Identification and characterization of methoxy- and dimethoxyhydroquinone 1,2-dioxygenase from Phanerochaete chrysosporium.

White-rot fungi, such as Phanerochaete chrysosporium, are the most efficient degraders of lignin, a major component of plant biomass. Enzymes produced by these fungi, such as lignin peroxidases and manganese peroxidases, break down lignin polymers into various aromatic compounds based on guaiacyl, syringyl, and hydroxyphenyl units. These intermediates are further degraded, and the aromatic ring is cleaved by 1,2,4-trihydroxybenzene dioxygenases. This study aimed to characterize homogentisate dioxygenase (HGD)-like proteins from P. chrysosporium that are strongly induced by the G-unit fragment of vanillin. We overexpressed two homologous recombinant HGDs, PcHGD1 and PcHGD2, in Escherichia coli. Both PcHGD1 and PcHGD2 catalyzed the ring cleavage in methoxyhydroquinone (MHQ) and dimethoxyhydroquinone (DMHQ). The two enzymes had the highest catalytic efficiency (kcat/Km) for MHQ, and therefore, we named PcHGD1 and PcHGD2 as MHQ dioxygenases 1 and 2 (PcMHQD1 and PcMHQD2), respectively, from P. chrysosporium. This is the first study to identify and characterize MHQ and DMHQ dioxygenase activities in members of the HGD superfamily. These findings highlight the unique and broad substrate spectra of PcHGDs, rendering them attractive candidates for biotechnological applications.IMPORTANCEThis study aimed to elucidate the properties of enzymes responsible for degrading lignin, a dominant natural polymer in terrestrial lignocellulosic biomass. We focused on two homogentisate dioxygenase (HGD) homologs from the white-rot fungus, P. chrysosporium, and investigated their roles in the degradation of lignin-derived aromatic compounds. In the P. chrysosporium genome database, PcMHQD1 and PcMHQD2 were annotated as HGDs that could cleave the aromatic rings of methoxyhydroquinone (MHQ) and dimethoxyhydroquinone (DMHQ) with a preference for MHQ. These findings suggest that MHQD1 and/or MHQD2 play important roles in the degradation of lignin-derived aromatic compounds by P. chrysosporium. The preference of PcMHQDs for MHQ and DMHQ not only highlights their potential for biotechnological applications but also underscores their critical role in understanding lignin degradation by a representative of white-rot fungus, P. chrysosporium.

Experience and impact of stigma in people with chronic hepatitis B: a qualitative study in Asia, Europe, and the United States.

BACKGROUND: People with chronic hepatitis B (CHB) commonly experience social and self-stigma. This study sought to understand the impacts of CHB-related stigma and a functional cure on stigma. METHODS: Adults with CHB with a wide range of age and education were recruited from 5 countries and participated in 90-minute qualitative, semi-structured interviews to explore concepts related to CHB-associated stigma and its impact. Participants answered open-ended concept-elicitation questions regarding their experience of social and self-stigma, and the potential impact of reduced CHB-related stigma. RESULTS: Sixty-three participants aged 25 to 71 years (15 from the United States and 12 each from China, Germany, Italy, and Japan) reported emotional, lifestyle, and social impacts of living with CHB, including prejudice, marginalization, and negative relationship and work experiences. Self-stigma led to low self-esteem, concealment of CHB status, and social withdrawal. Most participants stated a functional cure for hepatitis B would reduce self-stigma. CONCLUSIONS: CHB-related social and self-stigma are widely prevalent and affect many aspects of life. A functional cure for hepatitis B may reduce social and self-stigma and substantially improve the health-related quality of life of people with CHB. Incorporating stigma into guidelines along with infectivity considerations may broaden the patient groups who should receive treatment.

Risk factors and pattern of metastatic recurrence after endoscopic resection with additional treatment for esophageal cancer.

Although esophageal cancers invading the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic resection (ER) are associated with a risk of lymph node metastasis, details of metastatic recurrence after additional treatment remain unknown. We aimed to identify the risk factors for metastatic recurrence and recurrence patterns in patients receiving additional treatment after ER for esophageal cancer. Between 2006 and 2017, patients with pT1a-MM/pT1b-SM esophageal cancer who underwent ER with additional treatment (esophagectomy, chemoradiotherapy [CRT], and radiation therapy) at 21 institutions in Japan were enrolled. We evaluated the risk factors for metastatic recurrence after ER with additional treatment. Subsequently, the rate and pattern (locoregional or distant) of metastatic recurrence were investigated for each additional treatment. Of the 220 patients who received additional treatment, 57, 125, and 38 underwent esophagectomy, CRT, and radiation therapy, respectively. In the multivariate analysis, lymphatic invasion was the sole risk factor for metastatic recurrence after additional treatment (hazard ratio, 3.50; P = 0.029). Although the risk of metastatic recurrence with additional esophagectomy was similar to that with CRT (hazard ratio, 1.01; P = 0.986), the rate of locoregional recurrence tended to be higher with additional esophagectomy (80.0% (4/5) vs. 36.4% (4/11)), leading to a better prognosis in patients with metastatic recurrence after additional esophagectomy than CRT (survival rate, 80.0% (4/5) vs. 9.1% (1/11)). Patients with lymphatic invasion have a high risk of metastatic recurrence after ER with additional treatment for pT1a-MM/pT1b-SM esophageal cancer. Additional esophagectomy may result in a better prognosis after metastatic recurrence.

Raman silicon nanocavity laser with efficient light emission from the edge of an adjacent waveguide.

A Raman nanocavity laser can emit light into free space and into a properly designed waveguide adjacent to the cavity by mode coupling. In common device designs, the emission from the edge of this waveguide is relatively weak. However, a Raman silicon nanocavity laser with strong emission from the waveguide edge would be advantageous for certain applications. Here we investigate the increase in the edge emission that can be achieved by adding photonic mirrors to the waveguides adjacent to the nanocavity. We experimentally compare devices with and without photonic mirrors: the edge emission for devices with mirrors is 4.3 times stronger on average. This increase is analyzed using coupled-mode theory. The results indicate that the control of the round-trip phase shift (between the nanocavity and the mirror) and an increase of the quality factors of the nanocavity are important for further enhancement.

Suppressing the sample-to-sample variation of photonic crystal nanocavity Q-factors by air-hole patterns with broken mirror symmetry.

It is known that the quality factors (Q) of photonic crystal nanocavities vary from sample to sample due to air-hole fabrication fluctuations. In other words, for the mass production of a cavity with a given design, we need to consider that the Q can vary significantly. So far, we have studied the sample-to-sample variation in Q for symmetric nanocavity designs, that is, nanocavity designs where the positions of the holes maintain mirror symmetry with respect to both symmetry axes of the nanocavity. Here we investigate the variation of Q for a nanocavity design in which the air-hole pattern has no mirror symmetry (a so-called asymmetric cavity design). First, an asymmetric cavity design with a Q of about 250,000 was developed by machine learning using neural networks, and then we fabricated fifty cavities with the same design. We also fabricated fifty symmetric cavities with a design Q of about 250,000 for comparison. The variation of the measured Q values of the asymmetric cavities was 39% smaller than that of the symmetric cavities. This result is consistent with simulations in which the air-hole positions and radii are randomly varied. Asymmetric nanocavity designs may be useful for mass production since the variation in Q is suppressed.

Silicon nanocavity with a quality factor of 6.7 million fabricated by a CMOS-compatible process.

Here, we report on the increase of the quality-factors of photonic crystal nanocavities fabricated by a CMOS-compatible process. We fabricated nanocavities with the same cavity design but used either a binary photomask or a phase-shift photomask in the photolithography step to assess the impact of the photomask-type on the fabrication accuracy of the air holes. We characterized 62 cavities using time-resolved measurements and the best cavity had a quality-factor of 6.65 × 106. All cavities exhibited a quality-factor larger than 2 million and the overall average was 3.25 × 106. While the estimated magnitude of the scattering loss due to the air hole variations in the 33 cavities fabricated with the phase-shift photomask was slightly lower than that in the 29 cavities fabricated with binary photomask, the phase-shift photomask did not provide a significant improvement in the fabrication accuracy. On average, the scattering loss in these samples is more than 3 times larger than that of nanocavities fabricated using electron-beam lithography, which indicates room for further improvement.

Prognostic Benefit of Additional Treatment After Endoscopic Submucosal Dissection for Esophageal Squamous Cell Carcinoma.

BACKGROUND: Although additional treatment is considered for patients with esophageal squamous cell carcinoma (ESCC) invading into the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic submucosal dissection (ESD), the actual benefits of this method remain to be elucidated. AIMS: We aimed to evaluate the prognostic benefits of additional treatment in such patients. METHODS: Between 2006 and 2017, we enrolled patients with pT1a-MM/pT1b-SM ESCC after ESD at 21 institutions in Japan. Overall survival (OS) and disease-specific survival (DSS) were compared between the additional treatment and follow-up groups after propensity score matching, to reduce the bias of baseline characteristics. A subgroup analysis was performed according to the pathological findings: category A, pT1a-MM but negative for lymphovascular invasion (LVI) and vertical margin (VM); category B, tumor invasion into the submucosa ≤ 200 µm but negative for LVI and VM; category C, others. RESULTS: Of 593 patients with pT1a-MM/pT1b-SM ESCC after ESD, 101 matched pairs were extracted after propensity score matching. The OSs were similar between the additional treatment and follow-up groups (80.6% vs. 78.6% in 5 years; P = 0.972). In a subgroup analysis, the OS in the additional treatment group was significantly lower than that in the follow-up group (65.7% vs. 95.2% in 5 years; P = 0.037) in category A, whereas OS did not significantly differ in category C (76.8% vs. 69.5% in 5 years; P = 0.360). CONCLUSIONS: Additional treatment after ESD in patients with pT1a-MM/pT1b-SM ESCC was not associated with an improved prognosis.

Detection of ionized air using a photonic-crystal nanocavity excited by broadband light from a superluminescent diode.

It has been shown that silicon photonic crystal nanocavities excited by spectrally narrow light can be used to detect ionized air. Here, to increase the range of possible applications of nanocavity-based sensing, the use of broadband light is considered. We find that the use of a superluminescent diode (SLD) as an excitation source enables a more reproducible detection of ionized air. When our photonic-crystal nanocavity is exposed to ionized air, carriers are transferred to the cavity and the light emission from the cavity decreases due to free carrier absorption. Owing to the broadband light source, the resonance wavelength shifts caused by the carriers in this system (for example, due to temperature fluctuations) do not influence the emission intensity. SLD-excited cavities could be useful to determine the density of ions in air quantitatively.

Rationale, design and baseline characteristics of the effect of canagliflozin in patients with type 2 diabetes and microalbuminuria in the Japanese population: The CANPIONE study.

AIM: To evaluate the effect of canagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, on albuminuria and the decline of estimated glomerular filtration rate (eGFR) in participants with type 2 diabetes and microalbuminuria. METHODS: The CANPIONE study is a multicentre, randomized, parallel-group and open-labelled study consisting of a unique 24-week preintervention period, during which the rate of eGFR decline before intervention is estimated, followed by a 52-week intervention and a 4-week washout period. Participants with a geometric mean urinary albumin-to-creatinine ratio (UACR) of 50 and higher and less than 300 mg/g in two consecutive first-morning voids at two different time points, and an eGFR of 45 ml/min/1.73m2 or higher, are randomly assigned to receive canagliflozin 100 mg daily or to continue guideline-recommended treatment, except for SGLT2 inhibitors. The first primary outcome is the change in UACR, and the second primary outcome is the change in eGFR slope. RESULTS: A total of 258 participants were screened and 98 were randomized at 21 sites in Japan from August 2018 to May 2021. The mean baseline age was 61.4 years and 25.8% were female. The mean HbA1c was 7.9%, mean eGFR was 74.1 ml/min/1.73m2 and median UACR was 104.2 mg/g. CONCLUSIONS: The CANPIONE study will determine whether the SGLT2 inhibitor canagliflozin can reduce albuminuria and slow eGFR decline in participants with type 2 diabetes and microalbuminuria.

Combined assessment of clinical and pathological prognostic factors for deciding treatment strategies for esophageal squamous cell carcinoma invading into the muscularis mucosa or submucosa after endoscopic submucosal dissection.

OBJECTIVES: We aimed to clarify the prognostic factors for patients with esophageal squamous cell carcinoma (ESCC) invading into the muscularis mucosa (pT1a-MM) or submucosa (pT1b-SM) after endoscopic submucosal dissection (ESD). METHODS: This retrospective study enrolled such patients at 21 institutions in Japan between 2006 and 2017. We evaluated 15 factors, including pathological risk categories for ESCC-specific mortality, six non-cancer-related indices, and treatment strategies. RESULTS: In the analysis of 593 patients, the 5-year overall and disease-specific survival rates were 83.0% and 97.6%, respectively. In a multivariate Cox analysis, male sex (hazard ratio [HR] 3.56), Charlson comorbidity index (CCI) ≥3 (HR 2.53), ages of 75-79 (HR 1.61) and ≥80 years (HR 2.04), prognostic nutrition index (PNI) <45 (HR 1.69), and pathological intermediate-risk (HR 1.63) and high-risk (HR 1.89) were prognostic factors. Subsequently, we developed a clinical risk classification for non-ESCC-related mortality based on the number of prognostic factors (age ≥75 years, male sex, CCI ≥3, PNI <45): low-risk, 0; intermediate-risk, 1-2; and high-risk, 3-4. The 5-year non-ESCC-related mortality rates for patients without additional treatment were 0.0%, 10.2%, and 45.8% in the low-, intermediate-, and high-risk groups, respectively. Meanwhile, the 5-year ESCC-specific mortality rates for the pathological low-, intermediate-, and high-risk groups were 0.3%, 5.3%, and 18.2%, respectively. CONCLUSIONS: We clarified prognostic factors for patients with pT1a-MM/pT1b-SM ESCC after ESD. The combined assessment of non-ESCC- and ESCC-related mortalities by the two risk classifications might help clinicians in deciding treatment strategies for such patients.

Sub-100-nW-threshold Raman silicon laser designed by a machine-learning method that optimizes the product of the cavity Q-factors.

Raman silicon lasers based on photonic crystal nanocavities with a threshold of several hundred microwatts for continuous-wave lasing have been realized. In particular, the threshold depends on the degree of confinement of the excitation light and the Raman scattering light in the two nanocavity modes. Here, we report lower threshold values for Raman silicon nanocavity lasers achieved by increasing the quality (Q) factors of the two cavity modes. By using an optimization method based on machine learning, we first increase the product of the two theoretical Q values by a factor of 17.0 compared to the conventional cavity. The experimental evaluation demonstrates that, on average, the actually achieved product is more than 2.5 times larger than that of the conventional cavity. The input-output characteristic of a Raman laser with a threshold of 90 nW is presented and the lowest threshold obtained in our experiments is 40 nW.

Detection of negatively ionized air by using a Raman silicon nanocavity laser.

The performance of a Raman silicon laser based on a high quality-factor nanocavity depends on the degree of free-carrier absorption, and this characteristic may be useful for certain applications. Here we demonstrate that laser oscillation in a Raman silicon nanocavity laser stops abruptly after an exposure to a weak flux of negatively ionized air for a few seconds. Spectral measurements reveal that the laser interruption is mainly caused by the transfer of extra electrons from the negatively ionized air molecules to the silicon nanocavity. These electrons affect the efficiency of the Raman laser by free carrier absorption. We find that the laser output gradually recovers as the extra electrons escape from the nanocavity and confirm that such a detection of ionized air is repeatable. These results show that a Raman silicon nanocavity laser can be used for the detection of ionized air with a high spatial resolution.

1.2-µm-band ultrahigh-Q photonic crystal nanocavities and their potential for Raman silicon lasers.

Nanocavity devices based on silicon that can operate in the 1.2-µm band would be beneficial for several applications. We fabricate fifteen cavities with resonance wavelengths between 1.20 and 1.23 µm. Experimental quality (Q) factors larger than one million are obtained and the average Q values are lower for shorter wavelengths. Furthermore, we observe continuous-wave operation of a Raman silicon laser with an excitation wavelength of 1.20 µm and a Raman laser wavelength of 1.28 µm. The Q values of the nanocavity modes used to confine the excitation light and the Raman scattered light are about half of those for our Raman silicon laser operating in the 1.55-µm band. Nevertheless, this device exhibits an input-output characteristic with a clear laser threshold. Finally, we consider the effect of the higher scattering probability at shorter wavelengths on the Raman laser performance in the 1.2-µm band.

A micrometre-scale Raman silicon laser with a microwatt threshold.

The application of novel technologies to silicon electronics has been intensively studied with a view to overcoming the physical limitations of Moore's law, that is, the observation that the number of components on integrated chips tends to double every two years. For example, silicon devices have enormous potential for photonic integrated circuits on chips compatible with complementary metal-oxide-semiconductor devices, with various key elements having been demonstrated in the past decade. In particular, a focus on the exploitation of the Raman effect has added active optical functionality to pure silicon, culminating in the realization of a continuous-wave all-silicon laser. This achievement is an important step towards silicon photonics, but the desired miniaturization to micrometre dimensions and the reduction of the threshold for laser action to microwatt powers have yet to be achieved: such lasers remain limited to centimetre-sized cavities with thresholds higher than 20 milliwatts, even with the assistance of reverse-biased p-i-n diodes. Here we demonstrate a continuous-wave Raman silicon laser using a photonic-crystal, high-quality-factor nanocavity without any p-i-n diodes, yielding a device with a cavity size of less than 10 micrometres and an unprecedentedly low lasing threshold of 1 microwatt. Our nanocavity design exploits the principle that the strength of light-matter interactions is proportional to the ratio of quality factor to the cavity volume and allows drastic enhancement of the Raman gain beyond that predicted theoretically. Such a device may make it possible to construct practical silicon lasers and amplifiers for large-scale integration in photonic circuits.

The Use of Higher Dose Steroids Increases the Risk of Rebleeding After Endoscopic Hemostasis for Peptic Ulcer Bleeding.

BACKGROUND: Previous studies have shown that several factors such as hemodynamic instability at admission are risk factors for rebleeding of peptic ulcer bleeding. However, whether steroid use increases the risk of rebleeding remains elusive. AIMS: This study aimed to clarify the risk factors for rebleeding after endoscopic hemostasis for peptic ulcer bleeding. METHODS: A total of 185 patients who underwent endoscopic hemostasis for peptic ulcer bleeding at our institution between 2005 and 2017 were retrospectively analyzed. We evaluated factors, including comorbid conditions, in-hospital onset, and steroid use, associated with rebleeding by logistic regression analysis. In addition, we investigated the association between the dose of steroids and rebleeding. RESULTS: The rebleeding rate after endoscopic hemostasis for peptic ulcer bleeding was 14.6%. In the multivariate analysis, the independent risk factors for rebleeding were steroid use (odds ratio 4.56, p = 0.015), multiple ulcers (4.43, p = 0.005), number of comorbidities ≥ 3 3.18, p = 0.026), hemodynamic instability (3.06, p = 0.039), and number of comorbidities ≥ 3 (2.93, p = 0.047). Furthermore, the use of higher dose steroids (≥ 20 mg per day in prednisolone; 10.55, p = 0.002), but not lower dose (< 20 mg per day in prednisolone), was an independent risk factor for rebleeding in the multivariate analysis. The relationship between steroid use and rebleeding was observed in a dose-dependent manner (p for trend = 0.002). CONCLUSIONS: This study first revealed that using higher dose steroids was an independent risk factor for rebleeding after endoscopic hemostasis for peptic ulcer bleeding, with a dose-response relation.

Analysis of high-Q photonic crystal L3 nanocavities designed by visualization of the leaky components.

We experimentally study photonic crystal L3 nanocavities whose design Q factors (Qdesign) have been improved with the visualization of leaky components design method. The experimental Q values (Qexp) are monotonically increased from 6,000 to 2,100,000 by iteratively modifying the positions of some of the air holes, as determined by the referred design method. We investigate the Qexp tolerance to imperfections in the fabricated samples, which reveals that the cavities improved by the visualization method tend to lose some tolerance to structural differences between the fabricated samples and the design values.

Photonic crystal nanocavity with a Q factor exceeding eleven million.

Photonic crystal nanocavities that simultaneously possess small modal volumes and high quality (Q) factors have opened up novel research areas in photonics during this decade. Here, we present an important key for the increase of Q factors to ranges beyond ten million. A systematic investigation on photon lifetimes of air-bridge-type heterostructure nanocavities fabricated from silicon on insulator (SOI) substrates indicated the importance of cleaning the bottom side (buried oxide side) of the nanaocavites. Repeated thermal oxidation and an oxide removal process applied after the removal of the buried oxide layer underneath the nanocavities realized an experimental Q factor greater than eleven million, which is the highest experimental Q ever recorded. The results provide important information not only for Si PC nanocavities but also for general Si nanophotonic devices and photonic electronic convergence systems.

Ultrahigh-Q photonic crystal nanocavities fabricated by CMOS process technologies.

We fabricated photonic crystal high-quality factor (Q) nanocavities on a 300-mm-wide silicon-on-insulator wafer by using argon fluoride immersion photolithography. The heterostructure nanocavities showed an average experimental Q value of 1.5 million for 12 measured samples. The highest Q value was 2.3 million, which represents a record for a nanocavity fabricated by complementary metal-oxide-semiconductor (CMOS)-compatible machinery. We also demonstrated an eight-channel drop filter with 4 nm spacing consisting of arrayed nanocavities with three missing air holes. The standard deviation in the drop wavelength was less than 1 nm. These results will accelerate ultrahigh-Q nanocavity research in various areas.

Improvement in the quality factors for photonic crystal nanocavities via visualization of the leaky components.

A method that simply improves the quality (Q) factors of two-dimensional photonic crystal nanocavities using a three-dimensional finite-difference time domain calculation is described. The leaky area for a high-Q nanocavity mode is visualized in a real cavity structure by extracting the leaky components within a light cone in momentum space and by transferring them back into real space using an inverse Fourier transformation. The Q factor is remarkably improved by appropriately shifting the positions of air holes at the leaky area. We design three-missing-air-hole and zero-cell-defect nanocavities with Q factors of 5,000,000 and 1,700,000, respectively, for demonstration.