Targeting the dendritic cell-secreted immunoregulatory cytokine CCL22 alleviates radioresistance.

PURPOSE: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that dendritic cells (cDC) maintain Treg we sought to identify and target cDC signaling to block Treg infiltration after radiation. EXPERIMENTAL DESIGN: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT, but associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (αEGFR-IFNα) was examined to block Treg infiltration and promote a CD8+ T cell response after RT. RESULTS: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. αEGFR-IFNα blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration. CONCLUSIONS: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration, and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy.

Corynoline Suppresses Osteoclastogenesis and Attenuates ROS Activities by Regulating NF-κB/MAPKs and Nrf2 Signaling Pathways.

Declining estrogen production in postmenopausal females causes osteoporosis in which the resorption of bone exceeds the increase in bone formation. Although clinical drugs are currently available for the treatment of osteoporosis, sustained medication use is accompanied by serious side effects. Corydalis bungeana Herba, a famous traditional Chinese herb listed in the Chinese Pharmacopoeia Commission, constitutes various traditional Chinese Medicine prescriptions, which date back to thousands of years. One of the primary active components of C. bungeana Turcz. is Corynoline (Cor), a plant isoquinoline alkaloid derived from the Corydalis species, which possesses bone metabolism disease therapeutic potential. The study aimed at exploring the effects as well as mechanisms of Cor on osteoclast formation and bone resorption. TRAcP staining, F-actin belt formation, and pit formation were employed for assessing the osteoclast function. Western blot, qPCR, network pharmacology, and docking analyses were used for analyzing the expression of osteoclast-associated genes and related signaling pathways. The study focused on investigating how Cor affected OVX-induced trabecular bone loss by using a mouse model. Cor could weaken osteoclast formation and function by affecting the biological receptor activators of NF-κB and its ligand at various concentrations. Mechanistically, Cor inhibited the NF-κB activation, and the MAPKs pathway stimulated by RANKL. Besides, Cor enhanced the protein stability of the Nrf2, which effectively abolished the RANKL-stimulated ROS generation. According to an OVX mouse model, Cor functions in restoring bone mass, improving microarchitecture, and reducing the ROS levels in the distal femurs, which corroborated with its in vitro antiosteoclastogenic effect. The present study indicates that Cor may restrain osteoclast formation and bone loss by modulating NF-κB/MAPKs and Nrf2 signaling pathways. Cor was shown to be a potential drug candidate that can be utilized for the treatment of osteoporosis.

High resolution terahertz ATR frequency-domain spectroscopy for monitoring spinal cord injury in rats.

Traumatic spinal cord injury (SCI) can lead to permanent neurological impairment, underscoring the urgency of regular therapeutic intervention and monitoring. In this study, we propose a new strategy for monitoring spinal cord injury through serum based on high-resolution THz attenuated total reflection frequency domain spectroscopy (THz-ATR-FDS). We demonstrated serum spectral differences at different time points after experimental SCI in rats. We also studied the relationship between serum lipid concentration and the time of SCI, which revealed the potential of lipid molecules as biomarkers of SCI. In addition, based on the principal component analysis (PCA) and least squares regression (LSR) models, the quantitative relationship between the refractive index spectrum and lipid concentration in serum was automatically analyzed. This work highlights terahertz spectroscopy as a promising tool for label-free, periodic, and efficient monitoring of SCI.

Fast 3D positioning based on a simplified THz photonic stereo ISAR system.

In this work, a THz stereo inverse synthetic aperture radar scheme based on photonics is proposed, and proof-of-concept experimentally demonstrated, achieving high resolution and fast three-dimensional (3D) positioning of multiple targets. An optical frequency comb and a uni-traveling carrier photodiode are employed to photonically generate a linear frequency-modulation signal at 300-320 GHz. By two incoherent measurements at different angles with one pair of antennas, 3D positioning of plane reflectors over a distance of 0.6 m is successfully accomplished, achieving a resolution of 7.5 mm for both range and azimuth dimensions, and a maximum experimental height error of 4 mm.

5-Hydroxymethylcytosine signals in serum are a predictor of chemoresistance in high-grade serous ovarian cancer.

OBJECTIVE: The genome-wide profiling of 5-hydroxymethylcytosines (5hmC) on circulating cell-free DNA (cfDNA) has revealed promising biomarkers for various diseases. The purpose of this study was to investigate 5hmC signals in serum cfDNA and identify novel predictive biomarkers for the development of chemoresistance in high-grade serous ovarian cancer (HGSOC). We hypothesized that 5hmC profiles in cfDNA reflect the development of chemoresistance and elucidate pathways that may drive chemoresistance in HGSOC. Moreover, we sought to identify predictors that would better stratify outcomes for women with intermediate-sensitive HGSOC. METHODS: Women diagnosed with HGSOC and known platinum sensitivity status were selected for this study. Nano-hmC-Seal was performed on cfDNA isolated from archived serum samples, and differential 5hmC features were identified using DESeq2 to establish a model predictive of chemoresistance. RESULTS: A multivariate model consisting of three features (preoperative CA-125, largest residual implant after surgery, 5hmC level of OSGEPL), stratified samples from intermediate sensitive, chemo-naive women diagnosed with HGSOC into chemotherapy-resistant- and sensitive-like strata with a significant difference in overall survival (OS). Independent analysis of The Cancer Genome Atlas data further confirmed that high OSGEPL1 expression is a favorable prognostic factor for HGSOC. CONCLUSIONS: We have developed a novel multivariate model based on clinico-pathologic data and a cfDNA-derived 5hmC modified gene, OSGEPL1, that predicted response to platinum-based chemotherapy in intermediate-sensitive HGSOC. Our multivariate model applies to chemo-naïve samples regardless if the patint was treated with adjuvant or neoadjuvant chemotherapy. These results merit further investigation of the predictive capability of our model in larger cohorts.

Hesperetin promotes diabetic wound healing by inhibiting ferroptosis through the activation of SIRT3.

Hesperetin (HST) is a flavonoid compound naturally occurring in citrus fruits and is widespread in various traditional medicinal herbs such as grapefruit peel, orange peel, and tangerine peel. These plant materials are commonly used in traditional Chinese medicine to prepare herbal remedies. The study aimed to investigate the potential molecular mechanisms through which HST reduces ferroptosis in human umbilical vein endothelial cells (HUVECs) and promotes angiogenesis and wound healing. We employed network pharmacology to predict the downstream targets affected by HST. The expression of markers related to ferroptosis was assessed through Western blot (WB) and polymerase chain reaction. Intracellular levels of ferroptosis-related metabolism were examined using glutathione/oxidized glutathione (GSH/GSSG) and malondialdehyde (MDA) assay kits. Mitochondrial status and iron levels within the cells were investigated through staining with Mitosox, FerroOrange, and JC1 staining. Potential downstream direct targets of HST were identified using molecular docking. Additionally, wound healing and neovascularization within the wound site were analyzed using various methods including HE staining, Masson's staining, immunohistochemistry, and Doppler hemodynamics assessment. HST effectively inhibits the elevated levels of intracellular ferroptosis stimulated by ERASTIN. Furthermore, we observed that HST achieves this inhibition of ferroptosis by activating SIRT3. In a diabetic rat wound model, HST significantly promotes wound healing, reducing levels of tissue ferroptosis, consistent with our in vitro findings. This study demonstrates that HST can inhibit the progression of ferroptosis and protect the physiological function of HUVECs by activating SIRT3. HST holds promise as a natural compound for promoting diabetic wound healing.

Epitranscriptional regulation of TGF-ß pseudoreceptor BAMBI by m6A/YTHDF2 drives extrinsic radioresistance.

Activation of TGF-ß signaling serves as an extrinsic resistance mechanism that limits the potential for radiotherapy. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) antagonizes TGF-ß signaling and is implicated in cancer progression. However, the molecular mechanisms of BAMBI regulation in immune cells and its impact on antitumor immunity after radiation have not been established. Here, we show that ionizing radiation (IR) specifically reduces BAMBI expression in immunosuppressive myeloid-derived suppressor cells (MDSCs) in both murine models and humans. Mechanistically, YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) directly binds and degrades Bambi transcripts in an N6-methyladenosine-dependent (m6A-dependent) manner, and this relies on NF-κB signaling. BAMBI suppresses the tumor-infiltrating capacity and suppression function of MDSCs via inhibiting TGF-ß signaling. Adeno-associated viral delivery of Bambi (AAV-Bambi) to the tumor microenvironment boosts the antitumor effects of radiotherapy and radioimmunotherapy combinations. Intriguingly, combination of AAV-Bambi and IR not only improves local tumor control, but also suppresses distant metastasis, further supporting its clinical translation potential. Our findings uncover a surprising role of BAMBI in myeloid cells, unveiling a potential therapeutic strategy for overcoming extrinsic radioresistance.

RBFOX2 recognizes N6-methyladenosine to suppress transcription and block myeloid leukaemia differentiation.

N6-methyladenosine (m6A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. However, the mechanism by which MTC is recruited to distinct genomic loci remains elusive. Here we identify RBFOX2, a well-studied RNA-binding protein, as a chromatin factor that preferentially recognizes m6A on caRNAs. RBFOX2 can recruit RBM15, an MTC component, to facilitate methylation of promoter-associated RNAs. RBM15 also physically interacts with YTHDC1 and recruits polycomb repressive complex 2 (PRC2) to the RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this RBFOX2/m6A/RBM15/YTHDC1/PRC2 axis plays a critical role in myeloid leukaemia. Downregulation of RBFOX2 notably inhibits survival/proliferation of acute myeloid leukaemia cells and promotes their myeloid differentiation. RBFOX2 is also required for self-renewal of leukaemia stem/initiation cells and acute myeloid leukaemia maintenance. Our study presents a pathway of m6A MTC recruitment and m6A deposition on caRNAs, resulting in locus-selective chromatin regulation, which has potential therapeutic implications in leukaemia.

YTHDF2 inhibition potentiates radiotherapy antitumor efficacy.

RNA N6-methyladenosine (m6A) modification is implicated in cancer progression. However, the impact of m6A on the antitumor effects of radiotherapy and the related mechanisms are unknown. Here we show that ionizing radiation (IR) induces immunosuppressive myeloid-derived suppressor cell (MDSC) expansion and YTHDF2 expression in both murine models and humans. Following IR, loss of Ythdf2 in myeloid cells augments antitumor immunity and overcomes tumor radioresistance by altering MDSC differentiation and inhibiting MDSC infiltration and suppressive function. The remodeling of the landscape of MDSC populations by local IR is reversed by Ythdf2 deficiency. IR-induced YTHDF2 expression relies on NF-κB signaling; YTHDF2 in turn leads to NF-κB activation by directly binding and degrading transcripts encoding negative regulators of NF-κB signaling, resulting in an IR-YTHDF2-NF-κB circuit. Pharmacological inhibition of YTHDF2 overcomes MDSC-induced immunosuppression and improves combined IR and/or anti-PD-L1 treatment. Thus, YTHDF2 is a promising target to improve radiotherapy (RT) and RT/immunotherapy combinations.

METTL14 is a chromatin regulator independent of its RNA N6-methyladenosine methyltransferase activity.

METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell (mESC). While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-independent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification. Mechanistically, METTL14, but not METTL3, binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression. The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs. This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance, and differentiation of mESCs.

Optical amplification-free deep reservoir computing-assisted high-baudrate short-reach communication.

An optical amplification-free deep reservoir computing (RC)-assisted high-baudrate intensity modulation direct detection (IM/DD) system is experimentally demonstrated using a 100G externally modulated laser operated in C-band. We transmit 112 Gbaud 4-level pulse amplitude modulation (PAM4) and 100 Gbaud 6-level PAM (PAM6) signals over a 200-m single-mode fiber (SMF) link without any optical amplification. The decision feedback equalizer (DFE), shallow RC, and deep RC are adopted in the IM/DD system to mitigate impairment and improve transmission performance. Both PAM transmissions over a 200-m SMF with bit error rate (BER) performance below 6.25% overhead hard-decision forward error correction (HD-FEC) threshold are achieved. In addition, the BER of the PAM4 signal is below the KP4-FEC limit after 200-m SMF transmission enabled by the RC schemes. Thanks to the use of a multiple-layer structure, the number of weights in deep RC has been reduced by approximately 50% compared with the shallow RC, whereas the performance is comparable. We believe that the optical amplification-free deep RC-assisted high-baudrate link has a promising application in intra-data center communications.

Exon architecture controls mRNA m6A suppression and gene expression.

N6-methyladenosine (m6A) is the most abundant messenger RNA (mRNA) modification and plays crucial roles in diverse physiological processes. Using a massively parallel assay for m6A (MPm6A), we discover that m6A specificity is globally regulated by suppressors that prevent m6A deposition in unmethylated transcriptome regions. We identify exon junction complexes (EJCs) as m6A suppressors that protect exon junction-proximal RNA within coding sequences from methylation and regulate mRNA stability through m6A suppression. EJC suppression of m6A underlies multiple global characteristics of mRNA m6A specificity, with the local range of EJC protection sufficient to suppress m6A deposition in average-length internal exons but not in long internal and terminal exons. EJC-suppressed methylation sites colocalize with EJC-suppressed splice sites, which suggests that exon architecture broadly determines local mRNA accessibility to regulatory complexes.

Human recognition with the optoelectronic reservoir-computing-based micro-Doppler radar signal processing.

Current perception and monitoring systems, such as human recognition, are affected by several environmental factors, such as limited light intensity, weather changes, occlusion of targets, and public privacy. Human recognition using radar signals is a promising direction to overcome these defects; however, the low signal-to-noise ratio of radar signals still makes this task challenging. Therefore, it is necessary to use suitable tools that can efficiently deal with radar signals to identify targets. Reservoir computing (RC) is an efficient machine learning scheme that is easy to train and demonstrates excellent performance in processing complex time-series signals. The RC hardware implementation structure based on nonlinear nodes and delay feedback loops endows it with the potential for real-time fast signal processing. In this paper, we numerically study the performance of the optoelectronic RC composed of optical and electrical components in the task of human recognition with noisy micro-Doppler radar signals. A single-loop optoelectronic RC is employed to verify the application of RC in this field, and a parallel dual-loop optoelectronic RC scheme with a dual-polarization Mach-Zehnder modulator (DPol-MZM) is also used for performance comparison. The result is verified to be comparable with other machine learning tools, which demonstrates the ability of the optoelectronic RC in capturing gait information and dealing with noisy radar signals; it also indicates that optoelectronic RC is a powerful tool in the field of human target recognition based on micro-Doppler radar signals.

Ultrafast visible-infrared photodetector based on the SnSe2/Bi2Se3 heterostructure.

Using the inherent properties of a heterostructure, ultrafast photodetectors with high sensitivity can be progressively developed that have the potential to carve a niche among the optoelectronic devices. In this Letter, a heterojunction photodetector based on SnSe2/Bi2Se3 is constructed, and a visible-infrared photoresponse with good sensitivity at room temperature is obtained. The SnSe2/Bi2Se3 photodetector demonstrates a high Iph/Id ratio of 1.2 × 104 at 0 V. Moreover, the high responsivity of 2.3 A/W, detectivity of 1.6 × 1011 Jones, and fast response time of 40 µs are simultaneously achieved. The presented results offer an alternative route for ultrafast photodetectors with high sensitivity.

Ultrasensitive Anisotropic Room-Temperature Terahertz Photodetector Based on an Intrinsic Magnetic Topological Insulator MnBi2Te4.

Terahertz photodetectors based on emergent intrinsic magnetic topological insulators promise excellent performance in terms of highly sensitive, anisotropic and room-temperature ability benefiting from their extraordinary material properties. Here, we propose and conceive the response features of exfoliated MnBi2Te4 flakes as active materials for terahertz detectors. The MnBi2Te4-based photodetectors show the sensitivity rival with commercially available ones, and the noise equivalent power of 13 pW/Hz0.5 under 0.275 THz at room-temperature led by the nonlinear Hall effect, allowing for the high-resolution terahertz imaging. In addition, a large anisotropy of polarization-dependent terahertz response is observed when the MnBi2Te4 device is tuned into different directions. More interestingly, we discover an unprecedented power-controlled reversal of terahertz response in the MnBi2Te4-graphene device. Our results provide feasibility of manipulating and exploiting the nontrivial topological phenomena of MnBi2Te4 under a high-frequency electromagnetic field, representing the first step toward device implementation of intrinsic magnetic topological insulators.

Hybrid fiber-THz fronthaul supporting up to 16384-QAM-OFDM with the delta-sigma modulation.

With the progress of high-capacity radio access networks, ultra-dense small cells are rapidly being deployed in urban areas. As a result, the deployment of a large number of optical fibers in urban areas becomes a severe issue. In this Letter, we propose a hybrid fiber-terahertz (THz) mobile fronthaul system supporting flexible and high-order wireless signal transmission with the delta-sigma modulation. The photonic THz transmission is used as the seamless extension of fiber-based fronthaul in small cells. A 20-Gbit/s digital fiber-THz fronthaul system is experimentally demonstrated to validate the proposed scheme, with 10-km optical fiber transmission and 300-GHz wireless relay. Carrier aggregation of up to 10 40-MHz and 60-MHz 5G-new radio (5G-NR) channels at the radio carrier frequency of 3.9 GHz is reported. The design of quantization noise suppressed delta-sigma modulation enables the system to transmit orthogonal frequency division multiplexing (OFDM) modulation up to  16384 order quadrate amplitude modulation (QAM) mapping with the error vector magnitude (EVM) below 0.5%.

Channel Model and Performance Analysis for MIMO Systems with Single Leaky Coaxial Cable in Tunnel Scenarios.

Due to the limited space in the tunnel environment, multiple-input multiple-output (MIMO) systems with double-port fed leaky coaxial cables (LCXs) can not only reduce the number of LCXs, but also improve the channel capacity. Based on the geometry based on single bonce (GBSB) and electromagnetic field radiation theory of LCX, a MIMO channel model with double-port fed LCX in a tunnel scenario is proposed in this paper. The channel impulse response (CIR) is derived, and verified with measurement results in terms of channel capacity. The distribution of channel capacity of single double-port fed LCX under different LCX lengths in the tunnel scenarios has also been analyzed in this work, and the distribution of channel capacity for the LCX-MIMO system with long LCX is predicted. The results show that the single double-port fed LCX-MIMO system outperforms the dipole antenna MIMO system with respect to channel capacity in the considered tunnel scenarios.

Secure Transmission of Terahertz Signals with Multiple Eavesdroppers.

The terahertz (THz) band is expected to become a key technology to meet the ever-increasing traffic demand for future 6G wireless communications, and a lot of efforts have been paid to develop its capacity. However, few studies have been concerned with the transmission security of such ultra-high-speed THz wireless links. In this paper, we comprehensively investigate the physical layer security (PLS) of a THz communication system in the presence of multiple eavesdroppers and beam scattering. The method of moments (MoM) was adopted so that the eavesdroppers' channel influenced by the PEC can be characterized. To establish a secure link, the traditional beamforming and artificial noise (AN) beamforming were considered as transmission schemes for comparison. For both schemes, we analyzed their secrecy transmission probability (STP) and ergodic secrecy capacity (ESC) in non-colluding and colluding cases, respectively. Numerical results show that eavesdroppers can indeed degrade the secrecy performance by changing the size or the location of the PEC, while the AN beamforming technique can be an effective candidate to counterbalance this adverse effect.

FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development.

N6-methyladenosine (m6A) is the most abundant internal modification on mammalian messenger RNA. It is installed by a writer complex and can be reversed by erasers such as the fat mass and obesity-associated protein FTO. Despite extensive research, the primary physiological substrates of FTO in mammalian tissues and development remain elusive. Here, we show that FTO mediates m6A demethylation of long-interspersed element-1 (LINE1) RNA in mouse embryonic stem cells (mESCs), regulating LINE1 RNA abundance and the local chromatin state, which in turn modulates the transcription of LINE1-containing genes. FTO-mediated LINE1 RNA m6A demethylation also plays regulatory roles in shaping chromatin state and gene expression during mouse oocyte and embryonic development. Our results suggest broad effects of LINE1 RNA m6A demethylation by FTO in mammals.

Hybrid Dirac semimetal-based photodetector with efficient low-energy photon harvesting.

Despite the considerable effort, fast and highly sensitive photodetection is not widely available at the low-photon-energy range (~meV) of the electromagnetic spectrum, owing to the challenging light funneling into small active areas with efficient conversion into an electrical signal. Here, we provide an alternative strategy by efficiently integrating and manipulating at the nanoscale the optoelectronic properties of topological Dirac semimetal PtSe2 and its van der Waals heterostructures. Explicitly, we realize strong plasmonic antenna coupling to semimetal states near the skin-depth regime (λ/104), featuring colossal photoresponse by in-plane symmetry breaking. The observed spontaneous and polarization-sensitive photocurrent are correlated to strong coupling with the nonequilibrium states in PtSe2 Dirac semimetal, yielding efficient light absorption in the photon range below 1.24 meV with responsivity exceeding ∼0.2 A/W and noise-equivalent power (NEP) less than ~38 pW/Hz0.5, as well as superb ambient stability. Present results pave the way to efficient engineering of a topological semimetal for high-speed and low-energy photon harvesting in areas such as biomedical imaging, remote sensing or security applications.