SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

Adipose Tissue Targeting Ultra-Small Hybrid Nanoparticles for Synergistic Photodynamic Therapy and Browning Induction in Obesity Treatment.

Photodynamic therapy (PDT), as a means of locally and rapidly inducing adipocyte death via light illumination, in combination with adipose browning induction, a more gradual and widespread effect that could transform white adipose tissue into thermogenic adipose tissue, manifests a promising approach to combat obesity. Herein, adipose-targeting ultra-small hybrid nanoparticles (Pep-PPIX-Baic NPs) composed of an adipose-targeting peptide, Fe3+, a photosensitizer (protoporphyrin IX), and a browning agent (baicalin) are introduced. Pep-PPIX-Baic NPs have been designed to simultaneously enhance the photodynamic effect and induce browning. After intravenous injection in obese mice, the hybrid nanoparticles can specifically accumulate in white adipose tissues, especially those rich in blood supply, and drive adipose reduction owing to the synergy of the PDT effect and baicalin browning induction. Overall, Pep-PPIX-Baic NPs exhibited superior anti-obesity potential through PDT synergistic with adipose browning induction. The designed multifunctional adipose-targeting hybrid nanoparticles present a prospective nanoplatform for obesity treatment.

Capsule Shedding and Membrane Binding Enhanced Photodynamic Killing of Gram-Negative Bacteria by a Unimolecular Conjugated Polyelectrolyte.

The development of new antimicrobial agents to treat infections caused by Gram-negative bacteria is of paramount importance due to increased antibiotic resistance worldwide. Herein, we show that a water-soluble porphyrin-cored hyperbranched conjugated polyelectrolyte (PorHP) exhibits high photodynamic bactericidal activity against the Gram-negative bacteria tested, including a multidrug-resistant (MDR) pathogen, while demonstrating low cytotoxicity toward mammalian cells. Comprehensive analyses reveal that the antimicrobial activity of PorHP proceeds via a multimodal mechanism by effective bacterial capsule shedding, strong bacterial outer membrane binding, and singlet oxygen generation. Through this multimodal antimicrobial mechanism, PorHP displays significant performance for Gram-negative bacteria with >99.9% photodynamic killing efficacy. Overall, PorHP shows great potential as an antimicrobial agent in fighting the growing threat of Gram-negative bacteria.

Exploring the PDZ, DUF, and LIM Domains of Pdlim5 in Dendrite Branching.

The branched architecture of neuronal dendrites is a key factor in how neurons form ordered networks and discoveries continue to be made identifying proteins and protein-protein interactions that direct or execute the branching and extension of dendrites. Our prior work showed that the molecular scaffold Pdlim5 and delta-catenin, in conjunction, are two proteins that help regulate the branching and elongation of dendrites in cultured hippocampal neurons and do so through a phosphorylation-dependent mechanism triggered by upstream glutamate signaling. In this report we have focused on Pdlim5's multiple scaffolding domains and how each contributes to dendrite branching. The three identified regions within Pdlim5 are the PDZ, DUF, and a trio of LIM domains; however, unresolved is the intra-molecular conformation of Pdlim5 as well as which domains are essential to regulate dendritic branching. We address Pdlim5's structure and function by examining the role of each of the domains individually and using deletion mutants in the context of the full-length protein. Results using primary hippocampal neurons reveal that the Pdlim5 DUF domain plays a dominant role in increasing dendritic branching. Neither the PDZ domain nor the LIM domains alone support increased branching. The central role of the DUF domain was confirmed using deletion mutants in the context of full-length Pdlim5. Guided by molecular modeling, additional domain mapping studies showed that the C-terminal LIM domain forms a stable interaction with the N-terminal PDZ domain, and we identified key amino acid residues at the interface of each domain that are needed for this interaction. We posit that the central DUF domain of Pdlim5 may be subject to modulation in the context of the full-length protein by the intra-molecular interaction between the N-terminal PDZ and C-terminal LIM domains. Overall, our studies reveal a novel mechanism for the regulation of Pdlim5's function in the regulation of neuronal branching and highlight the critical role of the DUF domain in mediating these effects.

Long-period D-fiber grating based robust and efficient bidirectional coupler for whispering gallery mode excitation.

A robust and efficient bidirectional coupler for whispering gallery mode (WGM) excitation based on a long-period grating (LPG) inscribed in D-fiber is theoretically and experimentally demonstrated. The LPG coupling the fundamental core mode to the forward propagating cladding modes according to the phase-matching condition not only enhances the evanescent field of the fiber but also selectively excites the WGM in a wavelength band of interest. Experimental results show that a maximum resonance contrast as high as 10.5 dB and a quality factor (Q-factor) on the order of 104 can be achieved in an LPG coupled spherical silica WGM resonator with a diameter of 242 µm, where the LPG with a pitch of 680 µm is fabricated by arc-discharging in a side-polished D-fiber with a maximum polishing depth of 56 µm. In addition to high robustness and efficiency, such an LPG-based WGM coupler also demonstrates bidirectionality, i.e., it is independent of the injection direction of the input light, which provides a reliable and flexible fiber coupler for the WGM resonator based practical applications.

Rayleigh backscattering-based simultaneous linewidth narrowing of a multi-wavelength DFB laser array with an arbitrary wavelength spacing.

Simultaneous linewidth narrowing of a multi-wavelength laser array with an arbitrary wavelength spacing based on Rayleigh backscattering is experimentally demonstrated. Rayleigh backscattering from a single 30 m high numerical aperture fiber (HNAF) is employed to simultaneously narrow the linewidths of a DFB laser array consisting of four distributed feedback (DFB) semiconductor lasers with different wavelengths. Experimental results show that the instantaneous linewidths of the four DFB lasers can be simultaneously narrowed from megahertz to kilohertz no matter whether the wavelength spacing between the lasers is equally spaced or not, verifying the self-adaptivity of Rayleigh backscattering on laser linewidth narrowing. The method demonstrated here is also applicable for on-chip waveguides without wavelength dependence, providing a more compact narrow linewidth laser array for the wavelength-multiplexing division system and other promising applications.

Narrow linewidth semiconductor multi-wavelength DFB laser array simultaneously self-injection locked to a single microring resonator.

We experimentally demonstrate a narrow linewidth semiconductor multi-wavelength distributed feedback (DFB) laser array by simultaneously injection locking each laser to the corresponding resonance of a single on-chip microring resonator. The white frequency noises of all the DFB lasers is reduced by more than 40 dB once they are simultaneously injection locked to a single microring resonator with a quality factor (Q-factor) of 2.38 million. Correspondingly, the instantaneous linewidths of all the DFB lasers are narrowed by a factor of 104. In addition, frequency combs originating from non-degenerate four-wave mixing (FWM) between the locked DFB lasers are also observed. Simultaneously injection locking multi-wavelength lasers to a single on-chip resonator may enable the possibilities of integrating a narrow-linewidth semiconductor laser array on a single chip and having multiple microcombs in a single resonator, which are in high demand in wavelength division multiplexing coherent optical communication systems and metrological applications.

Central diastolic blood pressure, plasma aldosterone and uric acid are associated with microalbuminuria in essential hypertension: a case-control study.

OBJECTIVE: To study the development of microalbuminuria (MAU) in essential hypertension (EHT), we investigated the association of MAU with central blood pressure (CBP), direct renin concentration (DRC), plasma aldosterone (PA), and uric acid (UA). METHOD: We determined 24 h-urinary albumin excretion (24 h-UAE) in patients with EHT who were hospitalized at TEDA International Cardiovascular Hospital from June 2020 to May 2022. We defined MAU as 24 h-UAE in the range of 30 mg/24 h to 300 mg/24 h. Univariate and multivariate analyses were conducted to determine the associations of MAU with CBP, DRC, PA, and UA in EHT, considering demographic and clinical information. We also plotted receiver operating characteristic curves (ROCs) for predicting MAU using these results. RESULTS: More than a quarter of patients (26.5%, 107/404, 95% CI: 22.2-31.1%) were diagnosed with MAU in EHT. A higher body mass index (BMI), longer duration of hypertension, and higher severity were associated with MAU. Also, nearly 10% more creatinine levels were recorded in the MAU group than in the control group (69.5 ± 18.7 µmol/L vs. 64.8 ± 12.5 µmol/L, P = 0.004). The increase was also observed for PA (15.5, 9.7-20.6 ng/dL vs. 12.3, 9.0-17.3 ng/dL, P = 0.024) and UA (419.8 ± 105.6 µmol/L vs. 375.1 ± 89.5 µmol/L, P < 0.001) in the MAU group compared to that in the control group. Several variables were associated with MAU, including central diastolic blood pressure (CDBP) (OR = 1.017, 95% CI: 1.002-1.032, P = 0.027), PA (OR = 1.043, 95% CI: 1.009-1.078, P = 0.012) and UA (OR = 1.005, 95% CI: 1.002-1.008, P < 0.001). For MAU prediction, the area under the curve (AUC) was 0.709 (95% CI: 0.662-0.753; P < 0.001) when CDBP, PA, and UA were used in combination, and the optimal probability of the cut-off value was 0.337. CONCLUSION: We found that CDBP, PA, and UA, used for MAU prediction, might be associated with its development during EHT.

Discovery of dolutegravir-1,2,3-triazole derivatives against prostate cancer via inducing DNA damage.

Prostate cancer (PCa) is the second most frequently diagnosed cancer among men, causing a huge number of deaths each year. Traditional chemotherapy for PCa mostly focused on targeting androgen receptors. However, some of the patients would develop resistance to hormonal therapy. In these cases, it is suggested for these patients to administer treatments in combination with other chemotherapeutics. Current chemotherapeutics for metastatic castration-resistant PCa could hardly reach satisfying effects, therefore it is crucial to explore novel agents with low cytotoxicity. Herein, a common drug against the human immunodeficiency virus (HIV), the dolutegravir (DTG) was modified to become a series of dolutegravir-1,2,3-triazole derivatives. Among these compounds, the 4d and 4q derivatives were verified with high anti-tumor efficiency, suppressing the proliferation of the prostate cancer cells PC3 and DU145. These compounds function by binding to the poly (adenosine diphosphate-ribose) polymerase (PARP), inactivating the PARP and inducing DNA damage in cancer cells. It is noteworthy that the 4d and 4q derivatives showed almost no impact on normal cells and mice. Thereby, the results reveal that these dolutegravir-1,2,3-triazole compounds are potential chemotherapeutics for PCa treatment.

A carrier-free supramolecular nano-twin-drug for overcoming irinotecan-resistance and enhancing efficacy against colorectal cancer.

Irinotecan (Ir) is commonly employed as a first-line chemotherapeutic treatment for colorectal cancer (CRC). However, tremendous impediments remain to be addressed to surmount drug resistance and ameliorate adverse events. Poly-ADP-Ribose Polymerase (PARP) participates in the maintenance of genome stability and the repair of DNA damage, thus playing a critical role in chemotherapy resistance. In this work, we introduce a novel curative strategy that utilizes nanoparticles (NPs) prepared by dynamic supramolecular co-assembly of Ir and a PARP inhibitor (PARPi) niraparib (Nir) through π-π stacking and hydrogen bond interactions. The Ir and Nir self-assembled Nano-Twin-Drug of (Nir-Ir NPs) could enhance the therapeutic effect on CRC by synergistically inhibiting the DNA damage repair pathway and activating the tumor cell apoptosis process without obvious toxicity. In addition, the Nir-Ir NPs could effectively reverse irinotecan-resistance by inhibiting the expression of multiple resistance protein-1 (MRP-1). Overall, our study underscores the distinctive advantages and potential of Nir-Ir NPs as a complementary strategy to chemotherapy by simultaneously overcoming the Ir resistance and improving the anti-tumor efficacy against CRC.

Ultra-narrow linewidth vertical-cavity surface-emitting laser based on external-cavity weak distributed feedback.

We demonstrate an ultra-narrow linewidth vertical-cavity surface-emitting laser (VCSEL) based on external-cavity weak distributed feedback from Rayleigh backscattering (RBS). A single longitudinal mode VCSEL with the linewidth as narrow as 435 Hz and a contrast of 55 dB are experimentally achieved by RBS fiber with a feedback level of RBS signal of -27.6 dB. By adjusting the thermal resistance of the VCSEL from 4.5 kΩ to 7.0 kΩ, the laser wavelength can be tuned from 1543.324 nm to 1542.06 nm with a linear tuning slope of -0.506 nm/kΩ. In the tuning process, the linewidth fluctuates in the range of 553-419 Hz.

Emerging on-chip electrokinetic based technologies for purification of circulating cancer biomarkers towards liquid biopsy: A review.

Early detection of cancer can significantly reduce mortality and save lives. However, the current cancer diagnosis is highly dependent on costly, complex, and invasive procedures. Thus, a great deal of effort has been devoted to exploring new technologies based on liquid biopsy. Since liquid biopsy relies on detection of circulating biomarkers from biofluids, it is critical to isolate highly purified cancer-related biomarkers, including circulating tumor cells (CTCs), cell-free nucleic acids (cell-free DNA and cell-free RNA), small extracellular vesicles (exosomes), and proteins. The current clinical purification techniques are facing a number of drawbacks including low purity, long processing time, high cost, and difficulties in standardization. Here, we review a promising solution, on-chip electrokinetic-based methods, that have the advantage of small sample volume requirement, minimal damage to the biomarkers, rapid, and label-free criteria. We have also discussed the existing challenges of current on-chip electrokinetic technologies and suggested potential solutions that may be worthy of future studies.

Control of polarization switching in a VCSEL via resonant feedback from a whispering-gallery-mode cavity.

We report a method for flexibly switching the dominant polarization of a vertical-cavity surface-emitting laser (VCSEL) by introducing polarization-resolved resonant optical feedback from a whispering-gallery-mode (WGM) cavity to the lasing cavity. Switching between the originally dominant mode and a side mode is experimentally demonstrated under different bias currents once one of them is locked to the resonance mode of the WGM cavity. In addition to a controllable polarization state, the reported VCSEL also demonstrates a linewidth as narrow as tens of kilohertz, which is highly desirable for many applications, including high-speed data communication, light detection and ranging (lidar), and absorption spectroscopy.

The developmental toxicity and transcriptome analyses of zebrafish (Danio rerio) embryos exposed to carbon nanoparticles.

Long-term and short-term exposure to carbon nanoparticles (CNPs) can affect fetal development and subsequent adverse outcomes including preterm delivery, intrauterine growth restriction, low birth weight, increased health risk linked to cardiovascular, respiratory and nervous systems in adulthood. The adverse developmental outcomes of CNPs were well known, but the underlying mechanisms remain unresolved. In this study, zebrafish embryos were treated with CNPs of 50,100,200 µg/mL and the toxic effects were observed. Using the RNA-seq analysis approach, we examined the effects of CNPs (200 µg/mL) on gene expression in zebrafish embryos exposed from 4 to 96 h-post-fertilization (hpf). We observed that CNPs-treated embryos exhibited increased malformations and decreased hatching. A total of 236 differentially expressed genes were detected by transcriptome analyses, which were associated with phototransduction, amino acid metabolism, steroid and steroid hormone biosynthesis. Transcriptome results were verified by real-time fluorescence quantitative PCR (RT-qPCR). Our results indicated that CNPs exposure was most likely to lead to differential gene changes in steroid and hormone biosynthesis pathways, thus inducing developmental toxicity such as delayed incubation of zebrafish embryos, increased malformation rate and multiple malformation phenotypes.

Toxicity Analysis of Mesoporous Polydopamine on Intestinal Tissue and Microflora.

As a promising therapy, photothermal therapy (PTT) converts near-infrared (NIR) light into heat through efficient photothermal agents (PTAs), causing a rapid increase in local temperature. Considering the importance of PTAs in the clinical application of PTT, the safety of PTAs should be carefully evaluated before their widespread use. As a promising PTA, mesoporous polydopamine (MPDA) was studied for its clinical applications for tumor photothermal therapy and drug delivery. Given the important role that intestinal microflora plays in health, the impacts of MPDA on the intestine and on intestinal microflora were systematically evaluated in this study. Through biological and animal experiments, it was found that MPDA exhibited excellent biocompatibility, in vitro and in vivo. Moreover, 16S rRNA analysis demonstrated that there was no obvious difference in the composition and classification of intestinal microflora between different drug delivery groups and the control group. The results provided new evidence that MPDA was safe to use in large doses via different drug delivery means, and this lays the foundation for further clinical applications.

Simultaneous self-injection locking of two VCSELs to a single whispering-gallery-mode microcavity.

Simultaneous self-injection locking of two vertical-cavity surface-emitting lasers (VCSELs) to a single whispering-gallery-mode (WGM) microcavity is experimentally demonstrated. The linewidths of the two VCSELs are compressed from 3.5 MHz and 5 MHz to 20.9 kHz and 24.1 kHz, which is on the same order of magnitude as that of locking each VCSEL to the microcavity separately. Moreover, the frequency noises of the two simultaneously locked VCSELs are suppressed by more than 60 dB below the offset frequency of 100 kHz compared to that of the free-running VCSELs. The method demonstrated here might be used in the multi-wavelength laser array with low phase and frequency noises, especially the VCSELs with the unique architecture of a two-dimensional array.

Narrow linewidth VCSEL based on resonant optical feedback from an on-chip microring add-drop filter.

We demonstrate a narrow linewidth vertical-cavity surface-emitting laser (VCSEL) by injecting resonant optical feedback into the lasing cavity. A single longitudinal mode VCSEL with a Lorentzian linewidth of 32.6 kHz and a purified optical spectrum is experimentally achieved by an on-chip microring add-drop filter with a quality factor of 1.36 million, where the feedback level is ${-}{47.77}\;{\rm{dB}}$. The frequency noise spectrum of the VCSEL demonstrates that the thermo-optic effect in the microring resonator can also stabilize the lasing frequency. A VCSEL with narrow linewidth and stable frequency provides a high-performance light source for a single VCSEL or VCSEL array-based application.

Cancer-Cell-Activated in situ Synthesis of Mitochondria-Targeting AIE Photosensitizer for Precise Photodynamic Therapy.

Maximization of phototoxic damage on tumor with minimized side effect on normal tissue is essential for effective anticancer photodynamic therapy (PDT). This requires highly cancer-cell-specific or even cancer-cell-organelle-specific synthesis or delivery of efficient photosensitizers (PSs) in vitro and in vivo, which is difficult to achieve. Herein, we report a strategy of cancer-cell-activated PS synthesis, by which an efficient mitochondria-targeting photosensitizer with aggregation-induced-emission (AIE) feature can be selectively synthesized as an efficient image-guided PDT agent inside cancer cells. MOF-199, a CuII -based metal-organic framework, was selected as an inert carrier to load the PS precursors for efficient delivery and served as a CuI catalyst source for in situ click reaction to form PSs exclusively in cancer cells. The in situ synthesized PS showed mitochondria-targeting capability, allowing potent cancer-cell-specific ablation under light irradiation. The high specificity of PSs produced in cancer cells also makes it safer post-treatment.

Ultra-narrow multi-band polarization-insensitive plasmonic perfect absorber for sensing.

We theoretically propose a simple ultra-narrow multi-band perfect absorber for sensing applications. The perfect absorber consists of periodically arranged metallic nanodisks etched with regular prismatic holes standing on the dielectric-metal bi-layer films. Multiple ultra-narrow perfect absorption bands are obtained in the near-infrared region with the maximum bandwidth less than 21 nm and the intensity as high as 99.86%. The ultra-narrow multi-band perfect absorption originates from the synergy of localized surface plasmons, propagating surface plasmons and lattice resonances. The perfect absorber also presents other significant advantages, e.g. polarization insensitivity and high sensitivity of surrounding environments. Moreover, the prominent sensing performance for detecting the trace amounts of glucose in water is demonstrated. These features make it a promising candidate with great potential in the fields of perfect absorbers, plasmonic sensors, filters and multiplexing binding bio-molecular detection.

A fluorometric optical fiber nanoprobe for copper(II) by using AgInZnS quantum dots.

An optical fiber nanoprobe is presented for fluorometric determination of copper(II). The method based on the use of water-dispersible AgInZnS quantum dots (QDs) deposited at the end of an optical fiber in a poly(vinyl alcohol) matrix. The fluorescnece of the QDs, best measured at excitation/emisssion wavelengths of 365/570 nm, is quenched by Cu(II) due to both static and electron transfer from the QDs to Cu(II). This is experimentally confirmed by photoluminescence and UV-vis absorption spectra, and measurement of luminescence lifetimes. The probe is highly selective and possesses a linear detection range that extends from 2.5 to 800 nM. Graphical abstractSchematic representation of an optical fiber nanoprobe based on hydrophilic AgInZnS quantum dots for fluorometric determination of copper(II). The fluorescence is quenched by Cu(II) due to static quenching and dynamic quenching. It has a detection range of 2.5-800 nM.