Neoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: a pilot phase II trial.

Neoadjuvant chemoimmunotherapy has emerged as a potential treatment option for resectable head and neck squamous cell carcinoma (HNSCC). In this single-arm phase II trial (NCT04826679), patients with resectable locally advanced HNSCC (T2‒T4, N0‒N3b, M0) received neoadjuvant chemoimmunotherapy with camrelizumab (200 mg), nab-paclitaxel (260 mg/m2), and cisplatin (60 mg/m2) intravenously on day one of each three-week cycle for three cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included pathologic complete response (pCR), major pathologic response (MPR), two-year progression-free survival rate, two-year overall survival rate, and toxicities. Here, we report the perioperative outcomes; survival outcomes were not mature at the time of data analysis. Between April 19, 2021 and March 17, 2022, 48 patients were enrolled and received neoadjuvant therapy, 27 of whom proceeded to surgical resection and remaining 21 received non-surgical therapy. The ORR was 89.6% (95% CI: 80.9, 98.2) among 48 patients who completed neoadjuvant therapy. Of the 27 patients who underwent surgery, 17 (63.0%, 95% CI: 44.7, 81.2) achieved a MPR or pCR, with a pCR rate of 55.6% (95% CI: 36.8, 74.3). Treatment-related adverse events of grade 3 or 4 occurred in two patients. This study meets the primary endpoint showing potential efficacy of neoadjuvant camrelizumab plus nab-paclitaxel and cisplatin, with an acceptable safety profile, in patients with resectable locally advanced HNSCC.

Role of aminopeptidase N-like in the acquisition of begomoviruses by Bemisia tabaci, the whitefly vector.

Sri Lankan cassava mosaic virus (SLCMV) is a prominent causative agent of cassava mosaic disease in Asia and relies on the whitefly Bemisia tabaci cryptic complex for its transmission. However, the molecular mechanisms involved in SLCMV transmission by B. tabaci have yet to be understood. In this study, we identified an aminopeptidase N-like protein (BtAPN) in B. tabaci Asia II 1, an efficient vector of SLCMV, which is involved in the SLCMV transmission process. Through the use of glutathione S-transferase pull-down assay and LC-MS/MS analysis, we demonstrated the interaction between BtAPN and the coat protein (CP) of SLCMV. This interaction was further confirmed in vitro, and we observed an induction of BtAPN gene expression following SLCMV infection. By interfering with the function of BtAPN, the quantities of SLCMV were significantly reduced in various parts of B. tabaci Asia II 1, including the whole body, midgut, hemolymph, and primary salivary gland. Furthermore, we discovered that BtAPN is conserved in B. tabaci Middle East-Asia Minor 1 (MEAM1) and interacts with the CP of tomato yellow leaf curl virus (TYLCV), a begomovirus known to cause severe damage to tomato production. Blocking BtAPN with antibody led to a significant reduction in the quantities of TYLCV in whitefly whole body and organs/tissues. These results demonstrate that BtAPN plays a generic role in interacting with the CP of begomoviruses and positively regulates their acquisition by the whitefly.

A chromosome-level genome assembly of the parasitoid wasp Eretmocerus hayati.

Hymenoptera is an order accounting for a large proportion of species in Insecta, among which Chalcidoidea contains many parasitoid species of biocontrol significance. Currently, some species genomes in Chalcidoidea have been assembled, but the chromosome-level genomes of Aphelinidae are not yet available. Using Illumina, PacBio HiFi and Hi-C technologies, we assembled a genome assembly of Eretmocerus hayati (Aphelinidae, Hymenoptera), a worldwide biocontrol agent of whiteflies, at the chromosome level. The assembled genome size is 692.1 Mb with a contig N50 of 7.96 Mb. After Hi-C scaffolding, the contigs was assembled onto four chromosomes with a mapping rate of > 98%. The scaffold N50 length is 192.5 Mb, and Benchmarking Universal Single-Copy Orthologues (BUSCO) value is 95.9%. The genome contains 370.8 Mb repeat sequences and total of 24471 protein coding genes. P450 gene families were identified and analyzed. In conclusion, our chromosome-level genome assembly provides valuable support for future research on the evolution of parasitoid wasps and the interaction between hosts and parasitoid wasps.

Low-complexity amplitude-division irregular QAM formats for short-reach unamplified coherent optical systems.

A low-complexity scheme is proposed to realize irregular uniform quadrature amplitude modulation (QAM) formats with Gray mapping, which are named amplitude-division irregular QAM (AD-Ir-QAM) formats. Compared to conventional probabilistic shaping (PS) with the Maxwell-Boltzmann (MB) distribution (PS-MB), irregular QAM formats show a smaller peak-to-average power (PAPR) and achieve a better performance in systems with the peak-power constraint. Compared with irregular QAM formats realized by PS (PS-Ir-QAM), AD-Ir-QAM formats realize a more flexible rate adaptation and have a lower implementation complexity. Experimental results obtained in an unamplified coherent optical system show that, at a generalized mutual information (GMI) of 4.5 bits/2D-symbol, AD-Ir-100QAM achieves gains of 2.1 and 0.5 dB in the power budget over PS-MB-100QAM and PS-Ir-100QAM, respectively.

A shift of vector specificity acquired by a begomovirus through natural homologous recombination.

Recombination is common in plant viruses such as geminiviruses, but the ecological and pathogenic consequences have been explored only in a few cases. Here, we found that a new begomovirus, tomato yellow leaf curl Shuangbai virus (TYLCSbV), probably originated from the recombination of Ageratum yellow vein China virus (AYVCNV) and tobacco curl shoot virus (TbCSV). Agrobacterium-mediated inoculation showed that TYLCSbV and AYVCNV have similar levels of infectivity on tomato and tobacco plants. However, the two viruses exhibit contrasting specificities for vector transmission, that is, TYLCSbV was efficiently transmitted by the whitefly Bemisia tabaci Mediterranean (MED) rather than by the whitefly B. tabaci Middle East-Asia Minor 1 (MEAM1), whereas AYVCNV was more efficiently transmitted by MEAM1. We also showed that the transmission efficiencies of TYLCSbV and AYVCNV are positively correlated with the accumulation of the viruses in whitefly whole bodies and organs/tissues. The key coat protein amino acids that determine their accumulation are between positions 147 and 256. Moreover, field surveys suggest that MED has displaced MEAM1 in some regions where TYLCSbV was collected. Viral competition assays indicated that TYLCSbV outcompeted AYVCNV when transmitted by MED, while the outcome was the opposite when transmitted by MEAM1. Our findings suggest that recombination has resulted in a shift of vector specificity that could provide TYLCSbV with a potential selective transmission advantage, and the population shift of whitefly cryptic species could have influenced virus evolution towards an extended trajectory of transmission.

Biomimetic Nanoparticle with Glutathione Depletion and Amplified ROS Generation Capabilities for Synergistic Chemo-Sonodynamic Therapy in Squamous Cell Carcinomas.

Nanomedicines for combining chemotherapy and sonodynamic therapy (SDT) have enormous potential in squamous cell carcinoma treatment. However, the therapeutic efficacy of noninvasive SDT is severely limited because the generation of reactive oxygen species (ROS) by sonosensitizers is highly dependent on the levels of intracellular excess glutathione (GSH) in the tumor cells. To overcome this barrier, a red blood cell (RBC) membrane-camouflaged nanomedicine consisting of GSH-sensitive polyphosphoester (SS-PPE) and ROS-sensitive polyphosphoester (S-PPE) was designed for the simultaneous delivery of the sonosensitizer hematoporphyrin (HMME) and chemotherapeutic agent docetaxel (DTXL) for effectively enhanced antitumor efficacy. In vitro and in vivo studies demonstrated that HMME-driven ROS generation under ultrasound (US) inhibited SCC7 cell proliferation and accelerated DTXL release to further kill tumor cells via the hydrophobic-hydrophilic transition of the nanoparticle core. Meanwhile, the disulfide bond of SS-PPE effectively consumes GSH to prevent ROS consumption. This biomimetic nanomedicine provides GSH depletion and amplified ROS generation capabilities to achieve a novel synergistic chemo-SDT strategy for squamous cell carcinomas.

Asymmetric point-to-multipoint coherent architecture with a frequency aliasing recovery algorithm for cost-constraint short-reach access networks.

An asymmetric point-to-multipoint (PTMP) coherent architecture combined with a frequency aliasing recovery (FAR) algorithm is proposed for cost-constraint short-reach access networks. In this architecture, the uplink transmitters are simplified significantly with the uplink dual-polarization four-level pulse amplitude modulation (DP-PAM4) and downlink DP quadrature phase shift keying (DP-QPSK) asymmetric transmission design. Digital to analog converters (DACs) and radio frequency (RF) drivers are reduced by half, and in-phase and quadrature modulators (IQMs) are replaced by Mach-Zehnder modulators (MZMs), saving four MZ interferometers (MZIs). Furthermore, based on the asymmetric architecture, the FAR algorithm can recover signals from frequency aliasing caused by frequency offset (FO), even when half of the signal spectrum is aliased. This algorithm enables the asymmetric architecture to narrow down guard bands between subcarriers or even overlap the subcarriers, saving the receiver bandwidth at the aggregation/hub side. The performance of the asymmetric uplink DP-PAM4 transmission with the FAR algorithm is evaluated in both simualations and experiments. The effects of laser linewidths and IQ skew on the performance of the FAR algorithm are also analyzed. Simulation results show the algorithm can recover 16 Gbaud and 32 Gbaud signal from 8 GHz and 16 GHz aliasing, respectively. In the experiments with 10 km fiber transmissions, the FAR algorithm can recover 10 Gbaud signals from 5 GHz frequency aliasing, saving about 20.83% of the total receiver bandwidth in a 2-subcarrier system.

Coherent digital-analog radio-over-fiber (DA-RoF) system with a CPRI-equivalent data rate beyond 1 Tb/s for fronthaul.

We propose and experimentally demonstrate a coherent digital-analog radio-over-fiber (DA-RoF) system and achieve the transmission of Tb/s common public radio interface (CPRI)-equivalent data rate for fronthaul. The proposed coherent DA-RoF system includes DA-RoF modulation, demodulation and DA-RoF compatible coherent digital signal processing (DSP) blocks. A theoretical analysis of the DA-RoF scheme together with parameter optimization is accomplished as well. In the experiment, a 25 Gbaud DA-RoF signal with 1 Tb/s CPRI-equivalent data rate is transmitted in the system, satisfying the error vector magnitude (EVM) requirement for 256-quadrature amplitude modulation (QAM) signal transmission. With the symbol rate reduced to 10 Gbaud, an EVM below 2.5% is achieved, which meets the requirement for 1024-QAM transmission. The experimental results show that the coherent DA-RoF system is a promising solution for future fronthaul.

Bemisia tabaci Vesicle-Associated Membrane Protein 2 Interacts with Begomoviruses and Plays a Role in Virus Acquisition.

Begomoviruses cause substantial losses to agricultural production, especially in tropical and subtropical regions, and are exclusively transmitted by members of the whitefly Bemisia tabaci species complex. However, the molecular mechanisms underlying the transmission of begomoviruses by their whitefly vector are not clear. In this study, we found that B. tabaci vesicle-associated membrane protein 2 (BtVAMP2) interacts with the coat protein (CP) of tomato yellow leaf curl virus (TYLCV), an emergent begomovirus that seriously impacts tomato production globally. After infection with TYLCV, the transcription of BtVAMP2 was increased. When the BtVAMP2 protein was blocked by feeding with a specific BtVAMP2 antibody, the quantity of TYLCV in B. tabaci whole body was significantly reduced. BtVAMP2 was found to be conserved among the B. tabaci species complex and also interacts with the CP of Sri Lankan cassava mosaic virus (SLCMV). When feeding with BtVAMP2 antibody, the acquisition quantity of SLCMV in whitefly whole body was also decreased significantly. Overall, our results demonstrate that BtVAMP2 interacts with the CP of begomoviruses and promotes their acquisition by whitefly.

Ultra-fast RSOP tracking via 3 pilot tones for short-distance coherent SCM systems.

We propose an algorithm to track the rotation of state of polarization (RSOP) for short-distance coherent subcarrier-multiplexing systems. 3 pilot tones are used to estimate RSOP matrices on a block-by-block basis and recover phase noise as well. An ultra-fast RSOP tracking ability using the proposed algorithm is demonstrated by experiment. Specifically, the bit error rate increases from 2.3×10-3 to 5.6×10-3 when the RSOP speed increases from 0 rad/s to 50 Mrad/s. We also demonstrate the robustness of the algorithm against polarization mode dispersion and polarization dependent loss.

Fluorescence imaging-guided multifunctional liposomes for tumor-specific phototherapy for laryngeal carcinoma.

Reliable diagnosis and efficient targeted therapy are important and may lead to the effective treatment of laryngeal carcinoma. Multifunctional nano-theranostic agents demonstrate great potential in tumor theranostic applications. Thus, herein, we report novel targeting multifunctional theranostic nanoparticles, internalized RGD (iRGD)-modified indocyanine green (ICG) encapsulated liposomes (iLIPICG), for imaging-guided photothermal therapy (PTT) and photodynamic therapy (PDT) for the treatment of laryngeal carcinoma. The iRGD-PEG-DSPE lipid endowed iLIPICG with high affinity for tumor vascular targeting, tumor-penetration and tumor cell targeting. The in vivo results showed that iLIPICG exhibited excellent blood circulation and tumor accumulation. iLIPICG could be spatially and temporally controlled, simultaneously producing hyperthermia and reactive oxygen species as well as a fluorescence-guided effect through ICG to ablate laryngeal carcinoma cells under irradiation from an 808 nm laser. iLIPICG generated synergistic photodynamic-photothermal cytotoxicity against Hep-2 cells, resulting in the efficient ablation of laryngeal carcinoma. Thus, the iLIPICG system provides a promising strategy to improve the precision imaging and effective phototherapy for the treatment of laryngeal carcinoma.

Mutations in the coat protein of a begomovirus result in altered transmission by different species of whitefly vectors.

For many crop pathogens including viruses, high genetic variation provides them with potential to adapt to and prevail in a changing environment. Understanding genetic variation in viruses and their significance is a key to elaborate virus epidemiology and evolution. While genetic variation of plant viruses has been documented to impact virus-host interactions, how it affects virus-insect vector interactions remains elusive. Here, we report the impact of mutations in the coat protein of squash leaf curl China virus (SLCCNV), a begomovirus, on the interaction between the virus and its whitefly vectors. We characterized mutations in the coat protein of SLCCNV and found that some residues exhibited higher mutation frequency than the others. We assayed the impact of mutation on infectivity using agroinoculation and found these mutations marginally affect virus infectivity. We further analyze their functions using virus acquisition and transmission trials and found some of mutations resulted in altered transmission of SLCCNV by different species of the whitefly Bemisia tabaci complex. We then identified the key amino acid residue(s) involved by constructing several mutant viruses and found that a single-residue mutation in the coat protein of SLCCNV was sufficient to significantly alter the whitefly transmission characteristics of SLCCNV. We examined the competition between different genotypes of SLCCNV in plant infection and whitefly transmission. We found that mutations in the coat protein did not alter the fitness of SLCCNV in plants, but they rendered the virus more competitive in transmission by certain species of whiteflies. Our findings indicate that mutations in the coat protein may play a key role in both the adaptation of begomoviruses to the changing vector populations and the evolution of begomoviruses.

Differential transmission of Sri Lankan cassava mosaic virus by three cryptic species of the whitefly Bemisia tabaci complex.

In recent years, Sri Lankan cassava mosaic virus (SLCMV), a begomovirus (genus Begmovirus, family Geminiviridae) causing cassava mosaic disease in Asia, poses serious threats to cassava cultivation in Asia. However, the transmission of SLCMV in the areas into which it has recently been introduced remain largely unexplored. Here we have compared the transmission efficiencies of SLCMV by three widely distributed whitefly species in Asia, and found that only Asia II 1 whiteflies were able to transmit this virus efficiently. The transmission efficiencies of SLCMV by different whitefly species were found to correlate positively with quantity of virus in whitefly whole body. Further, the viral transmission efficiency was found to be associated with varied ability of virus movement within different species of whiteflies. These findings provide detailed information regarding whitefly transmission of SLCMV, which will help to understand the spread of SLCMV in the field, and facilitate the prediction of virus epidemics.

Study on synthesis and bioactivity of biotinylated emodin.

A novel compound biotinylated emodin was synthesized by a two-step acyl chloride method which connects the biotin to emodin with esterification reaction. The product was characterized with ultraviolet-visible spectrophotometry, fourier transform infrared and high-performance liquid chromatography tandem mass spectrometry techniques. Its antibacterial activity against Staphylococcus aureus CMCC 26003 was investigated, and the emodin- and biotinylated emodin-caused antibacterial mechanism was proposed. It was shown that the product was isolated and activity of emodin was remained. These results indicated that our study provides a kind of chemosynthesis method under mild conditions and a strong molecular tool for investigating the emodin-binding protein.

Numerical Simulation of Dry Granular Flow Impacting a Rigid Wall Using the Discrete Element Method.

This paper presents a clump model based on Discrete Element Method. The clump model was more close to the real particle than a spherical particle. Numerical simulations of several tests of dry granular flow impacting a rigid wall flowing in an inclined chute have been achieved. Five clump models with different sphericity have been used in the simulations. By comparing the simulation results with the experimental results of normal force on the rigid wall, a clump model with better sphericity was selected to complete the following numerical simulation analysis and discussion. The calculation results of normal force showed good agreement with the experimental results, which verify the effectiveness of the clump model. Then, total normal force and bending moment of the rigid wall and motion process of the granular flow were further analyzed. Finally, comparison analysis of the numerical simulations using the clump model with different grain composition was obtained. By observing normal force on the rigid wall and distribution of particle size at the front of the rigid wall at the final state, the effect of grain composition on the force of the rigid wall has been revealed. It mainly showed that, with the increase of the particle size, the peak force at the retaining wall also increase. The result can provide a basis for the research of relevant disaster and the design of protective structures.

PPM1A silences cytosolic RNA sensing and antiviral defense through direct dephosphorylation of MAVS and TBK1.

Cytosolic RNA sensing is a prerequisite for initiation of innate immune response against RNA viral pathogens. Signaling through RIG-I (retinoic acid-inducible gene I)-like receptors (RLRs) to TBK1 (Tank-binding kinase 1)/IKKε (IκB kinase ε) kinases is transduced by mitochondria-associated MAVS (mitochondrial antiviral signaling protein). However, the precise mechanism of how MAVS-mediated TBK1/IKKε activation is strictly controlled still remains obscure. We reported that protein phosphatase magnesium-dependent 1A (PPM1A; also known as PP2Cα), depending on its catalytic ability, dampened the RLR-IRF3 (interferon regulatory factor 3) axis to silence cytosolic RNA sensing signaling. We demonstrated that PPM1A was an inherent partner of the TBK1/IKKε complex, targeted both MAVS and TBK1/IKKε for dephosphorylation, and thus disrupted MAVS-driven formation of signaling complex. Conversely, a high level of MAVS can dissociate the TBK1/PPM1A complex to override PPM1A-mediated inhibition. Loss of PPM1A through gene ablation in human embryonic kidney 293 cells and mouse primary macrophages enabled robustly enhanced antiviral responses. Consequently, Ppm1a(-/-) mice resisted to RNA virus attack, and transgenic zebrafish expressing PPM1A displayed profoundly increased RNA virus vulnerability. These findings identify PPM1A as the first known phosphatase of MAVS and elucidate the physiological function of PPM1A in antiviral immunity on whole animals.