Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening.

Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines. We describe findings of this screen, outlining the classes of cancer dependency genes and their relationships to genetic, expression, and lineage features. In addition, we describe robust gene-interaction networks recapitulating both protein complexes and functional cooperation among complexes and pathways. This dataset along with a web portal is provided to the community to assist in the discovery and translation of new therapeutic approaches for cancer.

JMJD3 activation contributes to renal protection and regeneration following acute kidney injury in mice.

We have recently demonstrated that Jumonji domain-containing protein D3 (JMJD3), a histone demethylase of histone H3 on lysine 27 (H3K27me3), is protective against renal fibrosis, but its role in acute kidney injury (AKI) remains unexplored. Here, we report that JMJD3 activity is required for renal protection and regeneration in murine models of AKI induced by ischemia/reperfusion (I/R) and folic acid (FA). Injury to the kidney upregulated JMJD3 expression and induced expression of H3K27me3, which was coincident with renal dysfunction, renal tubular cell injury/apoptosis, and proliferation. Blocking JMJD3 activity by GSKJ4 led to worsening renal dysfunction and pathological changes by aggravating tubular epithelial cell injury and apoptosis in both murine models of AKI. JMJD3 inhibition by GSKJ4 also reduced renal tubular cell proliferation and suppressed expression of cyclin E and phosphorylation of CDK2, but increased p21 expression in the injured kidney. Furthermore, inactivation of JMJD3 enhanced I/R- or FA-induced expression of TGF-ß1, vimentin, and Snail, phosphorylation of Smad3, STAT3, and NF-κB, and increased renal infiltration by F4/80 (+) macrophages. Finally, GSKJ4 treatment caused further downregulation of Klotho, BMP-7, Smad7, and E-cadherin, all of which are associated with renal protection and have anti-fibrotic effects. Therefore, these data provide strong evidence that JMJD3 activation contributes to renal tubular epithelial cell survival and regeneration after AKI.

Inhibition of HDAC8 mitigates AKI by reducing DNA damage and promoting homologous recombination repair.

Nephrotoxicity is a major side effect of platinum-based antineoplastic drugs, and there is currently no available therapeutic intervention. Our study suggests that targeting histone deacetylase 8 could be a potential treatment for cisplatin-induced acute kidney injury (AKI). In a murine model of AKI induced by cisplatin, the administration of PCI-34051, a selective inhibitor of HDAC8, resulted in significant improvement in renal function and reduction in renal tubular damage and apoptosis. Pharmacological inhibition of HDAC8 also decreased caspase-3 and PARP1 cleavage, attenuated Bax expression and preserved Bcl-2 levels in the injured kidney. In cultured murine renal epithelial cells (mRTECs) exposed to cisplatin, treatment with PCI-34051 or transfection with HDAC8 siRNA reduced apoptotic cell numbers and diminished expression of cleaved caspase-3 and PARP1; conversely, overexpression of HDAC8 intensified these changes. Additionally, PCI-34051 reduced p53 expression levels along with those for p21, p-CDK2 and γ-H2AX while preserving MRE11 expression in the injured kidney. Similarly, pharmacological and genetic inhibition of HDAC8 reduced γ-H2AX and enhanced MRE11 expression; conversely, HDAC8 overexpression exacerbated these changes in mRTECs exposed to cisplatin. These results support that HDAC8 inhibition attenuates cisplatin-induced AKI through a mechanism associated with reducing DNA damage and promoting its repair.

K-means non-uniform-quantization digital-analog radio-over-fiber scheme for THz-band photonics-aided wireless fronthaul.

We propose a non-uniform-quantization digital-analog radio-over-fiber (NUQ-DA-RoF) scheme based on an advanced K-means NUQ algorithm and demonstrate it experimentally in a 2-m 300-GHz photonics-aided wireless fronthaul system. Results show that the NUQ-DA-RoF scheme achieves a SNR gain of ∼1.9 dB compared to the uniform-quantization DA-RoF (UQ-DA-RoF) at an equivalent Common Public Radio Interface equivalent data rate (CPRI-EDR). Remarkably, the NUQ-DA-RoF scheme exhibits an ∼1.6-dB power sensitivity enhancement over the UQ-DA-RoF at the 256-QAM SNR threshold. These findings highlight the advantages of the NUQ-DA-RoF scheme over UQ-DA-RoF in terms of power budget and SNR improvement, suggesting promising prospects for future radio access networks and wireless fronthaul.

Photonic-assisted high-order vector millimeter-wave signal generation enabled by DSM.

We propose an optical dual-single-sideband (dual-SSB) modulated 16384-quadrature amplitude modulation (QAM) photonic vector millimeter-wave (mm-wave) signal generation scheme based on delta-sigma modulation (DSM). With the aid of the DSM, the severe nonlinear distortion of envelope detection for high-order QAM modulation signals in wireless communication can be effectively resolved. For the validation of our proposed scheme, we experimentally demonstrate the generation of a 40 GHz 16384-QAM orthogonal frequency division multiplexing (OFDM) photonic vector mm-wave signal and transmission over a 25-km standard single-mode fiber (SSMF), and a 1-m wireless link with the bit error ratio (BER) reaches the hard-decision forward-error-correction (HD-FEC) threshold of 3.8 × 10-3.

Digital mobile fronthaul scheme based on diff-delta-sigma modulation and OCT precoding.

In this Letter, we experimentally demonstrate digital mobile fronthaul (MFH) for 65536 quadrature amplitude modulation (65536-QAM) signals based on a diff-delta-sigma modulation (D-DSM) scheme with orthogonal circulant matrix transform (OCT) precoding. By combining the D-DSM scheme with OCT precoding, we successfully solved the problem of uneven distribution of in-band quantization noise (IBN) while bringing about a quantization SNR gain of about 1.5 dB. In addition, we compare two signal combination schemes, Gray coding and power superposition, in the D-DSM scheme. The results show that the power superposition scheme can achieve similar performance to Gray coding with lower computational complexity. At the same time, the power superposition scheme is less affected by the saturation effect. Therefore, the D-DSM solution combined with OCT precoding and power superposition provides an effective solution for future 6 G digital mobile fronthaul.

High-order QAM NANF transmission utilizing MIMO equalizer integrated with low-complexity decision-directed carrier phase estimation.

We experimentally realized a high-speed nested anti-resonant nodeless fiber (NANF) transmission with the assistance of the polarization division multiplexing (PDM) and probabilistic shaping (PS) technology. In this system, a low-complexity multiple-input multiple-output (MIMO) real-valued equalizer (RVE) is integrated with decision-directed carrier phase estimation (DDCPE), which is robust against the IQ cross talk and a tiny phase disturbance between PS symbols. By using the proposed MIMO-RVEDDCPE, the 60-Gbaud PDM-PS-256QAM signal has been delivered through 2-km NANF satisfying the soft-decision forward error correction (SD-FEC) threshold.

Delta-sigma modulation supporting the 4194304QAM dual polarization signal at the W-band transmission over a 4.6†km wireless distance.

In this Letter, we propose a dual-polarized coherent millimeter-wave system based on differential delta-sigma modulation (D-DSM) intended for long-distance wireless transmission in the W-band. The proposed system can transmit polarization-division-multiplexed (PDM) D-DSM signals with modulation orders up to 4194304QAM over a wireless channel for 4.6 km at a signal baud rate of 20 G. After 4.6 km of wireless transmission, we successfully achieve a bit error rate (BER) lower than the hard-decision forward error correction (HD-FEC) of 3.8 × 10-3 for 34.51 Gbit/s PDM-524288QAM and a BER lower than the soft-decision forward error correction (SD-FEC) of 4.2 × 10-2 for 32.23 Gbit/s PDM-4194304QAM.

The miR-199a-5p/HIF1α dual-regulatory axis participates in hypoxia-induced aggressive phenotypes of oral squamous cell carcinoma (OSCC) cells.

BACKGROUND: The late-stage diagnosis and distant metastasis of oral squamous cell carcinoma (OSCC) remain a huge challenge to clinical treatment for OSCC. During the past decades, targeting glycolysis-inducing factors becomes an attractive new strategy in OSCC therapies. METHODS: OSCC cells were stimulated with hypoxia or transfected with agomir-199a-5p, antagomir-199a-5p, and siRNA for HIF1A, cell proliferation was detected by CCK-8 assay; HIF1α, GLUT1, HK2 and LDHA expression levels were examined with western blot; miR-199 expression was determined with RT-PCR; cell migratory and invasive abilities were examined using wound healing and transwell assays; the lactate and glucose in culture medium were also determined. Luciferase assay or CHIP assay was applied for confirm the binding between miR-199a-5p and HIF1A 3'UTR, or between HIF1α and miR-199a promoter. RESULTS: HIF1α showed to be abnormally up-regulated, and miR-199a-5p showed to be abnormally down-regulated within OSCC under hypoxia. Hypoxia considerably enhanced OSCC cell proliferation, glycolysis, migratory ability, and invasive ability. MiR-199a-5p bound to HIF1A 3'-UTR and suppressed HIF1A expression; HIF1α targeted miR-199a-5p promoter region and downregulated miR-199a-5p expression. Under hypoxia, miR-199a-5p overexpression significantly repressed HIF1α up-regulation inresponse to hypoxia, OSCC cell proliferation, glycolysis, migratory ability, and invasive ability. CONCLUSION: miR-199a-5p and HIF1α form a dual-regulatory axis in OSCC cells; the miR-199a-5p/HIF1α dual-regulatory axis contributes to hypoxia-induced aggressive OSCC phenotypes.

Application of radiomics model based on ultrasound image features in the prediction of carpal tunnel syndrome severity.

OBJECTIVE: The aim of our study is to develop and validate a radiomics model based on ultrasound image features for predicting carpal tunnel syndrome (CTS) severity. METHODS: This retrospective study included 237 CTS hands (106 for mild symptom, 68 for moderate symptom and 63 for severe symptom). There were no statistically significant differences among the three groups in terms of age, gender, race, etc. The data set was randomly divided into a training set and a test set in a ratio of 7:3. Firstly, a senior musculoskeletal ultrasound expert measures the cross-sectional area of median nerve (MN) at the scaphoid-pisiform level. Subsequently, a recursive feature elimination (RFE) method was used to identify the most discriminative radiomic features of each MN at the entrance of the carpal tunnel. Eventually, a random forest model was employed to classify the selected features for prediction. To evaluate the performance of the model, the confusion matrix, receiver operating characteristic (ROC) curves, and F1 values were calculated and plotted correspondingly. RESULTS: The prediction capability of the radiomics model was significantly better than that of ultrasound measurements when 10 robust features were selected. The training set performed perfect classification with 100% accuracy for all participants, while the testing set performed accurate classification of severity for 76.39% of participants with F1 values of 80.00, 63.40, and 84.80 for predicting mild, moderate, and severe CTS, respectively. Comparably, the F1 values for mild, moderate, and severe CTS predicted based on the MN cross-sectional area were 76.46, 57.78, and 64.00, respectively.. CONCLUSION: This radiomics model based on ultrasound images has certain value in distinguishing the severity of CTS, and was slightly superior to using only MN cross-sectional area for judgment. Although its diagnostic efficacy was still inferior to that of neuroelectrophysiology. However, this method was non-invasive and did not require additional costs, and could provide additional information for clinical physicians to develop diagnosis and treatment plans.

The effect of transvesical laparoscopic radical prostatectomy on sexual function and urinary continence.

OBJECTIVE: To analyze the effect of transvesical laparoscopic radical prostatectomy (TVLRP) on sexual function and urinary continence. METHOD: The data of 72 patients diagnosed with low-risk and localized prostate cancer, who underwent treatment at our hospital between January 2017 and June 2022, were retrospectively analyzed. All these patients underwent TVLRP under general anesthesia. Their serum prostate-specific antigen (PSA), urinary continence and erectile function were statistically analyzed. RESULTS: The operation went well with no intraoperative difficulties. The average surgical duration of 102 ± 22 min, coupled with the minimal intraoperative blood loss of 100 ± 32 mL, underscored the precision and efficacy of the surgical techniques employed. Following surgery, postoperative pathological assessments confirmed staging, revealing pT2a in 18 cases and pT2b in 54 cases, suggestive of localized tumors. Gleason scores ≤ 6 further indicated well-differentiated tumors, while consistently negative surgical margins affirmed the complete resection of tumors, reducing the likelihood of disease recurrence. Subsequent to the surgical intervention, the the average hospital stay was 13.94.1 days. A comprehensive 12-month follow-up revealed exceptionally high urinary continence rates, with 97.8% and 100% of patients achieving continence at 1 and 3 months postoperatively, respectively. Moreover, progressive improvement in erectile function recovery was observed, with recovery rates at 3, 6, and 12 months postoperatively reaching 82.2%, 88.4%, and 93.5%, respectively. There was no biochemical regression. CONCLUSION: Treatment of low-risk and localized prostate cancer by TVLRP has a satisfactory urinary continence and recovery of erectile function after operation, less and complications and definite tumor-control effect.

Dysbiosis of gut microbiota inhibits NMNAT2 to promote neurobehavioral deficits and oxidative stress response in the 6-OHDA-lesioned rat model of Parkinson's disease.

BACKGROUND: New data are accumulating on gut microbial dysbiosis in Parkinson's disease (PD), while the specific mechanism remains uncharacterized. This study aims to investigate the potential role and pathophysiological mechanism of dysbiosis of gut microbiota in 6-hydroxydopamine (6-OHDA)-induced PD rat models. METHODS: The shotgun metagenome sequencing data of fecal samples from PD patients and healthy individuals were obtained from the Sequence Read Archive (SRA) database. The diversity, abundance, and functional composition of gut microbiota were further analyzed in these data. After the exploration of the functional pathway-related genes, KEGG and GEO databases were used to obtain PD-related microarray datasets for differential expression analysis. Finally, in vivo experiments were performed to confirm the roles of fecal microbiota transplantation (FMT) and upregulated NMNAT2 in neurobehavioral symptoms and oxidative stress response in 6-OHDA-lesioned rats. RESULTS: Significant differences were found in the diversity, abundance, and functional composition of gut microbiota between PD patients and healthy individuals. Dysbiosis of gut microbiota could regulate NAD+ anabolic pathway to affect the occurrence and development of PD. As a NAD+ anabolic pathway-related gene, NMNAT2 was poorly expressed in the brain tissues of PD patients. More importantly, FMT or overexpression of NMNAT2 alleviated neurobehavioral deficits and reduced oxidative stress in 6-OHDA-lesioned rats. CONCLUSIONS: Taken together, we demonstrated that dysbiosis of gut microbiota suppressed NMNAT2 expression, thus exacerbating neurobehavioral deficits and oxidative stress response in 6-OHDA-lesioned rats, which could be rescued by FMT or NMNAT2 restoration.

Nonlinearity mitigation in a fiber-wireless integrated system based on low-complexity autoencoder and BiLSTM-ANN equalizer.

We propose and experimentally demonstrate an intelligent nonlinear compensation method using a stacked autoencoder (SAE) model in conjunction with principal component analysis (PCA) technology and a bidirectional long-short-term memory coupled with ANN (BiLSTM-ANN) nonlinear equalizer for an end-to-end (E2E) fiber-wireless integrated system. The SAE-optimized nonlinear constellation is utilized to mitigate nonlinearity during the optical and electrical conversion process. Our proposed BiLSTM-ANN equalizer is primarily based on time memory and information extraction characteristics, which can compensate for the remaining nonlinear redundancy. A low-complexity 50 Gbps E2E-optimized nonlinear 32 QAM signal is successfully transmitted over a span of 20 km standard single-mode fiber (SSMF) and 6 m wireless link at 92.5 GHz. The extended experimental results indicate that the proposed E2E system can achieve a reduction of up to 78% in BER and a gain in receiver sensitivity of over 0.7 dB at BER of 3.8 × 10-3. Moreover, computational complexity is reduced by more than 10 times compared to the classical training model.

Real-time demonstration of a low-complexity PS scheme for 16QAM-DMT signals in an IM-DD system.

We experimentally demonstrated a low-complexity probabilistic shaping (PS) 16-ary quadrature amplitude modulation (16QAM) scheme based on intra-symbol bit-weighted distribution matching (Intra-SBWDM) for discrete multi-tone (DMT) symbols with field-programmable gate array implementation in an intensity modulation and direct detection (IM-DD) system. Different from the traditional PS scheme such as Gallager many-to-one mapping, hierarchical distribution matching and constant composition distribution matching, the Intra-SBWDM scheme with lower computation and hardware complexity does not need to continuously refine the interval to find the target symbol probability, nor does it need a look-up table, so it does not introduce a large number of extra redundant bits. In our experiment, four PS parameter values (k = 4, 5, 6, and 7) are investigated in a real-time short-reach IM-DD system. 31.87-Gbit/s net bit PS-16QAM-DMT (k = 4) signal transmission is achieved. The results show that the receiver sensitivity in terms of the received optical power of the real-time PS scheme based on Intra-SBWDM (k = 4) over OBTB/20 km standard single-mode fiber can be improved by about 1.8/2.2 dB at the bit error rate (BER) of 3.8 × 10-3, compared to the uniformly-distributed DMT. In addition, the BER is steadily lower than 3.8 × 10-3 during a one-hour measurement for PS-DMT transmission system.

Sparse I/Q-joint DNN nonlinear equalization based on progressive pruning for a photonics-aided 256-QAM MMW communication system.

An efficient nonlinear equalizer based on the pruning I/Q-joint deep neural network (DNN) is proposed and experimentally demonstrated to mitigate the nonlinearity in a photonics-assisted millimeter-wave (MMW) system with a high-order 256 quadrature-amplitude-modulation (QAM) format. Experimental findings reveal that implementing pruning on the I/Q-joint DNN can compress the computational overhead by 32% while accommodating 256-QAM E-band MMW transmission for a net throughput of 66.67 Gbps with 20.21% less complexity than the traditional Volterra nonlinear equalizer. Compared with the I/Q dual DNN with the same complexity, a 16% pruning ratio improvement is enabled by a robust pruning I/Q-joint DNN that further deciphers the I/Q relationship.

FPGA implementation for 44.2368-Gbit/s PAM8 signal transmission with pruned pre-equalization.

In this experiment, we demonstrated an intensity modulation and direct-detection (IM/DD) system based on a field-programmable gate array (FPGA). The PAM8 signals are successfully delivered at 44.2368 Gbit/s over a 45-km standard single-mode fiber (SSMF), satisfying the soft-decision forward error correction (SD-FEC) criterion of 2.4 × 10-2, and the net bit rate may reach 36.864 Gbit/s without the need of optical amplifiers. At the transmitter, we used a pruned pre-equalization algorithm to process the PAM8 signals, and the high-speed parallel PAM8 signals were processed at the receiver using 64 parallel constant modulus algorithm (CMA) and decision-directed least mean square (DD-LMS) equalizers. Additionally, we analyzed the bit error rate (BER) performance of the DD-LMS equalizer in FPGA simulation with various data lengths, both before and after equalization.

Probabilistic shaping-based delta sigma modulation.

This Letter proposes a probabilistic shaping delta-sigma modulation technique. By performing delta-sigma modulation on the probability shaping signal at the transmitting end, under the same transmit power and the same net bit rate, the delta-sigma modulation signal based on probability shaping can obtain better anti-noise capability than the delta-sigma modulation signal only. Under the same information entropy conditions, the bit error rate performance of the PS-based 131072QAM signal modulated by delta-sigma modulation is better than that of the ordinary 65536QAM signal using the delta-sigma modulation scheme, and lower than that of soft decision-forward error correction (4 × 10-2).

FPGA-based 4 × 29.4912 Gbit/s PS-PAM4 signal transmission with a low-complexity probabilistic shaping scheme.

In this experiment, we demonstrate a real-time intensity modulation and direct detection (IM/DD) system based on a field programmable gate array (FPGA). For high-speed parallel signal processing, we propose and implement the simplified parallel-constant modulus algorithm (CMA) and decision-directed least mean square (DDLMS) equalizers with low complexity and low latency. Moreover, the bit-class probabilistic shaping (PS) scheme is adopted with very few hardware resources. The digital signal processing (DSP) steps are implemented in the XCVU9P-FLGB2104-2-I Xilinx FPGA with a clock frequency of 230.4 MHz. Based on the experimental results, 4 × 29.4912 Gbit/s PS-pulse amplitude modulation (PAM4) signals can be successfully transmitted over 25 km of standard single-mode fiber (SSMF) while satisfying the hard-decision forward error correction (HD-FEC) threshold at 3.8 × 10-3. Compared with the uniformly distributed PAM4 signal, the low-complexity PS scheme can improve the receiver sensitivity by more than 1 dB.

65,536-QAM OFDM signal transmission over a fiber-THz system at 320†GHz with delta-sigma modulation.

The transmission of a 65,536-ary quadrature amplitude modulation (QAM) orthogonal frequency division multiplexing (OFDM) signal supported by a hybrid fiber-terahertz (THz) multiple-input multiple-output (MIMO) system at 320 GHz is experimentally demonstrated in this Letter. We adopt the polarization division multiplexing (PDM) technique to double the spectral efficiency. Based on a 23-GBaud 16-QAM link, 2-bit delta-sigma modulation (DSM) quantization enables 65,536-QAM OFDM signal transmission over a 20-km standard single-mode fiber (SSMF) and a 3-m 2 × 2 MIMO wireless delivery, and satisfies the hard-decision forward error correction (HD-FEC) threshold of 3.8 × 10-3, corresponding to a net rate of 60.5 Gbit/s for THz-over-fiber transport. Meanwhile, below the fronthaul error vector magnitude (EVM) threshold of 0.34%, a maximum signal-to-noise ratio (SNR) of 52.6 dB is achieved. To the best of our knowledge, this is the highest modulation order achievable for DSM applications in THz communication.

Beyond 300-Gbps/λ photonics-aided THz-over-fiber transmission employing MIMO single-carrier frequency-domain equalizer.

We experimentally realized a 320-GHz 320-Gbps/λ terahertz (THz) radio-over-fiber (RoF) system based on a photonics-aided scheme with the help of polarization-division multiplexing (PDM) technology and multiple-input, multiple-output (MIMO) transmission. In this system, the low-complexity MIMO single-carrier frequency-domain equalizer (SCFDE) is implemented to compensate for the polarization-related impairments of the PDM signal, and the demultiplexing performances between SCFDE and the commonly used constant modulus algorithm (CMA) are also compared in this proposed system. After 20-km standard single-mode fiber (SSMF) and 3-m 2 × 2 MIMO wireless link transmission, the bit error rate (BER) of the received 46-GBaud PDM 16-ary quadrature amplitude modulation (16QAM) signal satisfies the soft-decision forward error correction (SD-FEC) threshold with 15% overhead, which corresponds to a record-breaking net bit rate of 320 Gbit/s.