TACH101, a first-in-class pan-inhibitor of KDM4 histone demethylase.

Histone lysine demethylase 4 (KDM4) is an epigenetic regulator that facilitates the transition between transcriptionally silent and active chromatin states by catalyzing the removal of methyl groups on histones H3K9, H3K36, and H1.4K26. KDM4 overamplification or dysregulation has been reported in various cancers and has been shown to drive key processes linked to tumorigenesis, such as replicative immortality, evasion of apoptosis, metastasis, DNA repair deficiency, and genomic instability. KDM4 also plays a role in epigenetic regulation of cancer stem cell renewal and has been linked to more aggressive disease and poorer clinical outcomes. The KDM4 family is composed of four main isoforms (KDM4A-D) that demonstrate functional redundancy and cross-activity; thus, selective inhibition of one isoform appears to be ineffective and pan-inhibition targeting multiple KDM4 isoforms is required. Here, we describe TACH101, a novel, small-molecule pan-inhibitor of KDM4 that selectively targets KDM4A-D with no effect on other KDM families. TACH101 demonstrated potent antiproliferative activity in cancer cell lines and organoid models derived from various histologies, including colorectal, esophageal, gastric, breast, pancreatic, and hematological malignancies. In vivo , potent inhibition of KDM4 led to efficient tumor growth inhibition and regression in several xenograft models. A reduction in the population of tumor-initiating cells was observed following TACH101 treatment. Overall, these observations demonstrate the broad applicability of TACH101 as a potential anticancer agent and support its advancement into clinical trials.

An Efficient Grid-Based Geocasting Scheme for Wireless Sensor Networks.

In a wireless sensor network (WSN), geocasting is a location-based routing protocol used for data collection or information delivery. In geocasting, a target region usually contains many sensor nodes with limited battery capacity, and sensor nodes in multiple target regions need to transmit data to the sink. Therefore, how to use location information to construct an energy efficient geocasting path is a very important issue. FERMA is a geocasting scheme for WSNs based on Fermat points. In this paper, an efficient grid-based geocasting scheme for WSNs, which is called GB-FERMA, is proposed. The scheme uses the Fermat point theorem to search for the specific nodes as Fermat points in a grid-based WSN, and it selects the optimal relay nodes (gateways) in the grid structure to realize energy-aware forwarding. In the simulations, when the initial power 0.25 J, the average energy consumption of GB-FERMA is about 53% of FERMA-QL, 37% of FERMA, and 23% of GEAR; however, when with the initial power 0.5 J, the average energy consumption of GB-FERMA is about 77% of FERMA-QL, 65% of FERMA, and 43% of GEAR. The proposed GB-FERMA can effectively reduce the energy consumption and thus prolong the lifetime of the WSN.

An Energy Efficient Load Balancing Tree-Based Data Aggregation Scheme for Grid-Based Wireless Sensor Networks.

A wireless sensor network (WSN) consists of a very large number of sensors which are deployed in the specific area of interest. A sensor is an electronic device equipped with a small processor and has a small-capacity memory. The WSN has the functions of low cost, easy deployment, and random reconfiguration. In this paper, an energy-efficient load balancing tree-based data aggregation scheme (LB-TBDAS) for grid-based WSNs is proposed. In this scheme, the sensing area is partitioned into many cells of a grid and then the sensor node with the maximum residual energy is elected to be the cell head in each cell. Then, the tree-like path is established by using the minimum spanning tree algorithm. In the tree construction, it must meet the three constraints, which are the minimum energy consumption spanning tree, the network depth, and the maximum number of child nodes. In the data transmission process, the cell head is responsible for collecting the sensing data in each cell, and the collected data are transmitted along the tree-like path to the base station (BS). Simulation results show that the total energy consumption of LB-TBDAS is significantly less than that of GB-PEDAP and PEDAP. Compared to GB-PEDAP and PEDAP, the proposed LB-TBDAS extends the network lifetime by more than 100%. The proposed LB-TBDAS can avoid excessive energy consumption of sensor nodes during multi-hop data transmission and can also avoid the hotspot problem of WSNs.

Computation efficient sparse DNN nonlinear equalization for IM/DD 112 Gbps PAM4 inter-data center optical interconnects.

In this Letter, we propose and experimentally demonstrate a novel, to the best of our knowledge, sparse deep neural network-based nonlinear equalizer (SDNN-NLE). By identifying only the significant weight coefficients, our approach remarkably reduces the computational complexity, while still upholding the desired transmission accuracy. The insignificant weights are pruned in two phases: identifying the significance of each weight by pre-training the fully connected DNN-NLE with an adaptive L2-regularization and then pruning those insignificant ones away with a pre-defined sparsity. An experimental demonstration is conducted on a 112 Gbps PAM4 link over 40 km standard single-mode fiber with a 25 GHz externally modulated laser in O-band. Our experimental results illustrate that, for the 112 Gbps PAM4 signal at a received optical power of -5dBm over 40 km, the proposed SDNN-NLE exhibits promising solutions to effectively mitigate nonlinear distortions and outperforms a conventional fully connected Volterra equalizer (VE), conventional fully connected DNN-NLE, and sparse VE by providing 71%, 63%, and 41% complexity reduction, respectively, without degrading the system performance.

FUSE binding protein FUBP3 is a potent regulator in Japanese encephalitis virus infection.

BACKGROUND: The JEV genome is a positive-sense RNA with a highly structured capped 5'UTR, 3'UTR and a large open reading frame. 3'UTR is the untranslated region of flavivirus and has various important functions during viral replication, such as translation, replication and encapsidation. During viral replication, the 3'UTR interacts with viral proteins and host proteins and is required for viral RNA replication and translocation. METHODS: The expression level of FUBP3 was knocked down by siRNA and Flag-tagged FUBP3 overexpression plasmid was constructed for overexpression. BHK-21 cells were cultured and infected with JEV to investigate the functional role of FUBP3 in the viral infection cycle. Subcellular localization of FUBP3 and viral replication complexes was observed by dual immunofluorescence staining. RESULTS: Four host proteins were specifically associated with the 3'UTR of JEV, and FUBP3 was selected to further investigate its potential functional role in the JEV infection cycle. Knockdown of FUBP3 protein resulted in a significant decrease in JEV viral titer, whereas ectopic overexpression of FUBP3 resulted in increased JE viral infectivity. In cells stably knocked down for FUBP3 and then infected with JEV, we found almost no detectable viral NS5 protein. In contrast, when cells stably knocking-down of FUBP3 overexpressed FUBP3, we found a significant increase in viral RNA production over time compared to controls. We also demonstrated that FUBP3 re-localized in the cytoplasm after infection with JEV and co-localized with viral proteins. Exogenous overexpression of FUBP3 was also shown to be located in the JE replication complex and to assist viral replication after JEV infection. CONCLUSIONS: The overall results suggest that FUBP3 regulates RNA replication of JEV and promotes subsequent viral translation and viral particle production.

Reducing computation complexity by using elastic net regularization based pruned Volterra equalization in a 80 Gbps PAM-4 signal for inter-data center interconnects.

Volterra equalization (VE) presents substantial performance enhancement for high-speed optical signals but suffers from high computation complexity which limits its physical implementations. To address these limitations, we propose and experimentally demonstrate an elastic net regularization-based pruned Volterra equalization (ENPVE) to reduce the computation complexity while still maintain system performance. Our proposed scheme prunes redundant weight coefficients with a three-phase configuration. Firstly, we pre-train the VE with an adaptive EN-regularizer to identify significant weights. Next, we prune the insignificant weights away. Finally, we retrain the equalizer by fine-tuning the remaining weight coefficients. Our proposed ENPVE achieves superior performance with reduced computation complexity. Compared with conventional VE and L1 regularization-based Volterra equalizer (L1VE), our approach show a complexity reduction of 97.4% and 20.2%, respectively, for an O-band 80-Gbps PAM4 signal at a received optical power of -4 dBm after 40 km SMF transmission.

Cloning and characterisation of type I interferon receptor 1 in orange-spotted grouper (Epinephelus coioides) for response to nodavirus infection.

Grouper is known as a highly economical teleost species in the Asian aquaculture industry; however, intensive culture activities easily cause disease outbreak, especially viral disease. For the prevention of viral outbreaks, interferon (IFN) is among the major defence systems being studied in different species. Fish type I IFNs are known to possess antiviral properties similar to mammalian type I IFNs. In order to stimulate antiviral function, IFN will bind to its cognate receptor, the type I interferon receptor (IFNAR), composed of heterodimeric receptor subunits known as IFNAR1 and IFNΑR2. The binding of type I interferon to receptors assists in the transduction of signals from the external to internal environments of cells to activate biological responses. In order to study the function of IFN, we first need to understand IFN receptors. In this study, we cloned and identified IFNAR1 in orange-spotted grouper (osgIFNAR1) and noted the up-regulated mRNA expression of the receptor and downstream effectors in the head kidney cells with cytokine treatment. The transcriptional expression of osgIFNAR1, which is characterised using polyinosinic-polycytidylic acid (poly[I:C]) and lipopolysaccharide (LPS) treatments, indicated the involvement of osgIFNAR1 in the immune response of grouper. The subcellular localisation of osgIFNAR1 demonstrated scattering across the grouper cell. Viral infection showed the negative feedback regulation of osgIFNAR1 in grouper larvae. Further loss of function of IFNAR1 showed a decreased expression of the virus. This study reported the identification of osgIFNAR1 and characterisation of receptor sensitivity towards immunostimulants, cytokine response, and viral challenge in the interferon pathway of orange-spotted grouper and possible different role of the receptor in viral production. Together, these results provide a frontline report of the potential function of osgIFNAR1 in the innate immunity of teleost.

Characterization of betanodavirus quasispecies influences on the subcellular localization and expression of tumor necrosis factor (TNF).

The aim of this study was to investigate the influence of variant coat proteins (CPs) from different quasispecies of betanodavirus on diverse aspects of nodavirus-induced pathogenesis. It is known that variant CPs can acquire either nuclear or cytoplasmic localization, depending on the nodavirus CP genotype, and this variation may arise during viral replication and influence the regulation of host and viral gene transcription. To investigate the role of these variant CPs in pathogenesis, six variant CP expression plasmids were constructed, each containing different quasispecies CP variants from nodavirus genotype red spotted grouper nervous necrosis virus (RGNNV). The CP expression plasmids were transiently transfected into grouper GF-1 cells. At different times, the cell cycle and cell proliferation were assayed using flow cytometry and methyl thiazolyl tetrazolium (MTT) assays, respectively. The proportion of G2/M-phase GF-1 cells transfected with CP expression plasmids was higher than that of cells transfected with the blank plasmid, especially in regards to quasispecies 2 (QS2). The proliferation ratio of cells transfected with the CP expression plasmids was significantly higher than that of cells transfected with the blank plasmid, with the exception of QS6. We also found that the different quasispecies CPs downregulated the promoter activity of the tumor necrosis factor (TNF) gene to different degrees. In addition, this is the first report showing the betanodavirus CP derived from different quasispecies of RGNNV provide evidence of a chronically nodavirus-infected grouper. Overall, this study represents the first comprehensive analysis of variant CPs from grouper with persistent nodavirus infections and their effects on different aspects of pathogenesis.

Rational discovery of a highly novel and selective mTOR inhibitor.

Aided by Structure Based Drug Discovery (SBDD), we rapidly designed a highly novel and selective series of mTOR inhibitors. This chemotype conveys exquisite kinase selectivity, excellent in vitro and in vivo potencies and ADME safety profiles. These compounds could serve as good tools to explore the potential of TORC inhibition in various human diseases.

Structure-based design and discovery of potent and selective lysine-specific demethylase 1 (LSD1) inhibitors.

The histone demethylase LSD1 is a key enzyme in the epigenetic regulation of gene transcription. Here we present our efforts to discover small molecule reversible inhibitors of LSD1 as an attractive approach to treat hematologic malignancies and certain solid tumors. Using structure-based drug design, we designed and synthesized a novel series of heteroaromatic imidazole inhibitors that demonstrate potent inhibition of the demethylase activity and low nanomolar cell-based activity. This novel LSD1 inhibitor series was further optimized by attenuating the hERG inhibition and improving oral bioavailability.

Inter-polarization mixers for coherent detection of optical signals.

Electro-magnetic (EM) mixers are fundamental building blocks in communication systems. They are used in frequency/wavelength filters, interferometric modulators, amplitude-phase receivers, to name a few. Traditional EM mixers have two or more input ports and work only for co-polarized signal and local-oscillator (LO) incident on its inputs. Here we report on novel designs, in silicon, of inter-polarization EM mixers operating at 1550 nm wavelength. The 180-degree optical mixer comprising a single input port is demonstrated to coherently mix orthogonally polarized signal and LO. Using the proposed 180-degree mixer, we report on a novel design for a 90-degree optical mixer on silicon with small footprint, broadband response, low loss and good fabrication tolerance. It exploits birefringence of a waveguide to achieve broadband and fabrication-tolerant 90° phase difference between the signal/LO relative phase in the in-phase and quadrature components. A monolithic silicon photonics coherent receiver is demonstrated using the reported 90-degree mixer, and its operation at 22 Gbaud and 44 Gbaud is shown. These mixers pave the way for novel coherent receiver architectures in long-haul, metro, passive optical networks and data-center interconnect applications.

Simultaneous four-channel thermal adaptation of polarization insensitive silicon photonics WDM receiver.

We propose a novel approach to demonstrate simultaneous multi-wavelength locking during temperature changes in a silicon photonic polarization insensitive microring-based wavelength division multiplexing (WDM) receiver. The DC component of a single monitoring photodetector at the through port of the microring filter array is exploited as a feedback signal with no additional power consumption. This feedback signal is used in control circuitry to properly tune the microring filters using ohmic heating, thus creating a feedback loop for thermal adaptation. We describe the necessary information, specifically each microring filter's room temperature resonant wavelength and tunability, which can be used to calibrate and achieve proper wavelength configurability and locking. In addition, we describe a simple control algorithm based on an adaptive gradient method often used in machine learning, allowing the receiver to endlessly demultiplex at different temperatures. We successfully achieve thermal adaptation over a temperature range >37°C and demultiplex a 4 × 25 Gb/s on-off-keying signal of 150 GHz channel spacing, all while the polarization is scrambling.

Optical filter requirements in an EML-based single-sideband PAM4 intensity-modulation and direct-detection transmission system.

The feasibility of a single sideband (SSB) PAM4 intensity-modulation and direct-detection (IM/DD) transmission based on a CMOS ADC and DAC is experimentally demonstrated in this work. To cost effectively build a >50 Gb/s system as well as to extend the transmission distance, a low cost EML and a passive optical filter are utilized to generate the SSB signal. However, the EML-induced chirp and dispersion-induced power fading limit the requirements of the SSB filter. To separate the effect of signal-signal beating interference, filters with different roll-off factors are employed to demonstrate the performance tolerance at different transmission distance. Moreover, a high resolution spectrum analysis is proposed to depict the system limitation. Experimental results show that a minimum roll-off factor of 7 dB/10GHz is required to achieve a 51.84Gb/s 40-km transmission with only linear feed-forward equalization.

Simultaneous wavelength locking of microring modulator array with a single monitoring signal.

A microring modulator array coupled to a common bus waveguide can be used to construct low power, compact and flexible wavelength-division-multiplexing (WDM) transmitters. However, due to extremely small working bandwidths of the rings, it is challenging to find the right resonant wavelength setting and locking the resonance to an external laser. In the paper, we propose a novel technique enabling simultaneous wavelength locking of a microring modulator array with a single monitor, together with automatically optimizing the wavelength setting. We experimentally demonstrate locking three rings over a temperature range >40 °C at 3x20 Gb/s on-off-keying (OOK) modulation and ~3x75 Gb/s discrete multi-tone (DMT) modulation.

128-Gb/s 100-km transmission with direct detection using silicon photonic Stokes vector receiver and I/Q modulator.

Recently, there is increasing interest in utilizing Stokes vector receiver, which is a direct-detection technique with the capability to digitally track the polarization changes in fibers and decode information in multiple dimensions. Here, we report a monolithically integrated silicon photonic Stokes vector receiver, which consists of one polarization beam splitter, two polarization rotators, one 90-degree optical hybrid, and six germanium photodetectors. Paired with a silicon in-phase/quadrature modulator incorporating a power-tunable carrier in the orthogonal polarization, transmission at 128-Gb/s over 100-km fiber is achieved with direct detection.

Molecular cloning of orange-spotted grouper (Epinephelus coioides) heat shock transcription factor 1 isoforms and characterization of their expressions in response to nodavirus.

Heat shock transcription factor 1 (HSF1) regulates heat shock proteins (HSPs), which assist in protein folding and inhibit protein denaturation following stress. HSF1 was firstly cloned from orange-spotted grouper and exists as two isoforms, one with (osgHSF1a) and one without (osgHSF1b) exon 11. Heat exposure increased the expression of osgHSF1b while cold exposure increased that of osgHSF1a. Both isoforms were mainly expressed in the brains, eyes, and fins. Expression of osgHSF1b was higher than osgHSF1a during development. Poly I:C and LPS could also induce osgHSF1 isoforms expression differentially. Exposure to nervous necrosis virus (NNV) increased the level of both osgHSF1 isoforms at 12 h. GF-1 cells with overexpression of osgHSF1 isoforms enhanced viral loads within 24 h, whereas both pharmacological inhibition and RNA interference of HSF1 reduced virus infection. This study shows that osgHSF1 can support the early stage of virus infection and provides a new insight into the molecular regulation of osgHSF1 between the influence of temperatures and immunity.

Salmonids have an extraordinary complex type I IFN system: characterization of the IFN locus in rainbow trout oncorhynchus mykiss reveals two novel IFN subgroups.

Fish type I IFNs are classified into two groups with two (group I) or four (group II) cysteines in the mature peptide and can be further divided into four subgroups, termed IFN-a, -b, -c, and -d. Salmonids possess all four subgroups, whereas other teleost species have one or more but not all groups. In this study, we have discovered two further subgroups (IFN-e and -f) in rainbow trout Oncorhynchus mykiss and analyzed the expression of all six subgroups in rainbow trout and brown trout Salmo trutta. In rainbow trout RTG-2 and RTS-11 cells, polyinosinic-polycytidylic acid stimulation resulted in early activation of IFN-d, whereas the IFN-e subgroup containing the highest number of members showed weak induction. In contrast with the cell lines, remarkable induction of IFN-a, -b, and -c was detected in primary head kidney leukocytes after polyinosinic-polycytidylic acid treatment, whereas a moderate increase of IFNs was observed after stimulation with resiquimod. Infection of brown trout with hemorrhagic septicemia virus resulted in early induction of IFN-d, -e, and -f and a marked increase of IFN-b and IFN-c expression in kidney and spleen. IFN transcripts were found to be strongly correlated with the viral burden and with marker genes of the IFN antiviral cascade. The results demonstrate that the IFN system of salmonids is far more complex than previously realized, and in-depth research is required to fully understand its regulation and function.

Applications of Multi-Channel Safety Authentication Protocols in Wireless Networks.

People can use their web browser or mobile devices to access web services and applications which are built into these servers. Users have to input their identity and password to login the server. The identity and password may be appropriated by hackers when the network environment is not safe. The multiple secure authentication protocol can improve the security of the network environment. Mobile devices can be used to pass the authentication messages through Wi-Fi or 3G networks to serve as a second communication channel. The content of the message number is not considered in a multiple secure authentication protocol. The more excessive transmission of messages would be easier to collect and decode by hackers. In this paper, we propose two schemes which allow the server to validate the user and reduce the number of messages using the XOR operation. Our schemes can improve the security of the authentication protocol. The experimental results show that our proposed authentication protocols are more secure and effective. In regard to applications of second authentication communication channels for a smart access control system, identity identification and E-wallet, our proposed authentication protocols can ensure the safety of person and property, and achieve more effective security management mechanisms.

High-power dual-fed traveling wave photodetector circuits in silicon photonics.

We introduce the concept of dual-illuminated photodetectors for high-power applications. Illuminating the photodetector on both sides doubles the number of optical channels, boosting DC and RF power handling capability. This concept is demonstrated utilizing multiple-stage dual-illuminated traveling wave photodetector circuits in silicon photonics, showing a maximum DC photocurrent of 112 mA and a 3-dB bandwidth of 40 GHz at 0.3 mA. Peak continuous-wave RF power is generated up to 12.3 dBm at 2 GHz and 5.3 dBm at 40 GHz, at a DC photocurrent of 55 mA. High speed broadband data signals are detected with eye amplitudes of 2.2 V and 1.3 V at 10 Gb/s and 40 Gb/s, respectively. A theoretical analysis is presented illustrating design tradeoffs for the multiple-stage photodetector circuits based on the bandwidth and power requirements.