IL-21, not IL-17A, exacerbates murine primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease caused by intrahepatic bile duct injuries, resulting in fibrosis, cirrhosis, and eventually liver failure. T helper (Th) 17 cells are proposed to involve in the pathogenesis of PBC. However, how and which Th17 cell-derived cytokines affect PBC remains unclear. In this study, we investigated the effects of Th17 effector cytokines, including interleukin (IL)-17A, IL-17F, and IL-21 in PBC using a xenobiotic-induced mouse model of autoimmune cholangitis (inducible chemical xenobiotic models of PBC) treated with cytokine-expressing adeno-associated virus. Our results showed that administration of IL-17A, the well-known main cytokine produced by Th17 cells, did not augment liver inflammation or fibrosis. In contrast, we noted IL-17A-treated mice had lower hepatic Th1 cell numbers and higher hepatic CD11b+Ly6G+ polymorphonuclear myeloid-derived suppressor cell numbers. IL-17F did not alter liver inflammation or fibrosis. However, the administration of IL-21 exacerbated liver inflammatory responses and portal cell infiltration. IL-21 markedly increased the numbers of activated CD8+ T cells and liver tissue-resident memory CD8+ T cells. Moreover, IL-21 aggravates liver fibrosis in mice with autoimmune cholangitis. These results emphasized that not IL-17A but IL-21 in Th17 cell-derived cytokines affected the pathogenesis of PBC. IL-21 enhanced liver inflammation and progression to fibrosis by enhancing the numbers and effector activities of CD8+ T cells. Delineation of the effects of different Th17 effector cytokines in PBC offers clues for developing new therapeutic approaches.

Regulatory T cells in inflamed liver are dysfunctional in murine primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune disease characterized by immune-mediated destruction of intrahepatic small bile ducts. CD8 T cells play a critical role in biliary destruction. However, regulatory T cells (Tregs) have also been identified in the portal tracts of PBC patients. This study tested the hypothesis that hepatic Tregs in PBC were dysfunctional in suppressing immune responses in disease by using our human PBC-like autoimmune cholangitis (AIC) mouse model induced by 2-octynoic acid-conjugated ovalbumin (2-OA-OVA). Our results showed that female and male mice immunized with 2-OA-OVA developed AIC; however, female AIC mice had more severe liver inflammation and fibrosis than male AIC mice. Levels of functional effector CD8 T cells and their chemoattractants, CXCL9 and CXCL10, in the liver were markedly elevated in female AIC mice than in male AIC mice. These results reinforce that CD8 T cells are the primary effector cells in PBC. The number of hepatic Tregs in AIC mice was also higher than in saline-treated mice, but there was no difference between male and female AIC mice. The suppressive function of AIC Tregs was evident despite a discrepancy in the changes in their co-inhibitory receptors and inhibitory cytokines. However, the expansion of hepatic Tregs by low-dose IL-2 treatment did not reduce immune responses to AIC, which may be due to the dysfunction of Tregs in inhibiting T cells. In conclusion, the function of Tregs in the inflamed liver of PBC was insufficient, and low-dose IL-2 treatment could not restore their function to suppress pathological immune responses. Transferring normal Tregs or directly targeting effector CD8 T cells may be beneficial for treating PBC.

RepE: unsupervised representation learning for image enhancement in nonlinear optical microscopy.

We present an unsupervised learning denoising method, RepE (representation and enhancement), designed for nonlinear optical microscopy images, such as second harmonic generation (SHG) and two-photon fluorescence (TPEF). Addressing the challenge of effectively denoising images with various noise types, RepE employs an encoder network to learn noise-free representations and a reconstruction network to generate denoised images. It offers several key advantages, including its ability to (i) operate without restrictive statistic assumptions, (ii) eliminate the need for clean-noisy pairs, and (iii) requires only a few training images. Comparative evaluations on real-world SHG and TPEF images from esophageal cancer tissue slides (ESCC) demonstrate that our method outperforms existing techniques in image quality metrics. The proposed method provides a practical, robust solution for denoising nonlinear optical microscopy images, and it has the potential to be extended to other nonlinear optical microscopy modalities.

Identifying Features that Enhance Older Adults' Acceptance of Robots: A Mixed Methods Study.

BACKGROUND: With global aging, robots are considered a promising solution for handling the shortage of aged care and companionships. However, these technologies would serve little purpose if their intended users do not accept them. While the socioemotional selectivity theory predicts that older adults would accept robots that offer emotionally meaningful relationships, selective optimization with compensation model predicts that older adults would accept robots that compensate for their functional losses. OBJECTIVE: The present study aims to understand older adults' expectations for robots and to compare older adults' acceptance ratings for 2 existing robots: one of them is a more human-like and more service-oriented robot and the other one is a more animal-like and more companion-oriented robot. METHODS: A mixed methods study was conducted with 33 healthy, community-dwelling Taiwanese older adults (age range: 59-82 years). Participants first completed a semi-structured interview regarding their ideal robot. After receiving information about the 2 existing robots, they then completed the Unified Theory of Acceptance and Use of Technology questionnaires to report their pre-implementation acceptance of the 2 robots. RESULTS: Interviews were transcribed for conventional content analysis with satisfactory inter-rater reliability. From the interview data, a collection of older adults' ideal robot characteristics emerged with highlights of humanlike qualities. From the questionnaire data, respondents showed a higher level of acceptance toward the more service-oriented robot than the more companion-oriented robot in terms of attitude, perceived adaptiveness, and perceived usefulness. From the mixed methods analyses, the finding that older adults had a higher level of positive attitude towards the more service-oriented robot than the more companion-oriented robot was predicted by higher expectation or preference for robots with more service-related functions. CONCLUSION: This study identified older adults' preference toward more functional and humanlike robots. Our findings provide practical suggestions for future robot designs that target the older population.

Endogenous IL-10 maintains immune tolerance but IL-10 gene transfer exacerbates autoimmune cholangitis.

The immunomodulatory effect of IL-10 as an immunosuppressive and anti-inflammatory cytokine is well known. Taking advantage of our established mouse model of autoimmune cholangitis using 2-octynoic acid conjugated ovalbumin (2-OA-OVA) induction, we compared liver pathology, immune cell populations and antimitochondrial antibodies between IL-10 knockout and wild type mice immunized with 2-OA-OVA. At 10 weeks post immunization, portal inflammation and fibrosis were more severe in 2-OA-OVA immunized IL-10 knockout mice than in wild type mice. This was accompanied by significant higher levels of collagen I and III expression, T, NK and NKT subsets in liver and IgG anti-mitochondrial autoantibodies (AMAs) compared to 2-OA-OVA immunized wild type mice, suggesting that endogenous IL-10 is necessary for the maintenance of immune tolerance in primary biliary cholangitis (PBC). Further, we investigated whether administration of exogenous IL-10 could prevent PBC by administration of IL-10 expressing recombinant adeno-associated virus (AAV-IL-10) either 3 days before or 3 weeks after the establishment of liver pathology. Interestingly, administration of AAV-IL-10 resulted in increased liver inflammation and fibrosis, accompanied by increases in IFN-γ in liver CD4+ T cell, granzyme B, FasL, and CD107a in liver CD8+ T and NKT cells, and granzyme B and FasL in liver NK cells of AAV-IL-10 administered mice compared with control mice. Furthermore, administration of AAV-IL-10 significantly increased levels of proinflammatory cytokines and chemokines (IFN-γ, TNF-α, CXCL9 and CXCL10) and collagen I and III production in naïve mice, together with increase in immune cell infiltration and collagen deposition in the liver, suggesting a role of IL-10 in fibrosis. In conclusion, our data demonstrate that endogenous IL-10 is critical in the maintenance of immune tolerance but exogenous administration of IL-10 exacerbates liver inflammation and fibrosis. Furthermore, the distinctive presence of inflammatory immune cell populations and collagen expression in AAV-IL-10 treated naïve mice cautions against the clinical use of exogenous IL-10 in patients with autoimmune cholangitis.

Emergency percutaneous nephrostomy versus emergency percutaneous nephrolithotomy in patients with sepsis associated with large uretero-pelvic junction stone impaction: a randomized controlled trial.

INTRODUCTION: A randomized trial was conducted prospectively to evaluate the efficacy, related complications, and convalescence of emergency percutaneous nephrolithotomy compared to percutaneous nephrostomy for decompression of the collecting system in cases of sepsis associated with large uretero-pelvic junction stone impaction. MATERIALS AND METHODS: The inclusion criteria included a WBC count of 10.000/mm3 or more and/or a temperature of 38°C or higher. Besides, all enrolled patients should maintain stable hemodynamic status and proper organ perfusions. A total of 113 patients with large, obstructive uretero-pelvic junction stones and clinical signs of sepsis completed the study protocol. Of those, 56 patients were placed in the emergency percutaneous nephrostomy group, while the other 57 patients were part of the percutaneous nephrolithotomy group. The primary end point was the time until normalization of white blood cells (WBC) at a count of 10.000/mm3 or less, and a temperature of 37.4°C or lower. The secondary end points included the comparison of analgesic consumption, length of stay, and related complications. Statistical analysis was performed using SPSS® version 14.0.1. The Mann-Whitney U test, chi-square test, and Fisher's exact test were used as appropriate. RESULTS: The length of hospital stays (in days) was 10.09±3.43 for the emergency percutaneous nephrostomy group and 8.18±2.72 for the percutaneous nephrolithotomy group. This set of data noted a significant difference between groups. There was no difference between groups in regard to white blood cell count (in mm3), time to normalization of white blood cell count (in days), body temperature (in ºC), time to normalization of body temperature (in days), C-reactive proteins (in mg/dL), time taken for C-reactive proteins to decrease over 25% (in days), procalcitonin (in ng/mL), or complication rates. CONCLUSIONS: This study confirms that emergency percutaneous nephrolithotomy may be as safe as early percutaneous nephrolithotomy in a selected low risk patients with sepsis-associated large, obstructive stone.

3 GHz, watt-level femtosecond Raman soliton source.

We demonstrate a 3 GHz repetition rate, femtosecond Raman soliton source with its wavelength tunable from 1.15 to 1.35 µm. We investigate the dependence of Raman soliton formation on different photonic-crystal fibers (PCFs), input powers, and fiber lengths. To produce a Raman soliton peaking at the same wavelength, shorter PCFs demand higher input average powers and consequently generate stronger Raman soliton pulses. Using 30 cm PCF NL-3.2-945, the resulting Raman soliton pulse at 1.35 µm has 0.9 W average power. The integrated relative intensity noise of the Raman soliton pulse at 1.35 µm generated from the 54-cm PCF NL-3.2-945 is as low as 0.33% from 100 Hz to 10 MHz.

An economical single-shot pulse picker without nonlinear effect and dispersion.

An economical and stable single-shot pulse picker design without dispersion, nonlinear effect, and limitation on wavelength is proposed. This design is composed of a periodic pulse blocker (PPB), a control unit, and a mechanical shutter. It has successfully been applied to the commercial high-fluence femtosecond laser with 11-mm beam diameter, 2-mJ pulse energy, and 1-kHz repetition rate. Significantly, by incorporating commercial optical choppers equipped with custom-designed chopper blades in the PPB, this design can accommodate lasers with fluences reaching 610 mJ/cm2 and the standard 1 kHz repetition rate typical of high-fluence lasers. Furthermore, the proposed design provides a cost-effective substitute compared to using electro-optic modulators or acousto-optic modulators.

Deep learning-based photodamage reduction on harmonic generation microscope at low-level optical power.

The trade-off between high-quality images and cellular health in optical bioimaging is a crucial problem. We demonstrated a deep-learning-based power-enhancement (PE) model in a harmonic generation microscope (HGM), including second harmonic generation (SHG) and third harmonic generation (THG). Our model can predict high-power HGM images from low-power images, greatly reducing the risk of phototoxicity and photodamage. Furthermore, the PE model trained only on normal skin data can also be used to predict abnormal skin data, enabling the dermatopathologist to successfully identify and label cancer cells. The PE model shows potential for in-vivo and ex-vivo HGM imaging.

Refining silicon nitride waveguide quality through femtosecond laser annealing.

We present a method for modification of silicon nitride (Si3N4) waveguide resonators using femtosecond laser annealing. The quality (Q) factor of the waveguide resonators can be improved by approximately 1.3 times after annealing. Notably, waveguides that originally had a high Q value maintained their quality after the annealing process. However, those with a lower initial Q value experienced a noticeable improvement post-annealing. To characterize the annealing effect, the surface morphologies of Si3N4 films, both pre- and post-annealing, were analyzed using atomic force microscopy. The findings suggest a potential enhancement in surface refinement. Furthermore, Raman spectroscopy confirmed that the Si3N4 film's composition remains largely consistent with its original state within the annealing power range of 0.6-1.6 W. This research underscores the potential of femtosecond laser annealing as an efficient, cost-effective, and localized technique for fabricating low-loss integrated photonics.

Frequency comb based on a narrowband Yb-fiber oscillator: pre-chirp management for self-referenced carrier envelope offset frequency stabilization.

Laser frequency combs are normally based on mode-locked oscillators emitting ultrashort pulses of ~100-fs or shorter. In this paper, we present a self-referenced frequency comb based on a narrowband (5-nm bandwidth corresponding to 415-fs transform-limited pulses) Yb-fiber oscillator with a repetition rate of 280 MHz. We employ a nonlinear Yb-fiber amplifier to both amplify the narrowband pulses and broaden their optical spectrum. To optimize the carrier envelope offset frequency (fCEO), we optimize the nonlinear pulse amplification by pre-chirping the pulses at the amplifier input. An optimum negative pre-chirp exists, which produces a signal-to-noise ratio of 35 dB (100 kHz resolution bandwidth) for the detected fCEO. We phase stabilize the fCEO using a feed-forward method, resulting in 0.64-rad (integrated from 1 Hz to 10 MHz) phase noise for the in-loop error signal. This work demonstrates the feasibility of implementing frequency combs from a narrowband oscillator, which is of particular importance for realizing large line-spacing frequency combs based on multi-GHz oscillators usually emitting long (>200 fs) pulses.

3 GHz, Yb-fiber laser-based, few-cycle ultrafast source at the Ti:sapphire laser wavelength.

We demonstrate a compact ultrafast source centered at 850 nm with >200 nm bandwidth (full width at half-maximum) based on a 3 GHz Yb-fiber master-oscillator-power-amplifier system. The output pulses (with up to 13 W average power) from the laser system are coupled into short (<50 mm) pieces of photonic crystal fibers to excite broadband fiber-optic Cherenkov radiation; the resulting broad phase-matching bandwidth due to short fiber length produces an upconverted spectrum spanning in the wavelength range of 750-950 nm with average power of 94, 184, and 380 mW for fiber length of 28, 37, and 48 mm, respectively. The spectrum generated from the 37 mm fiber is then dechirped by eight double-chirped mirrors, leading to compressed pulses ~14 fs in duration. Such an ultrafast source is a promising substitute of multigigahertz mode-locked Ti:sapphire lasers for applications in optical frequency metrology and multiphoton coherent microscopy.

Orf Infection on the Scalp of a Taiwanese Woman: A Case Report and Literature Review.

BACKGROUND: Orf, or ecthyma contagiosum, is a zoonosis caused by Parapoxvirus that infects sheep and goats. Human transmission typically occurs in persons in contact with the infected animals or contaminated fomites and environment. In humans, it generally occurs as solitary or multiple skin lesions on the hands or fingers. Involvement of the head region has rarely been reported. CASE PRESENTATION: We report an unusual case with multiple orf lesions on the scalp of a middle-aged woman, along with a review of previously reported Orf cases on the head region. CONCLUSIONS: Although Orf infection rarely happens on the head region, it should be considered in the differential diagnosis of cases with relevant animal exposure.

Apoptotic biliary epithelial cells and gut dysbiosis in the induction of murine primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a female-predominant liver autoimmune disease characterized by the specific immune-mediated destruction of the intrahepatic small bile duct. Although apoptosis of biliary epithelial cells (BECs) and alterations in gut microbiota are observed in patients with PBC, it is still unclear whether these events happen in the early stage and cause the breakdown of tolerance in PBC. In this study, we examined the early events in the loss of tolerance in our well-defined 2-OA-OVA-induced murine autoimmune cholangitis (AIC) model. We report herein that apoptosis of BECs was notable in the early stage of murine AIC. An altered gut microbiota, in particular, an increased percentage of gram-positive Firmicutes in AIC mice was also observed. BECs in AIC mice expressed adhesion molecule ICAM-1, cytokines/chemokines TNF-α, CCL2, CXCL9, CXCL10, and toll-like receptor (TLR) 2. Moreover, BECs treated with TLR2 ligand had elevated apoptosis and CXCL10 production. These data collectively suggest a new mechanism of tolerance breakdown in AIC. Altered gut microbiota induces apoptosis of BECs through TLR2 signaling. BECs secrete chemokines to recruit CD8 T cells to damage BECs further.

Optimization of femtosecond Yb-doped fiber amplifiers for high-quality pulse compression.

We both theoretically and experimentally investigate the optimization of femtosecond Yb-doped fiber amplifiers (YDFAs) to achieve high-quality, high-power, compressed pulses. Ultrashort pulses amplified inside YDFAs are modeled by the generalized nonlinear Schrödinger equation coupled to the steady-state propagation-rate equations. We use this model to study the dependence of compressed-pulse quality on the YDFA parameters, such as the gain fiber's doping concentration and length, and input pulse pre-chirp, duration, and power. The modeling results confirmed by experiments show that an optimum negative pre-chirp for the input pulse exists to achieve the best compression.

3 GHz, fundamentally mode-locked, femtosecond Yb-fiber laser.

We demonstrate a fundamentally mode-locked Yb-fiber laser with 3 GHz repetition rate and ∼206 fs pulse duration. The laser incorporates two enabling technologies: a 1 cm heavily Yb-doped phosphate glass fiber as the gain medium and a high-dispersion (-1300 fs2) output coupler to manage cavity dispersion. The oscillator self-starts and generates up to 53 mW average power.

Analysis of Functional Arch Support Insoles on the Biomechanics and Performance in Right-Forward Lunging Step of Badminton Players.

The purpose of this study was to examine the differences in biomechanical parameters and sports-specific performance of lower limbs between arch support insoles (ASI) and flat insoles (FLI) when performing net strides. After installing the MVN IMU system, 18 college badminton team members were asked to take the following tests: (1) Consecutive net stride tests; (2) Six-point footwork tests; (3) Retrieve/stroke the ball at the left and right net; (4) Smash and retrieve/stroke the ball at the net; (5) Smash at the front and back crossover step. The joint angle of the lower limbs and ground reaction force during the support phase was collected. The results demonstrated that the peak right hip flexion angle was significantly greater with ASI than FLI (63.09 ± 10.70; 60.08 ± 13.82; p = 0.028), while the peak right foot inversion angle was significantly smaller with ASI than FLI (20.68 ± 7.87; 23.85 ± 8.11; p = 0.013). The principal conclusion was that the arch support insole avoids the decrease in the hip flexion angle and the increase in the foot inversion angle during the net stride tests.

The expression levels of outer membrane proteins STM1530 and OmpD, which are influenced by the CpxAR and BaeSR two-component systems, play important roles in the ceftriaxone resistance of Salmonella enterica serovar Typhimurium.

Significant increases in STM3031, STM1530, and AcrD protein levels and significant decreases in OmpC and OmpD protein levels are present when the ceftriaxone-resistant Salmonella enterica serovar Typhimurium R200 strain is compared with the ceftriaxone-susceptible strain 01-4. AcrD is known to be involved in drug export, and STM3031 seems to play a key role in ceftriaxone resistance. Here, we examine the roles of STM1530, OmpC, and OmpD in ceftriaxone resistance. An ompD gene deletion mutant showed 4-fold higher ceftriaxone resistance than 01-4. An ompC gene deletion mutant showed 4-fold higher cephalothin and erythromycin resistance than 01-4, but there was no effect on ceftriaxone resistance. However, a stm1530 deletion mutant did show >64-fold lower ceftriaxone resistance than R200. Moreover, the STM3031 protein was significantly decreased in R200(Δstm1530) compared to R200. STM3031 expression has been shown to be influenced by the two-component system regulator gene baeR. CpxR seems to modulate BaeR. A cpxA-cpxR gene deletion mutant showed >2,048-fold lower ceftriaxone resistance than R200. The outer membrane protein profile of R200(ΔcpxAR) showed significant decreases in STM3031 and STM1530 compared to R200, while OmpD had returned to the level found in 01-4. Furthermore, the stm3031, stm1530, and ompD mRNA levels were correlated with their protein expression levels in these strains, while decreases in the mRNA levels of the efflux pump acrB, acrD, and acrF genes were found in R200(ΔcpxAR). Findings similar to those for R200(ΔcpxAR) were found for R200(ΔbaeSR). These results, together with those for STM3031 and the fact that STM1530 is an outer membrane protein, suggest that STM1530 and OmpD are influenced by the CpxAR and BaeSR two-component systems and that this contributes to S. enterica serovar Typhimurium ceftriaxone resistance.

Interleukin-30 Suppresses Not Only CD4+ T Cells but Also Regulatory T Cells in Murine Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is a chronic liver autoimmune disease with augmented T helper (Th) 1 and corresponding cytokine IFN-γ immune responses. Using 2-octynoic acid (2-OA) coupled to OVA (2-OA-OVA)-induced mouse models of autoimmune cholangitis (inducible chemical xenobiotic models of PBC), our previous study demonstrated that overexpression of IFN-γ in the model mice enhanced liver inflammation upon disease initiation, but subsequently led to the suppression of chronic inflammation with an increase in interleukin-30 (IL-30) levels. In this study, we investigated whether IL-30 had an immunosuppressive function and whether it could be part of an immune therapeutic regimen for PBC, by treating model mice with murine IL-30-expressing recombinant adeno-associated virus (AAV-mIL-30). We first defined the effects of AAV-mIL-30 in vivo by administering it to a well-known concanavalin A (ConA)-induced hepatitis model of mice and found that AAV-mIL-30 reduced the numbers of activated CD25+CD4+ T cells and the levels of serum IFN-γ and IL-12. In autoimmune cholangitis, decreased numbers of activated CD4+ T cells and Foxp3+ regulatory T cells were noted in the mice treated with AAV-mIL-30 at 3 weeks after the 2-OA-OVA immunization. Treatment with IL-30 did not change the features of autoimmune cholangitis including autoantibodies, cell infiltration, and collagen deposition in the liver at 11 weeks of examination. However, increased levels of cytokines and chemokines were observed. These results suggest that IL-30 suppresses not only CD4+ T cells but also regulatory T cells. Additionally, the administration of IL-30 did not suppress liver inflammation in the murine model of PBC.

Chirally-coupled-core Yb-fiber laser delivering 80-fs pulses with diffraction-limited beam quality warranted by a high-dispersion mirror based compressor.

We demonstrate a high-energy femtosecond laser system that incorporates two rapidly advancing technologies: chirally-coupled-core large-mode-area Yb-fiber to ensure fundamental-mode operation and high-dispersion mirrors to enable loss-free pulse compression while preserving the diffraction-limited beam quality. Mode-locking is initiated by a saturable absorber mirror and further pulse shortening is achieved by nonlinear polarization evolution. Centered at 1045 nm with 39-MHz repetition rate, the laser emits 25-nJ, positively chirped pulses with 970-mW average power. 6 bounces from double-chirped-mirrors compress these pulses down to 80 fs, close to their transform-limited duration. The loss-free compression gives rise to a diffraction-limited optical beam (M2 = 1.05).