Acarbose glycosylation by AcbE for the production of acarstatins with enhanced α-amylase inhibitory activity.

Acarbose is a potent glycosidase inhibitor widely used in the clinical treatment of type 2 diabetes mellitus (T2DM). Various acarbose analogs have been identified while exploring compounds with improved pharmacological properties. In this study, we found that AcbE from Actinoplanes sp. SE50/110 catalyzes the production of acarbose analogs that exhibit significantly improved inhibitory activity towards α-amylase than acarbose. Recombinant AcbE mainly catalyzed the formation of two new compounds, namely acarstatins A and B, using acarbose as substrate. Using high-resolution mass spectrometry, nuclear magnetic resonance, and glycosidase hydrolysis, we elucidated their chemical structures as O-α-d-maltosyl-(1 â†’ 4)-acarbose and O-α-d-maltotriosyl-(1 â†’ 4)-acarbose, respectively. Acarstatins A and B exhibited 1584- and 1478-fold greater inhibitory activity towards human salivary α-amylase than acarbose. Furthermore, both acarstatins A and B exhibited complete resistance to microbiome-derived acarbose kinase 1-mediated phosphorylation and partial resistance to acarbose-preferred glucosidase-mediated hydrolysis. Therefore, acarstatins A and B have great potential as candidate therapeutic agents for T2DM.

Potential application mechanism of traditional Chinese medicine in treating immune checkpoint inhibitor-induced colitis.

Cancer ranks among the foremost causes of mortality worldwide, posing a significant threat to human lives. The advent of tumor immunotherapy has substantially transformed the therapeutic landscape for numerous advanced malignancies, notably non-small cell lung cancer and melanoma. However, as immune checkpoint inhibitors (ICIs) are increasingly applied in clinical settings, a spectrum of undesired reactions, termed immune-related adverse events (irAEs), has emerged. These adverse reactions are associated with immunotherapy and can result in varying degrees of harm to the human body. Among these reactions, Immune checkpoint inhibitor-induced colitis (ICIIC) stands out as one of the most prevalent clinical adverse events. In contemporary times, traditional Chinese medicine (TCM) has demonstrated remarkable efficacy in addressing various maladies. Consequently, investigating the potential application and mechanisms of Chinese medicine in countering immune checkpoint inhibitor-induced colitis assumes significant importance in the treatment of this condition.

A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance.

The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.

Biosynthesis of ansamitocin P-3 incurs stress on the producing strain Actinosynnema pretiosum at multiple targets.

Microbial bioactive natural products mediate ecologically beneficial functions to the producing strains, and have been widely used in clinic and agriculture with clearly defined targets and underlying mechanisms. However, the physiological effects of their biosynthesis on the producing strains remain largely unknown. The antitumor ansamitocin P-3 (AP-3), produced by Actinosynnema pretiosum ATCC 31280, was found to repress the growth of the producing strain at high concentration and target the FtsZ protein involved in cell division. Previous work suggested the presence of additional cryptic targets of AP-3 in ATCC 31280. Herein we use chemoproteomic approach with an AP-3-derived photoaffinity probe to profile the proteome-wide interactions of AP-3. AP-3 exhibits specific bindings to the seemingly unrelated deoxythymidine diphosphate glucose-4,6-dehydratase, aldehyde dehydrogenase, and flavin-dependent thymidylate synthase, which are involved in cell wall assembly, central carbon metabolism and nucleotide biosynthesis, respectively. AP-3 functions as a non-competitive inhibitor of all three above target proteins, generating physiological stress on the producing strain through interfering diverse metabolic pathways. Overexpression of these target proteins increases strain biomass and markedly boosts AP-3 titers. This finding demonstrates that identification and engineering of cryptic targets of bioactive natural products can lead to in-depth understanding of microbial physiology and improved product titers.

Development of a Multichannel Membrane Reactor with a Solid Oxide Cell Design.

In this study, we aim to adapt a solid oxide cell (SOC) to a membrane reactor for general chemical reactions to leverage the readily available multichannel design of the SOC. As a proof-of-concept, the developed reactor is tested for syngas production by the partial oxidation of methane using oxygen ion transport membranes (ITMs) to achieve oxygen separation and permeation. A La0.6Sr0.4Co0.2Fe0.8O3-δ (LSCF) membrane and Ni/MgAl2O4 catalyst are used for oxygen permeation and the partial oxidation of methane, respectively. ANSYS Fluent is used to assess the reactor performance with the help of computational fluid dynamics (CFD) simulations. The membrane permeation process is chemical kinetics achieved by user-defined functions (UDFs). The simulation results show that the oxygen permeation rate depends on the temperature, air, and fuel flow rates, as well as the occurrence of reactions, which is consistent with the results reported in the literature. During isothermal operation, the product composition and the species distribution in the reactor change with the methane flow rate. When the molar ratio of fed methane to permeated oxygen is 2.0, the methane conversion and CO selectivity reach a high level, namely 95.8% and 97.2%, respectively, which agrees well with the experimental data reported in the literature. Compared to the isothermal operation, the methane conversion of the adiabatic operation is close to 100%. Still, the CO selectivity only reaches 61.6% due to the hot spot formation of 1491 K in the reactor. To reduce the temperature rise in the adiabatic operation, reducing the methane flow rate is an approach, but the price is that the productivity of syngas is sacrificed as well. In conclusion, the adaption of the SOC to a membrane reactor is achieved, and other reaction applications can be explored in the same way.

Quantification of dissipative effects in a complex Ginzburg-Landau equation governed laser system by tracing soliton dynamics.

The concept of dissipative solitons has provided new insight into the complex pulse dynamics in mode-locked lasers and stimulated novel laser cavity designs. However, most of these studies are restricted to qualitative regimes, because it is difficult to quantify dissipative effects in a mode-locked laser. Meanwhile, the quantification of dissipative effects is a general problem that can be also encountered in other dissipative systems. In this paper, we demonstrate a method for quantifying dissipative effects in a mode-locked laser based on analyzing the soliton dynamics traced by time-stretch dispersive Fourier transform. As a result, we are able to quantitatively reproduce the evolution of the pulse that seeds mode-locking through simulations and gain a deeper understanding of the whole process. The obtained physical picture of mode-locking allows us to propose a simple method to quantify the energy threshold for mode-locking buildup and the stability of mode-locked states. A parameter is introduced to evaluate mode-locking conditions, which can serve as a criterion for designing mode-locked lasers. This work opens up new possibilities in the diagnosis and improvement of mode-locked lasers and studies of soliton physics.

MED27 plays a tumor-promoting role in breast cancer progression by targeting KLF4.

The mediator complex usually cooperates with transcription factors to be involved in RNA polymerase II-mediated gene transcription. As one component of this complex, MED27 has been reported in our previous studies to promote thyroid cancer and melanoma progression. However, the precise function of MED27 in breast cancer development remains poorly understood. Here, we found that MED27 was more highly expressed in breast cancer samples than in normal tissues, especially in triple-negative breast cancer, and its expression level was elevated with the increase in pathological stage. MED27 knockdown in triple-negative breast cancer cells inhibited cancer cell metastasis and stemness maintenance, which was accompanied by downregulation of the expression of EMT- and stem traits-associated proteins, and vice versa in non-triple-negative breast cancer. Furthermore, MED27 knockdown sensitized breast cancer cells to epirubicin treatment by inducing cellular apoptosis and reducing tumorsphere-forming ability. Based on RNA-seq, we identified KLF4 as the possible downstream target of MED27. KLF4 overexpression reversed the MED27 silencing-mediated arrest of cellular metastasis and stemness maintenance capacity in breast cancer in vitro and in vivo. Mechanistically, MED27 transcriptionally regulated KLF4 by binding to its promoter region at positions -156 to +177. Collectively, our study not only demonstrated the tumor-promoting role of MED27 in breast cancer progression by transcriptionally targeting KLF4, but also suggested the possibility of developing the MED27/KLF4 signaling axis as a potential therapeutic target in breast cancer.

Simple and cost-effective broad bandwidth fiber chirped pulse amplification laser system seeded by a nonlinear amplifier.

In this paper, we demonstrate a simple and cost-effective fiber chirped pulse amplification (CPA) laser system, where a nonlinear amplifier is employed to generate broadband seeding pulses. The nonlinear amplifier can generate stable pulses with 50 nm spectral bandwidth and linear chirp. With such a seeding configuration being adapted into a fiber CPA laser system, the output bandwidth can be expanded from 7 nm to 20 nm, with only minor changes to a standard industrial fiber CPA system. The increased bandwidth allows for pulse durations of less than 100 fs, which is significantly shorter than the original configuration's 250 fs. When combined with a Fourier pulse shaper, such a fiber laser system is expected to produce pulses with energy exceeding 100 µJ and duration shorter than 100 fs.

BPTF inhibition antagonizes colorectal cancer progression by transcriptionally inactivating Cdc25A.

As the largest subunit of the nuclear remodeling factor complex, Bromodomain PHD Finger Transcription Factor (BPTF) has been reported to be involved in tumorigenesis and development in several cancers. However, to date, its functions and related molecular mechanisms in colorectal cancer (CRC) are still poorly defined and deserve to be revealed. In this study, we uncovered that, under the expression regulation of c-Myc, BPTF promoted CRC progression by targeting Cdc25A. BPTF was found to be highly expressed in CRC and promoted the proliferation and metastasis of CRC cells through BPTF specific siRNAs, shRNAs or inhibitors. Based on RNA-seq, combined with DNA-pulldown, ChIP and luciferase reporter assay, we proved that, by binding to -178/+107 region within Cdc25A promoter, BPTF transcriptionally activated Cdc25A, thus accelerating the cell cycle process of CRC cells. Meanwhile, BPTF itself was found to be transcriptionally regulated by c-Myc. Moreover, BPTF knockdown or inactivation was verified to sensitize CRC cells to chemotherapeutics, 5-Fluorouracil (5FU) and Oxaliplatin (Oxa), c-Myc inhibitor and cell cycle inhibitor not just at the cellular level in vitro, but in subcutaneous xenografts or AOM/DSS-induced in situ models of CRC in mice, while Cdc25A overexpression partially reversed BPTF silencing-caused tumor growth inhibition. Clinically, BPTF, c-Myc and Cdc25A were highly expressed in CRC tissues simultaneously, the expression of any two of the three was positively correlated, and their expressions were highly relevant to tumor differentiation, TNM staging and poor prognosis of CRC patients. Thus, our study indicated that the targeted inhibition of BPTF alone, or together with chemotherapy and/or cell cycle-targeted therapy, might act as a promising new strategy for CRC treatment, while c-Myc/BPTF/Cdc25A signaling axis is expected to be developed as an associated set of candidate biomarkers for CRC diagnosis and prognosis prediction.

Panicle Ratio Network: streamlining rice panicle measurement by deep learning with ultra-high-definition aerial images in the field.

The heading date and effective tiller percentage are important traits in rice, and they directly affect plant architecture and yield. Both traits are related to the ratio of the panicle number to the maximum tiller number, referred to as the panicle ratio (PR). In this study, an automatic PR estimation model (PRNet) based on a deep convolutional neural network was developed. Ultra-high-definition unmanned aerial vehicle (UAV) images were collected from cultivated rice varieties planted in 2384 experimental plots in 2019 and 2020 and in a large field in 2021. The determination coefficient between estimated PR and ground-measured PR reached 0.935, and the root mean square error values for the estimations of the heading date and effective tiller percentage were 0.687 d and 4.84%, respectively. Based on the analysis of the results, various factors affecting PR estimation and strategies for improving PR estimation accuracy were investigated. The satisfactory results obtained in this study demonstrate the feasibility of using UAVs and deep learning techniques to replace ground-based manual methods to accurately extract phenotypic information of crop micro targets (such as grains per panicle, panicle flowering, etc.) for rice and potentially for other cereal crops in future research.

Energy deposition and incubation effects of nonlinear absorption of ultrashort laser pulses in dielectrics.

Although ultrashort laser has been widely employed in micromachining thanks to its excellent processing precision, one of the main challenges it faces when applied to 3D modification inside dielectrics is its processing efficiency. Many applications require multiple pulses to achieve significant modification to create structure such as microlenses. We report incubation experiments on energy deposition and the control of material modification in fused silica. This allows us to develop a practical incubation model by taking account different ionization mechanisms, in which coefficients relating to multiphoton and avalanche ionization change with laser shots due to accumulating defects. We then extend our study to the scheme where a pre-pulse is used to limit the absorption volume through pre-seeding. Both experiments and simulations show that the efficiency of laser processing can be significantly improved without sacrificing the spatial resolution with this method, especially for longer pulses.

Study on the polarization dependence of nonlinear absorption of ultrafast laser pulses in bulk fused silica.

By studying the nonlinear absorption of ultrafast laser pulses in fused silica, we examine, both with experiments and numerical simulations, the different polarization dependence of multiphoton ionization and avalanche ionization. Results show multiphoton ionization and avalanche ionization play different roles in femtosecond and picosecond laser micromachining, and the contribution via avalanche ionization increases with pulse duration. Meanwhile, the spatial distribution of the free carriers generated by circularly polarized pulses is more concentrated than those generated by linear polarization for picosecond laser pulses. These properties make the circular polarized ultrafast laser a possible way to improve the ultrafast laser micromachining efficiency and spatial quality, and can help to reduce some problematic nonlinear effects in ultrafast laser micromachining of low energy band materials.

Legacy effects of a multi-year extreme drought on belowground bud banks in rhizomatous vs bunchgrass-dominated grasslands.

Belowground bud banks play a crucial role in plant population regeneration, community dynamics, and functional responses of ecosystems to environmental change and disturbance. In mesic grasslands, belowground bud banks are largely resistant to short-term drought. However, the sensitivity of belowground bud banks to long-term extreme drought in semi-arid grasslands is less understood. We investigated the legacy effects of a four-year experimental drought (i.e., 66% reduction in growing season precipitation) on belowground bud density, aboveground shoot density, and the meristem limitation index (MLI; the ratio of bud to shoot density) in two semi-arid grasslands that differ in dominant grass species growth forms (i.e., rhizomatous vs. bunchgrasses). Measurements were made during the first recovery year following drought; thus, we report the legacy effects of drought on belowground bud banks. At the community level, drought reduced belowground bud density and aboveground shoot density with no change in MLI. However, drought had no significant influences on belowground buds, aboveground shoots and MLI of the dominant plant growth form in each community. The legacy effects of drought were largely dependent on plant community type and growth form. Specifically, bunchgrasses and bunchgrass-dominated communities were characterized by greater meristem limitation than rhizomatous grasses, likely due to their cluster/phalanx clonal growth. Overall, our study suggests bud banks may indeed be sensitive to long-term drought, although this depends on plant growth forms and community characteristics.

Single-shot method to study high order solitons in all-polarization-maintaining soliton mode-locked fiber lasers.

A single-shot experimental method is proposed to study non-repetitive evolutions of high order solitons. In our experiments, high order solitons are prepared in the building up process of a soliton fiber laser, and the order of high order soliton is controlled via changing the parameters of the laser. The evolution of high order soliton is recorded by the single-shot spectral measurements-time stretch dispersive Fourier transform. A 4th order soliton evolution under perturbations of gain saturation and saturable loss is studied, showing how a leading pulse wins the competition against the tailing one. Our work provides a controllable technique to study the high order solitons evolutions, which can be applied in the research of ultrafast laser amplifications and supercontinuum generations.

MiR-296-5p ameliorates deep venous thrombosis by inactivating S100A4.

Deep venous thrombosis is one of the most common venous thromboembolic diseases and has a low cure rate and a high postoperative recurrence rate. Furthermore, emerging evidence indicates that microRNAs are involved in deep venous thrombosis. miR-296-5p is an important microRNA that plays a critical role in various cellular functions, and S100A4 is closely related to vascular function. miR-296-5p is downregulated in deep venous thrombosis patients, and its predicted target S100A4 is upregulated in deep venous thrombosis patients. Therefore, it was hypothesized that miR-296-5p may play a vital role in the development of deep venous thrombosis by targeting S100A4. An Ox-LDL-stimulated HUVEC and deep venous thrombosis mouse model was employed to detect the biological functions of miR-296-5p and S100A4. Dual luciferase reporter assays and pull-down assays were used to authenticate the interaction between miR-296-5p and S100A4. ELISA and Western blotting were employed to detect the protein levels of thrombosis-related factors and the endothelial-to-mesenchymal transition (EndMT)-related factors. The miR-296-5p levels were reduced, while the S100A4 levels were enhanced in deep venous thrombosis patients, and the miR-296-5p levels were negatively correlated with the S100A4 levels in deep venous thrombosis patients. miR-296-5p suppressed S100A4 expression by targeting the 3' UTR of S100A4. MiR-296-5p knockdown accelerated ox-LDL-induced HUVEC apoptosis, oxidative stress, thrombosis-related factor expression, and EndMT, while S100A4 knockdown antagonized these effects in ox-LDL-induced HUVECs. S100A4 knockdown reversed the effect induced by miR-296-5p knockdown. Moreover, the in vivo studies revealed that miR-296-5p knockdown in deep venous thrombosis mice exacerbated deep venous thrombosis formation, whereas S100A4 knockdown had the opposite effect. These results indicate that elevated miR-296-5p inhibits deep venous thrombosis formation by inhibiting S100A4 expression. Both miR-296-5p and S100A4 may be potential diagnostic markers and therapeutic targets for deep venous thrombosis.

Development, Status Quo, and Challenges to China's Health Informatization During COVID-19: Evaluation and Recommendations.

By applying advanced health information technology to the health care field, health informatization helps optimize health resource allocation, improve health care services, and realize universal health coverage. COVID-19 has tested the status quo of China's health informatization, revealing challenges to the health care system. This viewpoint evaluates the development, status quo, and practice of China's health informatization, especially during COVID-19, and makes recommendations to address the health informatization challenges. We collected, assessed, and evaluated data on the development of China's health informatization from five perspectives-health information infrastructure, information technology (IT) applications, financial and intellectual investment, health resource allocation, and standard system-and discussed the status quo of the internet plus health care service pattern during COVID-19. The main data sources included China's policy documents and national plans on health informatization, commercial and public welfare sources and websites, public reports, institutional reports, and academic papers. In particular, we extracted data from the 2019 National Health Informatization Survey released by the National Health Commission in China. We found that China developed its health information infrastructure and IT applications, made significant financial and intellectual informatization investments, and improved health resource allocations. Tested during COVID-19, China's current health informatization system, especially the internet plus health care system, has played a crucial role in monitoring and controlling the pandemic and allocating medical resources. However, an uneven distribution of health resources and insufficient financial and intellectual investment continue to challenge China's health informatization. China's rapid development of health informatization played a crucial role during COVID-19, providing a reference point for global pandemic prevention and control. To further promote health informatization, China's health informatization needs to strengthen top-level design, increase investment and training, upgrade the health infrastructure and IT applications, and improve internet plus health care services.

Combining UAV-RGB high-throughput field phenotyping and genome-wide association study to reveal genetic variation of rice germplasms in dynamic response to drought stress.

Accurate and high-throughput phenotyping of the dynamic response of a large rice population to drought stress in the field is a bottleneck for genetic dissection and breeding of drought resistance. Here, high-efficiency and high-frequent image acquisition by an unmanned aerial vehicle (UAV) was utilized to quantify the dynamic drought response of a rice population under field conditions. Deep convolutional neural networks (DCNNs) and canopy height models were applied to extract highly correlated phenotypic traits including UAV-based leaf-rolling score (LRS_uav), plant water content (PWC_uav) and a new composite trait, drought resistance index by UAV (DRI_uav). The DCNNs achieved high accuracy (correlation coefficient R = 0.84 for modeling set and R = 0.86 for test set) to replace manual leaf-rolling rating. PWC_uav values were precisely estimated (correlation coefficient R = 0.88) and DRI_uav was modeled to monitor the drought resistance of rice accessions dynamically and comprehensively. A total of 111 significantly associated loci were detected by genome-wide association study for the three dynamic traits, and 30.6% of them were not detected in previous mapping studies using nondynamic drought response traits. Unmanned aerial vehicle and deep learning are confirmed effective phenotyping techniques for more complete genetic dissection of rice dynamic responses to drought and exploration of valuable alleles for drought resistance improvement.

Optimal conditions for self-starting of soliton mode-locked fiber lasers with a saturable absorber.

With the recently developed single-shot time-stretch dispersive Fourier transform technique, we investigate the buildup process of an all-polarization-maintaining soliton mode-locked fiber laser. Considering the multi-pulse competitions and the evolution of the survived pulse, we find an optimal range of intra-cavity energy for self-starting related to the saturation energy of the employed saturable absorber. Under the conditions, one dominant pulse can build up quickly against the others, and it finally drives to single-pulse operation. The conclusions drawn here hold for other soliton mode-locked lasers.

Simultaneous In Situ Characterizations of Ultrashort Laser Pulses and the Nonlinear Susceptibility of the Irradiated Medium via Time-Resolved Hybrid Coherent Anti-Stokes Raman Scattering Spectroscopy.

We propose and test a method of simultaneously characterizing ultrashort laser pulses and the nonlinear susceptibility of the irradiated medium at the site where nonlinear interactions occur. In this method, a coherent anti-Stoke Raman scattering (CARS) spectrogram is generated with the hybrid CARS technique. We confirm that abundant information is contained in, and can be extracted from, this spectrogram and develop an extraction algorithm. With this method, quantitative and comparable broadband CARS imaging based on phase retrieval is achievable without a second material for nonresonant background generation. Furthermore, this method also paves the way for studying highly localized nonlinear light-matter interactions.

Time-lens perspective on fiber chirped pulse amplification systems.

Time-lens is an analogy of the conventional lens in the time-domain, which constitutes a source of inspiration to design and implement optical systems based on concepts borrowed from the well-established field of Fourier optics. We propose a design method of chirped pulse amplification systems based on this analogy. In this simple physics picture, the relation between dispersion and nonlinear phase shift under gain saturation can be obtained in a straightforward way. We demonstrate that this simple model agrees well with experimental results. It is a simple, effective and practical design method for chirped pulse amplification systems, especially for ultrafast fiber amplification systems.