniques and properly utilizing a new-generation single-line bidirectional add/drop multiplexer (SBOADM) into the proposed system. Moreover, when the ring–fiber link of the system is interrupted for any reason, the system operator can recover the broken connections quickly only by transforming an optical switch state at the CO end to allow the downlink optical signals to transmit along the clockwise and counterclockwise directions of the ring–fiber link simultaneously. In this case, the downstream optical signals can be delivered to each set of BS-groups through the two-way transmission characteristics of the SBOADM automatically, and the uplink optical signals, originally, from each set of BS-groups can be transmitted back to the CO end along the opposite direction of the downlink signal-routing path. In this way, the interference caused by fiber breakage can be avoided immediately, and the entire transport system can be reconnected to ensure the quality of network services. Our experimental results prove that the overall transmission performances are similar to those under normal circumstances