CK2-HTATSF1-TOPBP1 signaling axis modulates tumor chemotherapy response.

Homologous recombination (HR) plays a key role in maintaining genomic stability, and the efficiency of the HR system is closely associated with tumor response to chemotherapy. Our previous work reported that CK2 kinase phosphorylates HIV Tat-specific factor 1 (HTATSF1) Ser748 to facilitate HTATSF1 interaction with TOPBP1, which in turn, promotes RAD51 recruitment and HR repair. However, the clinical implication of the CK2-HTATSF1-TOPBP1 pathway in tumorigenesis and chemotherapeutic response remains to be elucidated. Here, we report that the CK2-HTATSF1-TOPBP1 axis is generally hyperactivated in multiple malignancies and renders breast tumors less responsive to chemotherapy. In contrast, deletion mutations of each gene in this axis, which also occur in breast and lung tumor samples, predict higher HR deficiency scores, and tumor cells bearing a loss-of-function mutation of HTATSF1 are vulnerable to poly(ADP-ribose) polymerase inhibitors or platinum drugs. Taken together, our study suggests that the integrity of the CK2-HTATSF1-TOPBP1 axis is closely linked to tumorigenesis and serves as an indicator of tumor HR status and modulates chemotherapy response.

Multifunctional cell membranes-based nano-carriers for targeted therapies: a review of recent trends and future perspective.

Nanotechnology has ignited a transformative revolution in disease detection, prevention, management, and treatment. Central to this paradigm shift is the innovative realm of cell membrane-based nanocarriers, a burgeoning class of biomimetic nanoparticles (NPs) that redefine the boundaries of biomedical applications. These remarkable nanocarriers, designed through a top-down approach, harness the intrinsic properties of cell-derived materials as their fundamental building blocks. Through shrouding themselves in natural cell membranes, these nanocarriers extend their circulation longevity and empower themselves to intricately navigate and modulate the multifaceted microenvironments associated with various diseases. This comprehensive review provides a panoramic view of recent breakthroughs in biomimetic nanomaterials, emphasizing their diverse applications in cancer treatment, cardiovascular therapy, viral infections, COVID-19 management, and autoimmune diseases. In this exposition, we deliver a concise yet illuminating overview of the distinctive properties underpinning biomimetic nanomaterials, elucidating their pivotal role in biomedical innovation. We subsequently delve into the exceptional advantages these nanomaterials offer, shedding light on the unique attributes that position them at the forefront of cutting-edge research. Moreover, we briefly explore the intricate synthesis processes employed in creating these biomimetic nanocarriers, shedding light on the methodologies that drive their development.

Ultrafast mode-locked laser in nanophotonic lithium niobate.

Mode-locked lasers (MLLs) generate ultrashort pulses with peak powers substantially exceeding their average powers. However, integrated MLLs that drive ultrafast nanophotonic circuits have remained elusive because of their typically low peak powers, lack of controllability, and challenges when integrating with nanophotonic platforms. In this work, we demonstrate an electrically pumped actively MLL in nanophotonic lithium niobate based on its hybrid integration with a III-V semiconductor optical amplifier. Our MLL generates [Formula: see text]4.8-ps optical pulses around 1065 nm at a repetition rate of ∼10 GHz, with energies exceeding 2.6 pJ and peak powers beyond 0.5 W. The repetition rate and the carrier-envelope offset frequency of the output can be controlled in a wide range by using the driving frequency and the pump current, providing a route for fully stabilized on-chip frequency combs.

Visible-to-mid-IR tunable frequency comb in nanophotonics.

Optical frequency comb is an enabling technology for a multitude of applications from metrology to ranging and communications. The tremendous progress in sources of optical frequency combs has mostly been centered around the near-infrared spectral region, while many applications demand sources in the visible and mid-infrared, which have so far been challenging to achieve, especially in nanophotonics. Here, we report widely tunable frequency comb generation using optical parametric oscillators in lithium niobate nanophotonics. We demonstrate sub-picosecond frequency combs tunable beyond an octave extending from 1.5 up to 3.3 µm with femtojoule-level thresholds on a single chip. We utilize the up-conversion of the infrared combs to generate visible frequency combs reaching 620 nm on the same chip. The ultra-broadband tunability and visible-to-mid-infrared spectral coverage of our source highlight a practical and universal path for the realization of efficient frequency comb sources in nanophotonics, overcoming their spectral sparsity.

Octave-spanning tunable infrared parametric oscillators in nanophotonics.

Widely tunable coherent sources are desirable in nanophotonics for a multitude of applications ranging from communications to sensing. The mid-infrared spectral region (wavelengths beyond 2 µm) is particularly important for applications relying on molecular spectroscopy. Among tunable sources, optical parametric oscillators typically offer some of the broadest tuning ranges; however, their implementations in nanophotonics have been limited to narrow tuning ranges in the infrared or to visible wavelengths. Here, we surpass these limits in dispersion-engineered periodically poled lithium niobate nanophotonics and demonstrate ultrawidely tunable optical parametric oscillators. Using 100 ns pulses near 1 µm, we generate output wavelengths tunable from 1.53 µm to 3.25 µm in a single chip with output powers as high as tens of milliwatts. Our results represent the first octave-spanning tunable source in nanophotonics extending into the mid-infrared, which can be useful for numerous integrated photonic applications.

ScRNAPip: A systematic and dynamic pipeline for single-cell RNA sequencing analysis.

With the advancement of sequencing technology, cell separation, and whole-genome amplification techniques, single cell technology for genome sequencing is emerging gradually. In comparison to traditional genome sequencing at the multi-cellular level, single-cell sequencing can not only measure the gene expression level more accurately but also can detect a small amount of gene expression or rare noncoding RNA. This technology has garnered increasing interest among researchers engaged in single-cell studies in recent years. Here, we developed a reproducible computational workflow for scRNA-seq data analysis which including tasks like quality control, normalization, data correction, pseudotime analysis, copy number analysis, etc. We illustrate the application of these steps using publicly available datasets and provide practical recommendations for their implementation. This study serves as a comprehensive tutorial for researchers keen on single-cell data analysis, aiding users in constructing and refining their own analysis pipelines.

Few-cycle vacuum squeezing in nanophotonics.

One of the most fundamental quantum states of light is the squeezed vacuum, in which noise in one of the quadratures is less than the standard quantum noise limit. In nanophotonics, it remains challenging to generate, manipulate, and measure such a quantum state with the performance required for a wide range of scalable quantum information systems. Here, we report the development of a lithium niobate-based nanophotonic platform to demonstrate the generation and all-optical measurement of squeezed states on the same chip. The generated squeezed states span more than 25 terahertz of bandwidth supporting just a few optical cycles. The measured 4.9 decibels of squeezing surpass the requirements for a wide range of quantum information systems, demonstrating a practical path toward scalable ultrafast quantum nanophotonics.

A PARylation-phosphorylation cascade promotes TOPBP1 loading and RPA-RAD51 exchange in homologous recombination.

The efficiency of homologous recombination (HR) in the repair of DNA double-strand breaks (DSBs) is closely associated with genome stability and tumor response to chemotherapy. While many factors have been functionally characterized in HR, such as TOPBP1, their precise regulation remains unclear. Here, we report that TOPBP1 interacts with the RNA-binding protein HTATSF1 in a cell-cycle- and phosphorylation-dependent manner. Mechanistically, CK2 phosphorylates HTATSF1 to facilitate binding to TOPBP1, which promotes S-phase-specific TOPBP1 recruitment to damaged chromatin and subsequent RPA/RAD51-dependent HR, genome integrity, and cancer-cell viability. The localization of HTATSF1-TOPBP1 to DSBs is potentially independent of the transcription-coupled RNA-binding and processing capacity of HTATSF1 but rather relies on the recognition of poly(ADP-ribosyl)ated RPA by HTATSF1, which can be blunted with PARP inhibitors. Together, our study provides a mechanistic insight into TOPBP1 loading at HR-prone DSB sites via HTATSF1 and reveals how RPA-RAD51 exchange is tuned by a PARylation-phosphorylation cascade.

LAP2α preserves genome integrity through assisting RPA deposition on damaged chromatin.

BACKGROUND: Single-stranded DNA (ssDNA) coated with replication protein A (RPA) acts as a key platform for the recruitment and exchange of genome maintenance factors in DNA damage response. Yet, how the formation of the ssDNA-RPA intermediate is regulated remains elusive. RESULTS: Here, we report that the lamin-associated protein LAP2α is physically associated with RPA, and LAP2α preferentially facilitates RPA deposition on damaged chromatin via physical contacts between LAP2α and RPA1. Importantly, LAP2α-promoted RPA binding to ssDNA plays a critical role in protection of replication forks, activation of ATR, and repair of damaged DNA. We further demonstrate that the preference of LAP2α-promoted RPA loading on damaged chromatin depends on poly ADP-ribose polymerase PARP1, but not poly(ADP-ribosyl)ation. CONCLUSIONS: Our study provides mechanistic insight into RPA deposition in response to DNA damage and reveals a genome protection role of LAP2α.

Disrupting PHF8-TOPBP1 connection elicits a breast tumor-specific vulnerability to chemotherapeutics.

The DNA damage response (DDR) pathway generally protects against genome instability, and defects in DDR have been exploited therapeutically in cancer treatment. We have reported that histone demethylase PHF8 demethylates TOPBP1 K118 mono-methylation (K118me1) to drive the activation of ATR kinase, one of the master regulators of replication stress. However, whether dysregulation of this physiological signalling is involved in tumorigenesis remains unknown. Here, we showed PHF8-promoted TOPBP1 demethylation is clinically associated with breast tumorigenesis and patient survival. Mammary gland tumors from Phf8 knockout mice grow slowly and exhibit higher level of K118me1, lower ATR activity, and increased chromosomal instability. Importantly, we found that disruption of PHF8-TOPBP1 axis suppresses breast tumorigenesis and creates a breast tumor-specific vulnerability to PARP inhibitor (PARPi) and platinum drug. CRISPR/Cas9 mutation modelling of the deleted or truncated mutation of PHF8 in clinical tumor samples demonstrated breast tumor cells expressing the mimetic variants are more vulnerable to PARPi. Together, our study supports the pursuit of PHF8-TOPBP1 signalling pathway as promising avenues for targeted therapies of PHF8-TOPBP1 proficient tumors, and provides proof-of-concept evidence for loss-of-function of PHF8 as a therapeutic indicator of PARPis.

Ultrafast Silicon Nanomembrane Microbolometer for Long-Wavelength Infrared Light Detection.

The microbolometer is the cornerstone device for imaging in the long-wavelength infrared range (LWIR) at room temperature. The state-of-the-art commercial microbolometers usually have a large thermal time constant (TTC) of over 10 ms, limited by their substantial device heat capacity. Moreover, the minimal pixel size of state-of-the-art bolometer is around 10 µm by 10 µm to ensure sufficient power absorption per pixel. Here, we demonstrate an ultrafast silicon nanomembrane microbolometer with a small heat capacity of around 1.9 × 10-11J/K, which allows for its operation at a speed of over 10 kHz, corresponding to a TTC of less than 16 µs. Moreover, a compact diabolo antenna is leveraged for efficient LWIR light absorption, enabling the downscaling of the active area size to 6.2 µm by 6.2 µm. Because of the complementary metal oxide semiconductor (CMOS)-compatible fabrication processes, our demonstration here may lead to a future high-resolution and high-speed LWIR imaging solution.

Extract from Dioscorea bulbifera L. rhizomes aggravate pirarubicin-induced cardiotoxicity by inhibiting the expression of P-glycoprotein and multidrug resistance-associated protein 2 in the mouse liver.

Chinese herbal medicine is widely used because it has a good safety profile and few side effects. However, the risk of adverse drug reactions caused by herb-drug interactions (HDIs) is often overlooked. Therefore, the task of identifying possible HDIs and elucidating their mechanisms is of great significance for the prevention and treatment of HDI-related adverse reactions. Since extract from Dioscorea bulbifera L. rhizomes (DB) can cause various degrees of liver damage, it is speculated that HDIs may occur between DB extract and chemicals metabolized or excreted by the liver. Our study revealed that the cardiotoxicity of pirarubicin (THP) was increased by co-administration of DB, and the expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2) in the liver was inhibited by DB extract, which led to the accumulation of THP in heart tissue. In conclusion, there are risks of the co-administration of DB extract and THP. The mechanism of HDIs can be better revealed by targeting the efflux transporters.

PHF8-promoted TOPBP1 demethylation drives ATR activation and preserves genome stability.

The checkpoint kinase ATR [ATM (ataxia-telangiectasia mutated) and rad3-related] is a master regulator of DNA damage response. Yet, how ATR activity is regulated remains to be investigated. We report here that histone demethylase PHF8 (plant homeodomain finger protein 8) plays a key role in ATR activation and replication stress response. Mechanistically, PHF8 interacts with and demethylates TOPBP1 (DNA topoisomerase 2-binding protein 1), an essential allosteric activator of ATR, under unperturbed conditions, but replication stress results in PHF8 phosphorylation and dissociation from TOPBP1. Consequently, hypomethylated TOPBP1 facilitates RAD9 (RADiation sensitive 9) binding and chromatin loading of the TOPBP1-RAD9 complex to fully activate ATR and thus safeguard the genome and protect cells against replication stress. Our study uncovers a demethylation and phosphorylation code that controls the assembly of TOPBP1-scaffolded protein complex, and provides molecular insight into non-histone methylation switch in ATR activation.

Non-dispersive infrared multi-gas sensing via nanoantenna integrated narrowband detectors.

Non-dispersive infrared (NDIR) spectroscopy analyzes the concentration of target gases based on their characteristic infrared absorption. In conventional NDIR gas sensors, an infrared detector has to pair with a bandpass filter to select the target gas. However, multiplexed NDIR gas sensing requires multiple pairs of bandpass filters and detectors, which makes the sensor bulky and expensive. Here, we propose a multiplexed NDIR gas sensing platform consisting of a narrowband infrared detector array as read-out. By integrating plasmonic metamaterial absorbers with pyroelectric detectors at the pixel level, the detectors exhibit spectrally tunable and narrowband photoresponses, circumventing the need for separate bandpass filter arrays. We demonstrate the sensing of H2S, CH4, CO2, CO, NO, CH2O, NO2, SO2. The detection limits of common gases such as CH4, CO2, and CO are 63 ppm, 2 ppm, and 11 ppm, respectively. We also demonstrate the deduction of the concentrations of two target gases in a mixture.

SPOCK1 Involvement in Epithelial-to-Mesenchymal Transition: A New Target in Cancer Therapy?

BACKGROUND: Cancer metastasis is the main obstacle to increasing the lifespan of cancer patients. Epithelial-to-mesenchymal transition (EMT) plays a significant role in oncogenic processes, including tumor invasion, intravasation, and micrometastasis formation, and is especially critical for cancer invasion and metastasis. The extracellular matrix (ECM) plays a crucial role in the occurrence of EMT corresponding to the change in adhesion between cells and matrices. CONCLUSION: SPOCK1 is a critical regulator of the ECM and mediates EMT in cancer cells. This suggests an important role for SPOCK1 in tumorigenesis, migration and invasion. SPOCK1 is a critical regulator of some processes involved in cancer progression, including cancer cell proliferation, apoptosis and migration. Herein, the functions of SPOCK1 in cancer progression are expounded, revealing the association between SPOCK1 and EMT in cancer metastasis. SPOCK1 is a positive downstream regulator of transforming growth factor-ß, and SPOCK1-mediated EMT regulates invasion and metastasis through the Wnt/ß-catenin pathway and PI3K/Akt signaling pathway. It is of significance that SPOCK1 may be an attractive prognostic biomarker and therapeutic target in cancer treatment.

Enhancing infrared emission of mercury telluride (HgTe) quantum dots by plasmonic structures.

The coupling of HgTe quantum dots to a gold nanobump plasmonic array can enhance the spontaneous infrared emission by a factor of five and reduce the influence of nonradiative decay channels.

Widely tunable mid-infrared light emission in thin-film black phosphorus.

Thin-film black phosphorus (BP) is an attractive material for mid-infrared optoelectronic applications because of its layered nature and a moderate bandgap of around 300 meV. Previous photoconduction demonstrations show that a vertical electric field can effectively reduce the bandgap of thin-film BP, expanding the device operational wavelength range in mid-infrared. Here, we report the widely tunable mid-infrared light emission from a hexagonal boron nitride (hBN)/BP/hBN heterostructure device. With a moderate displacement field up to 0.48 V/nm, the photoluminescence (PL) peak from a ~20-layer BP flake is continuously tuned from 3.7 to 7.7 µm, spanning 4 µm in mid-infrared. The PL emission remains perfectly linear-polarized along the armchair direction regardless of the bias field. Moreover, together with theoretical analysis, we show that the radiative decay probably dominates over other nonradiative decay channels in the PL experiments. Our results reveal the great potential of thin-film BP in future widely tunable, mid-infrared light-emitting and lasing applications.

Black Phosphorus High-Frequency Transistors with Local Contact Bias.

Having a sizable band gap and high carrier mobility, black phosphorus (BP) is a promising two-dimensional material for high-frequency electronic and optoelectronic devices. Further, for metal-oxide-semiconductor field-effect transistors (MOSFETs) operating at high frequencies, they must have a top gate of submicron length instead of the commonly used global back gate. However, without the global back gate to electrostatically induce doping in BP, top-gated submicron BP MOSFETs have not reached their full potential mainly due to large contact resistances. Here, we report top-gated submicron BP MOSFETs with local contact bias electrodes to induce doping in the contact region. This resulted in reduced contact resistance and, in turn, orders of magnitude improvement in current capacity (>500 µA/µm) and peak transconductance (>40 µS/µm), if compared with top-gated BP transistors without any back-gating scheme. In turn, these improvements resulted in a forward current gain cutoff frequency of 37 GHz and a maximum frequency of oscillation of 22 GHz at room temperature, the highest reported for BP MOSFETs up to date.

Erratum: Photothermal Engineering of Graphene Plasmons [Phys. Rev. Lett. 121, 057404 (2018)].

This corrects the article DOI: 10.1103/PhysRevLett.121.057404.

miR-218 regulates diabetic nephropathy via targeting IKK-ß and modulating NK-κB-mediated inflammation.

Diabetic nephropathy (DN) is a common clinically relevant complication of diabetes that is associated with damage to the capillaries, yet the etiology of this condition remains unclear. Nuclear factor-kappa B (NF-κB) activation is known to be associated with DN-related inflammation and disease progression. Recent work indicated that microRNAs are diagnostic biomarkers of DN progression associated with inflammation in the progression of DN. miR-218 is known to play key regulatory roles in certain cancers in humans, while its influence on DN pathology remains uncertain. The present study, therefore, sought to assess how miR-218 influences the progression of disease in both a rat streptozotocin-induced model of DN and as well as an in vitro model system in which mouse podocytes were stimulated with high glucose levels. We found miR-218 to be markedly downregulated in both model systems relative to appropriate controls, and this downregulation was associated with IKK-ß upregulation. In DN rat model, overexpressing miR-218 was sufficient to reduce renal injury. We further determined that podocyte proliferation was markedly impaired by glucose treatment, leading to the apoptotic death of these cells, and miR-218 mimics were able to reduce these phenotypes. Overexpressing miR-218 also significantly dampened inflammatory responses in this model system, as evidenced by reduced tumor necrosis factor-α, interleukin-6 (IL-6), IL-1ß, and MCP-1 levels. We then confirmed that miR-218 targeting the messenger RNA encoding IKK-ß using a dual-luciferase reporter assay. Together, our results provide clear evidence that miR-218 regulate NF-κB-mediated inflammation, which is central to DN progression.