HIF-1α/METTL1/m7G axis is involved in CRC response to hypoxia.

BACKGROUND: In recent years, many studies have confirmed that hypoxia and hypoxia inducible factor (HIF)-1α drive the development of colorectal cancer (CRC). HIF-1α also modulates epitranscriptomic remodeling to regulate cancer development. However, the mechanism by which RNA methylation is altered under hypoxic conditions and the underlying regulatory mechanisms in CRC remain unclear. METHODS: Here, seven common types of modifications of mRNA and tRNA were quantitated using liquid chromatography-tandem mass spectrometry. To validate the robustness of the profiling data, modifications that were consistently altered across the three CRC cell lines under hypoxia were validated via dot blot analysis. Then, 10 enzymes that could regulate the abundance of three RNA modifications in tRNA were measured in CRC cells after hypoxia treatment using quantitative real-time polymerase chain reaction. Furthermore, the regulatory role of HIF-1α in the expression of methyltransferase 1 (METTL1) under hypoxic conditions was confirmed using METTL1 promoter activity assays and HIF-1α small interfering RNA (siRNA). The binding capacity of HIF-1α to each hypoxia response element (HRE) in the promoter of METTL1 was investigated by performing Chromatin immunoprecipitation assay (ChIP). RESULTS: Abundance of RNA modifications was altered more consistently and significantly in tRNA than in mRNA under hypoxic conditions. In addition, the abundance of N7-methyleguanosine (m7G) modification in tRNA decreased significantly under hypoxic conditions. As a methyltransferase of the m7G modification in tRNA, the expression of METTL1 mRNA was drastically downregulated under hypoxic conditions. Mechanistically, suppression of HIF-1α by siRNA upregulated the METTL1 promoter activity. Furthermore, ChIP showed that HIF-1α could bind with an HRE in the promoter region of METTL1, indicating that METTL1 is a direct target of HIF-1α in CRC cells under hypoxic conditions. CONCLUSIONS: Our study revealed that the abundance of the m7G modification in tRNA was drastically reduced in CRC cells dependent on the HIF-1α-mediated inhibition of METTL1 transcription under hypoxic conditions.

Two-sample Mendelian randomization analysis of the relationship between periodontitis and risk of upper gastrointestinal cancers.

PURPOSE: The aim of the present study is to explore the possible association between periodontitis and upper gastrointestinal (UGI) cancers, including esophageal and gastric cancers, utilizing the Mendelian randomization method. METHODS: In this research, we utilized the Mendelian randomization method to examine the causal association between periodontitis and UGI cancers. Genome-wide association studies data for periodontitis were obtained from the Gene-Lifestyle Interactions in Dental Endpoints consortium, while UGI cancers' data were accessed from FinnGen's Biobank. After rigorously screening instrumental variables for periodontitis, we analyzed them with UGI cancers primarily using the inverse variance weighted. Finally, to identify outliers, the results were subjected to a leave-one-out sensitivity analysis. RESULTS: Inverse variance weighted (fixed effect) results revealed that periodontitis is a risk factor for gastric cancer (OR = 1.7735, 95% CI: 1.1576 to 2.7170, P = 0.0085). As for esophageal cancer, no statistically significant correlation was observed. Furthermore, no outliers were detected in any of the results. CONCLUSION: Our two-sample Mendelian randomization study obviously demonstrates a significant positive association between periodontitis and gastric cancer, while no statistically significant correlation was found for esophageal cancer.

Thermal-birefringence-induced depolarization in a 450 W Ho:YAG MOPA system.

We demonstrated an efficient, high-power Ho:YAG master-oscillator power amplifier (MOPA) system and investigated its thermal-birefringence-induced depolarization. The maximum output power was 450 W with a depolarized power of 32.1 W and depolarization of 0.071 via three power amplifiers. To our knowledge, this is the highest average power generated from a Ho:YAG MOPA system. In theory, a simplified model was built to calculate the depolarization in the amplifier, and the theoretical results agreed with the actual value well. Moreover, the overall optical-to-optical efficiency of the MOPA system was near 60%, and the beam quality M2 factors of s-polarized laser were measured to be ∼ 1.8 at 400 W. In pulse operation, the per pulse energy was ∼ 11 mJ at the pulse repetition frequency of 40 kHz with the corresponding peak power of 220 kW.

113 W Ho:YLF oscillator with good beam quality efficiently pumped by a Tm:YAP laser.

We demonstrate a linearly polarized Tm:YAP slab laser pumped by fiber-coupled laser diodes. The maximum output power is 202 W at 1937.5 nm with a slope efficiency of 47.4% and an optical-to-optical efficiency of 35.6%. The beam quality M2 factors are 10.1 and 8.33 in x and y directions, respectively. Using the Tm:YAP laser as the pump source, the maximum power of the Ho:YLF oscillator is 113 W at 2063.3 nm, corresponding to an optical-to-optical efficiency of 55.9%. In addition, the beam quality factors of the Ho:YLF laser are ∼1.5 at maximum power.

161 W middle infrared ZnGeP2 MOPA system pumped by 300 W-class Ho:YAG MOPA system.

We demonstrated a high-power Q-switched two-stage Ho:YAG master-oscillator power-amplifier (MOPA) system dual-end pumped by Tm:YLF lasers. A new method was introduced by rotating and swapping spatial axial directions of pump beams to improve the beam quality of the Ho:YAG oscillator and first-stage amplifier. Two parallel second-stage Ho:YAG amplifiers were employed to output high power. A total maximum average output power of 332 W at 2091 nm with pulse repetition frequency of 20 kHz was achieved. Then a ZnGeP2 MOPA system was demonstrated using the Ho:YAG MOPA as the pump source. A maximum average output power of 161 W at 3-5 µm was obtained with 290 W incident Ho pump power, corresponding to beam quality factors M2 of 3.42 and 3.83 for horizontal and vertical directions, respectively.

570†MHz harmonic mode-locking in an all polarization-maintaining Ho-doped fiber laser.

In this paper, we demonstrate a 570.0 MHz harmonically mode-locked all-polarization-maintaining Ho-doped fiber laser based on semiconductor saturable absorbed mirror. Firstly, the laser operates in the 15.4 MHz fundamental mode-locked soliton regime, emitting 2051.5 nm, 1.62 ps soliton pulse without Kelly sidebands. And then, the stable 37th-order harmonic mode-locked soliton with maximum repetition rate up to 570.0 MHz at 2053nm is generated. Moreover, colorful soliton rain behaviors are also discussed.

11 µm, high beam quality idler-resonant CdSe optical parametric oscillator with continuous-wave injection-seeded at 2.58 µm.

We report an idler-resonant, continuous-wave (CW) seed injected, optical parametric oscillator (OPO) based on cadmium selenide (CdSe). The CdSe OPO was pumped by a 2.09 µm ns-pulsed laser and injection-seeded by a 2.58 µm CW laser. The idler-resonant oscillator was designed to maximize the optical-to-optical conversion efficiency and optimize the beam quality. The injected seed laser was designed to reduce the pump threshold. With this setup, the average idler output power of 802 mW was obtained corresponding to a pulse energy of 0.8 mJ at the wavelength of 11.01 µm and linewidth (FWHM) of 0.6 cm-1, optical-to-optical conversion efficiency of 4.4%, quantum conversion efficiency of 23.3%, beam quality of M2x = 1.23, M2y = 1.12, and pulse width of 21 ns. In addition, by turning the angle of the CdSe, wavelength tuning of 10.55-11.98 µm was achieved.

High-beam-quality 2.1 µm pumped mid-infrared type-II phase-matching BaGa4Se7 optical parametric oscillator with a ZnGeP2 amplifier.

We firstly demonstrated a tunable 2.1 µm pumped mid-infrared type-II phase-matching BaGa4Se7 (BGSe) optical parametric oscillator (OPO). A signal tuning range of 3.82-3.99 µm was achieved. With a signal light produced by the BGSe OPO serving as seed, the ZnGeP2 (ZGP) optical parametric amplifier (OPA) was first introduced. A 4.35 W mid-infrared laser was obtained in the novel type-II BGSe OPO with a ZGP OPA system, which was pumped by a 24 W 1 kHz Q-switched Ho:YAG laser. The beam quality factor M2 of the whole system is ∼2.3, which is over a 50% promotion on the previous M2 results of single BGSe OPO.

Research on performance improvement technology of a BaGa4Se7 mid-infrared optical parametric oscillator.

In this Letter, we demonstrate an average output power of 5.12 W at 3-5 µm from a type-I phase-matching BaGa4Se7 (BGSe) optical parametric oscillator (OPO), which is pumped by a 2090 nm Q-switched Ho:YAG laser with pulse repetition frequency of 1 kHz. At maximum output level, the corresponding slope efficiency and optical-to-optical conversion efficiency are 30.0% and 18.3%, respectively. Moreover, under ring cavity conditions, the BGSe OPO produced a 3.04 W mid-infrared laser with high beam quality factors M2 of 1.47 in the horizontal direction and 1.51 in the vertical direction. Besides, the wavelength-tuning curve for type-I BGSe was also investigated, corresponding to an idler wavelength-tuning range of 4.5-5.3 µm, and the signal light wavelength was 4.5 to 4.1 µm.

1 W, 10.1 µm, CdSe optical parametric oscillator with continuous-wave seed injection.

We demonstrated a 2.1 µm nanosecond laser pumped, 2.6 µm continuous-wave (CW) seed injected, cadmium selenide (CdSe) signal singly resonant optical parametric oscillator (OPO). A maximum average power of 1.05 W was obtained corresponding to a pulse energy of 1.05 mJ at the idler wavelength of 10.1 µm and optical-to-optical conversion efficiency of 4.69%, beam quality of $M_x^2={2.25}$Mx2=2.25, $M_y^2={2.12}$My2=2.12 and pulse width of 24.4 ns. To the best of our knowledge, this is the first time to achieve 10-12 µm laser with watt-level average power using OPO technology.

3.5 W long-wave infrared ZnGeP2 optical parametric oscillator at 9.8 µm.

We demonstrated a high-power long-wave infrared optical parametric oscillator at 9.8 µm based on a type-I phase-matching ${{\rm ZnGeP}_2}$ZnGeP2 crystal. By using a ${Q}$Q-switched 2091 nm Ho:YAG laser with pulse repetition frequency of 10 kHz as the pump source, the maximum average output power of 3.51 W at 9.8 µm was achieved with incident pump power of 90 W, corresponding to a slope efficiency of 4.81% and conversion efficiency at maximum pump power of 3.9%. The pulse width of 19.6 ns and linewidth of 142 nm were obtained at maximum output level. In addition, the beam quality factor ${M^2}$M2 was measured to be ${\sim}{2.2}$∼2.2.

Measurement of optical homogeneity of ZnGeP2 crystal using a 2.02 µm single-longitudinal-mode Tm:LuAG ring laser.

We demonstrate a single-longitudinal-mode Tm:LuAG unidirectional ring laser based on the Faraday effect and its application in measuring the optical homogeneity of ZnGeP2 (ZGP) crystal. The maximum single-longitudinal-mode power was 511 mW at 2022.4 nm, with a slope efficiency of 9.7%, and the M2 factors were 1.13 and 1.23 in the x and y directions, respectively. The laser was s polarized with a polarization degree of 30 dB. Also, the optical homogeneity of ZGP crystal was measured by the Mach-Zehnder interference method, which adopts the single-longitudinal-mode laser as the monochrome source. According to the interference fringes, the quantitative calculation or qualitative analysis of the optical homogeneity of ZGP crystal was achieved, which could quickly and conveniently judge the quality of ZGP crystal, and provided high-quality crystals for high-power mid-infrared lasers. To our knowledge, it is the first report of the optical homogeneity measurement of ZGP crystal by a 2 µm single-longitudinal-mode laser.

SUB1 promotes colorectal cancer metastasis by activating NF-κB signaling via UBR5-mediated ubiquitination of UBXN1.

Metastasis accounts for the major cause of colorectal cancer (CRC) related mortality due to the lack of effective treatments. In this study, we integrated the single-cell RNA-seq (scRNA-seq) and bulk RNA-seq data and identified the transcriptional coactivator SUB1 homolog (Sac-Saccharomyces cerevisiae)/PC4 (positive cofactor 4) associated with CRC metastasis. Elevated SUB1 expression was correlated with advanced tumor stage and poor survival in CRC. In vivo and vitro assays showed that SUB1 depletion could inhibit the invasive and metastatic abilities of CRC cells. SUB1 activated NF-κB signaling and its transcriptional target genes CXCL1 and CXCL3 to drive CRC metastasis. Mechanistically, SUB1 integrated with the E3 ubiquitin-protein ligase UBR5 and increased its protein level in CRC cells. Subsequently, the increased UBR5 mainly mediated Lys11-linked polyubiquitination and degradation of NF-κB negative regulator UBXN1, thus to activate the NF-κB signaling. Overall, our study demonstrated that SUB1 promoted CRC progression by modulating UBR5/UBXN1 and activating NF-κB signaling, providing a new therapeutic strategy for treating metastatic CRC through targeting SUB1.

ALKBH1-mediated m1 A demethylation of METTL3 mRNA promotes the metastasis of colorectal cancer by downregulating SMAD7 expression.

Colorectal cancer (CRC) is one of the most common malignancies, and the main cause of death from CRC is tumor metastasis. m1 A RNA modification plays critical role in many biological processes. However, the role of m1 A modification in CRC remains unclear. Here, we find that the m1 A demethylase alkB homolog 1, histone H2A dioxygenase (ALKBH1) is overexpressed in CRC and is associated with metastasis and poor prognosis. Upregulation of ALKBH1 expression promotes CRC metastasis in vitro and in vivo. Mechanistically, knockdown of ALKBH1 results in a decrease in methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3) expression, probably due to m1 A modification of METTL3 mRNA, followed by m6 A demethylation of SMAD family member 7 (SMAD7) mRNA. In addition, downregulation of SMAD7 establishes an aggressive phenotype. More importantly, the cell migration and invasion defects caused by ALKBH1 depletion or METTL3 depletion are significantly reversed by SMAD7 silencing. Considering these results collectively, we propose that ALKBH1 promotes CRC metastasis by destabilizing SMAD7 through METTL3.

MFAP2, upregulated by m1A methylation, promotes colorectal cancer invasiveness via CLK3.

BACKGROUND: Distant metastasis is the main cause of mortality in colorectal cancer (CRC) patients. N1-methyladenosine (m1A) is a type of epitranscriptome modification. While its regulatory effect on mRNA and its role in CRC metastasis remain unclear. METHODS: The m1A methylation profile of mRNAs in CRC was revealed by m1A methylated RNA immunoprecipitation sequencing. The expression of MFAP2 in tumor tissues was measured by immunohistochemistry and then correlated with the clinical characteristics and prognosis of CRC patients. The role of MFAP2 in the invasiveness of CRC cells was evaluated by transwell assays and peritoneal metastatic model in nude mice. The downstream targets of MFAP2 was screened by mass spectrometry analysis. Then the role of MFAP2-CLK3 signaling axis was verified by cotransfecting MFAP2 siRNA and CLK3 plasmid in CRC cells. RESULTS: Microfibril associated protein 2 (MFAP2) mRNA was overexpressed and m1A-hypermethylated in CRC. High expression of MFAP2 was closely related to lymph node metastasis and distant metastasis, leading to poor prognosis in patients with CRC. In vivo and in vitro studies showed that silencing of MFAP2 inhibited the migration, invasion and metastasis of CRC cells. CDC Like Kinase 3 (CLK3) was a potential downstream target of MFAP2. Further studies showed that MFAP2 depletion might induce autophagic degradation of CLK3, and the role of MFAP2 in the invasiveness of CRC cells was dependent on CLK3. CONCLUSIONS: Our results uncover a newly identified MFAP2-CLK3 signaling axis, which is a potential therapeutic target for CRC metastasis.

Wood-based superblack.

Light is a powerful and sustainable resource, but it can be detrimental to the performance and longevity of optical devices. Materials with near-zero light reflectance, i.e. superblack materials, are sought to improve the performance of several light-centered technologies. Here we report a simple top-down strategy, guided by computational methods, to develop robust superblack materials following metal-free wood delignification and carbonization (1500 °C). Subwavelength severed cells evolve under shrinkage stresses, yielding vertically aligned carbon microfiber arrays with a thickness of ~100 µm and light reflectance as low as 0.36% and independent of the incidence angle. The formation of such structures is rationalized based on delignification method, lignin content, carbonization temperature and wood density. Moreover, our measurements indicate a laser beam reflectivity lower than commercial light stoppers in current use. Overall, the wood-based superblack material is introduced as a mechanically robust surrogate for microfabricated carbon nanotube arrays.

Aberrant lipid metabolism in cancer cells and tumor microenvironment: the player rather than bystander in cancer progression and metastasis.

As the primary cause of cancer-induced fatality and morbidity, cancer metastasis has been a hard nut to crack. Existing studies indicate that lipid metabolism reprogramming occurring in cancer cells and surrounding cells in TME also endows the aggressive and spreading properties with malignant cells. In this review we describe the lipid metabolic reprogramming of cancer cells at different steps along the metastatic process, we also summarize the altered lipid metabolism of non-cancer cells in TME during tumor metastasis. Additionally, we reveal both intrinsic and extrinsic factors which influence the cellular lipid metabolism reprogramming.

Friend or Foe? An Unrecognized Role of Uric Acid in Cancer Development and the Potential Anticancer Effects of Uric Acid-lowering Drugs.

In recent years, metabolic syndrome (Mets) has been a hot topic among medical scientists. Mets has an intimate relationship with the incidence and development of various cancers. As a contributory factor of Mets, hyperuricemia actually plays an inseparable role in the formation of various metabolic disorders. Although uric acid is classically considered an antioxidant with beneficial effects, mounting evidence indicates that a high serum uric acid (SUA) level may serve as a pro-oxidant to generate inflammatory reactions and oxidative stress. In this review, we describe the unrecognized role of hyperuricemia in cancer development and summarize major mechanisms linking uric acid to carcinogenesis. Furthermore, we also discuss the potential mechanism of liver metastasis of cancer and list some types of uric acid-lowering agents, which may exert anticancer effects.

Opening a Window on Attention: Adjuvant Therapies for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), most commonly known as Crohn's disease (CD) and ulcerative disease (UC), is a chronic and relapsing intestinal disease which cannot be cured completely. The prevalence of IBD in Europe and in North America has increased over the past 20 years. As most IBD patients are young at onset, their quality of life (QOL) can be influenced to varying degrees. Thus, current treatment goals are typically focused on preventing complications, including maintaining clinical remission and improving the QOL. Adjuvant therapies have been widely concerned as an effective treatment in alleviating IBD symptoms, including dietary intervention, traditional Chinese medicine, smoking, alcohol, and physical activities. This review focuses on different ancillary therapies for IBD treatments, in particular the mechanism of reducing inflammation based on the actual data from research studies. Moreover, comparing the latest data, this review also presented potential future prospect for adjuvant therapies.