A microbial metabolite synergizes with endogenous serotonin to trigger C. elegans reproductive behavior.

Natural products are a major source of small-molecule therapeutics, including those that target the nervous system. We have used a simple serotonin-dependent behavior of the roundworm Caenorhabditis elegans, egg laying, to perform a behavior-based screen for natural products that affect serotonin signaling. Our screen yielded agonists of G protein-coupled serotonin receptors, protein kinase C agonists, and a microbial metabolite not previously known to interact with serotonin signaling pathways: the disulfide-bridged 2,5-diketopiperazine gliotoxin. Effects of gliotoxin on egg-laying behavior required the G protein-coupled serotonin receptors SER-1 and SER-7, and the Gq ortholog EGL-30. Furthermore, mutants lacking serotonergic neurons and mutants that cannot synthesize serotonin were profoundly resistant to gliotoxin. Exogenous serotonin restored their sensitivity to gliotoxin, indicating that this compound synergizes with endogenous serotonin to elicit behavior. These data show that a microbial metabolite with no structural similarity to known serotonergic agonists potentiates an endogenous serotonin signal to affect behavior. Based on this study, we suggest that microbial metabolites are a rich source of functionally novel neuroactive molecules.

Radiofrequency ablation versus surgical resection for the treatment of solitary hepatocellular carcinoma 2 cm or smaller: A cohort study in Taiwan.

BACKGROUND/PURPOSE: Radiofrequency ablation (RFA) is increasingly being used instead of surgical resection for the treatment of hepatocellular carcinoma (HCC) tumor measuring ≦2 cm. However, the long-term outcomes of RFA, especially in comparison to surgical resection, are still debated. We compared the outcomes of surgical resection and RFA in patients with a solitary HCC tumor measuring ≦2 cm from a 10-year cohort study. METHODS: From Jan 2006 to Dec 2016, 156 patients with a resectable HCC measuring ≦2 cm who underwent surgical resection (n = 83) or RFA (n = 73) at the Buddhist Tzu Chi Medical Foundation were enrolled. Patient characteristics, overall survival (OS), and recurrence-free survival (RFS) were retrospectively examined, and comparisons were made between the two groups and through subgroup analyses. RESULTS: The 1-year, 3-year, 5-year, and 7-year OS outcomes were comparable between the surgical resection group and the RFA group (P = 0.193), but the surgical resection group had significantly higher 1-year, 3-year, 5-year, 7-year, and 10-year RFS than the RFA group (P = 0.018). Multivariate analysis revealed that patients with lower age, Child-Turcotte-Pugh score, or albumin-bilirubin score before treatment had better OS, and patients with an HCV infection or receiving RFA treatment had higher HCC recurrence rates. CONCLUSION: The liver reserve determined the long-term OS of patients with an HCC tumor ≦ 2 cm, and surgical resection offered better RFS than RFA (ClinicalTrials.gov number, NCT04525833.).

Decreased swallowing function in the sarcopenic elderly without clinical dysphagia: a cross-sectional study.

BACKGROUND: Sarcopenia and dysphagia are prevalent health issues as the elderly population continues to grow. However, whether sarcopenia, defined by either reduced handgrip strength or gait speed, would lead to pathological effects on swallowing function is still a matter of debate. Studies focusing on subclinical changes in the swallowing function in the sarcopenic elderly are lacking. This study evaluates the swallowing function in the sarcopenic elderly without dysphagia. METHODS: A cross-sectional study was conducted including subjects recruited from the community. Ninety-four individuals aged 65 and older without dysphagia were divided into two groups: sarcopenia and nonsarcopenia. The swallowing assessment included tongue pressure measurement, hyoid displacement (HD), hyoid velocity (HV) measurement with submental ultrasonography, 100-ml water-swallowing test, and the 10-item Eating Assessment Tool (EAT-10). RESULTS: The average tongue pressure was 47.0 ± 13.7 and 48.6 ± 11.5 kPa in the sarcopenia and nonsarcopenia groups, respectively (p = 0.55), whereas the average HD during swallowing was 15.3 ± 4.4 and 13.0 ± 4.2 mm in the sarcopenia and nonsarcopenia groups, respectively (p < 0.05). The median of HV during swallowing was 19.5 (6.41-45.86) and 15.9 (3.7-39.7) mm/s in the sarcopenia and nonsarcopenia group (p < 0.05). The median of time needed for consuming 100 ml water was 12.43 (3.56-49.34) and 5.66 (2.07-19.13) seconds in the sarcopenia and nonsarcopenia groups, respectively (p < 0.05). The median of the EAT-10 score was 0 (0-2) and 0 (0-1) in the sarcopenia and nonsarcopenia groups, respectively (p < 0.05). CONCLUSIONS: In elderly individuals, swallowing function was significantly impaired with sarcopenia before clinical symptoms become clear. However, tongue muscles exhibited resistance to sarcopenia. We observed compensative strategies in patients with sarcopenia, such as reduced swallowing speed and increased hyoid bone movement.

Foveal microvascular anomalies on optical coherence tomography angiography and the correlation with foveal thickness and visual acuity in retinopathy of prematurity.

PURPOSE: To assess foveal microvascular structure and the correlation between foveal retinal thickness and best corrected visual acuity (BCVA) in children with retinopathy of prematurity (ROP). METHODS: This is a retrospective case-control study. A total 42 eyes in 23 patients with history of anti-vascular endothelial factor (VEGF) agent treatment and 51 eyes of 27 healthy age-matched subjects as the control group were analyzed. Foveal avascular zone (FAZ) and foveal vessel density (VD) were measured by optical coherence tomography angiography (OCT-A). Foveal thickness was measured by cross-sectional OCT. Correlations between FAZ area, foveal VD, foveal thickness, BCVA, gestational age (GA), and birth body weight (BBW) were performed. RESULTS: ROP children had a significantly smaller FAZ area and higher foveal VD, and the foveal thickness was significantly higher as compared to controls (all P < 0.0001). We noted a significant negative correlation between FAZ area and foveal thickness. In addition, a significant positive correlation between foveal VD and foveal thickness was identified. With regard to prematurity status, gestational age and birth body weight were both significantly correlated with FAZ area, foveal VD, and fovea inner retinal thickness. Multivariable analysis showed that thicker inner retinal thickness and higher superficial vascular density were associated with suboptimal visual acuity. CONCLUSION: By using OCT-A, we identified significant foveal microvascular anomalies in ROP children. The correlation between the microvascular anomalies, central foveal thickness, and suboptimal visual acuity was also noted. Because of the retrospective nature, more studies are necessary to further establish the relationship.

Genetic analysis of a novel tubulin mutation that redirects synaptic vesicle targeting and causes neurite degeneration in C. elegans.

Neuronal cargos are differentially targeted to either axons or dendrites, and this polarized cargo targeting critically depends on the interaction between microtubules and molecular motors. From a forward mutagenesis screen, we identified a gain-of-function mutation in the C. elegans α-tubulin gene mec-12 that triggered synaptic vesicle mistargeting, neurite swelling and neurodegeneration in the touch receptor neurons. This missense mutation replaced an absolutely conserved glycine in the H12 helix with glutamic acid, resulting in increased negative charges at the C-terminus of α-tubulin. Synaptic vesicle mistargeting in the mutant neurons was suppressed by reducing dynein function, suggesting that aberrantly high dynein activity mistargeted synaptic vesicles. We demonstrated that dynein showed preference towards binding mutant microtubules over wild-type in microtubule sedimentation assay. By contrast, neurite swelling and neurodegeneration were independent of dynein and could be ameliorated by genetic paralysis of the animal. This suggests that mutant microtubules render the neurons susceptible to recurrent mechanical stress induced by muscle activity, which is consistent with the observation that microtubule network was disorganized under electron microscopy. Our work provides insights into how microtubule-dynein interaction instructs synaptic vesicle targeting and the importance of microtubule in the maintenance of neuronal structures against constant mechanical stress.

Reliability of Ultrasonography in Evaluating Hyoid Bone Movement.

BACKGROUND: Timely and adequate laryngeal elevation along with hyoid bone movement is an essential component of the swallowing movement under normal physiological conditions. The purpose of this study was to verify the reproducibility of using ultrasonography to evaluate hyoid bone displacement during swallowing through the assessment of inter- and intrarater reliability and examine its accuracy by comparing the results with videofluoroscopic swallowing study (VFSS). METHODS: A self-designed water balloon was fixed to the transducer, which provided good contact between the transducer and the submental skin. Ten participants with dysphagia were recruited. The measurements of hyoid bone displacement using ultrasonography were performed by two of the authors. All the participants underwent ultrasonographic examinations and VFSS within 24 hours. RESULTS: The intrarater intraclass correlation coefficient (ICC) of the two examiners was 0.996 and 0.959, respectively (p < 0.01); the interrater ICC between the two examiners was 0.892 (p < 0.05). ICCs between VFSS and ultrasonography for two researchers were 0.815 and 0.916 (p < 0.01). CONCLUSION: Submental ultrasonography is a reliable and accurate method for assessing the hyoid bone movement.

Effects of free carriers on piezoelectric nanogenerators and piezotronic devices made of GaN nanowire arrays.

This study investigates the role of carrier concentration in semiconducting piezoelectric single-nanowire nanogenerators (SNWNGs) and piezotronic devices. Unintentionally doped and Si-doped GaN nanowire arrays with various carrier concentrations, ranging from 10(17) (unintentionally doped) to 10(19) cm(-3) (heavily doped), are synthesized. For SNWNGs, the output current of individual nanowires starts from a negligible level and rises to the maximum of ≈50 nA at a doping concentration of 5.63 × 10(18) cm(-3) and then falls off with further increase in carrier concentration, due to the competition between the reduction of inner resistance and the screening effect on piezoelectric potential. For piezotronic applications, the force sensitivity based on the change of the Schottky barrier height works best for unintentionally doped nanowires, reaching 26.20 ± 1.82 meV nN(-1) and then decreasing with carrier concentration. Although both types of devices share the same Schottky diode, they involve different characteristics in that the slope of the current-voltage characteristics governs SNWNG devices, while the turn-on voltage determines piezotronic devices. It is demonstrated that free carriers in piezotronic materials can influence the slope and turn-on voltage of the diode characteristics concurrently when subjected to strain. This work offers a design guideline for the optimum doping concentration in semiconductors for obtaining the best performance in piezotronic devices and SNWNGs.

Six years follow-up of type 1 retinopathy of prematurity (ROP) treated with intravitreal injection of ranibizumab and bevacizumab: Long-Term Outcomes of intravitreal injection in Type 1 ROP.

To investigate biometric and refractive results in patients with type 1 retinopathy of prematurity (ROP) treated by intravitreal injection (IVI) of ranibizumab (R) and bevacizumab (B) at the corrected age of 6. This is a single-center retrospective study. Infants diagnosed with type 1 ROP and treated with IVI of either R or B as the primary therapy were included. Data on axial length, anterior chamber depth (ACD), and lens thickness (LT) were obtained using A-scan ultrasound. Cycloplegic refraction, keratometry (K), and best-corrected visual acuity were also documented. Additionally, optical coherence tomography angiography was performed to assess the foveal avascular zone and the density of superficial and deep vessels. We analyzed the structural and functional differences between the 2 groups and compared them with findings from a previous study conducted when these children were between the ages of 1 and 3. The study included 60 eyes from 34 patients, with 34 eyes receiving B and 26 eyes receiving R injections for ROP. In biometric outcomes, there was still a deeper ACD (3.36 ±â€…0.24 mm in the B group; 3.52 ±â€…0.21 mm in the R group) and thinner LT (3.63 ±â€…0.16 mm in the B group; 3.53 ±â€…0.12 mm in the R group) in the R group, as previously reported at the age of 3. In the refractive aspect, the eyes treated with B had higher myopia at the ages of 1 and 3; however, at the age of 6, refractive errors did not differ significantly between the 2 groups. At the corrected age of 6, the eyes treated with IVI of R were associated with deeper ACD and thinner LT. Interestingly, the emmetropization process resulted in a similar incidence of high myopia at the age of 6, which was different from the outcomes observed at younger ages.

Diagnosis and treatment of syphilitic uveitis: Taiwan experts consensus.

A recent resurgence in the incidence of syphilis has sparked a new interest in this old disease. Syphilitic uveitis remains a challenging disease, among the variable syphilis infections, due to the diagnostic complexity and the wide clinical manifestations. Here, we provide recommendations regarding clinical manifestations, diagnosis, and treatment for patients with syphilitic uveitis in Taiwan based on an expert meeting and consensus from experienced uveitis specialists.

Disinfection by-product formation potentials in wastewater effluents and their reductions in a wastewater treatment plant.

Disinfection by-product formation potentials (DBPFPs) in wastewater effluents from eight wastewater treatment plants (WWTPs) were investigated. In addition, a WWTP with one primary effluent and two different biological treatment processes was selected for a comparative study. Formation potential tests were carried out to determine the levels of DBP precursors in wastewater. WWTPs that achieved better organic matter removal and nitrification tended to result in lower DBPFPs in effluents. For the WWTP with two processes, haloacetic acid, trihalomethane, and chloral hydrate precursors were predominant DBP precursors in the primary and secondary effluents. The percent reductions of haloacetonitrile and haloketone formation potentials averaged at 96% which was high in comparison to the reductions of other classes of DBPFPs. In addition, biological treatment changed the DBPFP speciation profile by lowering the HAAFP/THMFP ratio. The eight plant survey and the comparative analysis of the WWTP with two processes implied that besides nitrification, there may be other confounding factors impacting DBPFPs. Oxic and anoxic conditions, formation and degradation of soluble microbial products had impacts on the DBPFP reductions. This information can be used by water and wastewater professionals to better control wastewater-derived DBPs in downstream potable water supplies.

Chorioretinal Atrophy in Punctate Inner Choroidopathy/multifocal Choroiditis: A Five-year Follow-up Study.

PURPOSE: To report the 5-year results of chorioretinal atrophy (CRA) progression in patients with punctate inner choroidopathy (PIC) or multifocal choroiditis (MFC). METHODS: A retrospective study included PIC/MFC patients with secondary CRA formation. The area of CRA was measured and the progression rate was calculated. Multiple regression analysis was performed to investigate risk factors associated with CRA progression. RESULTS: Forty-five eyes of 36 patients were included. The mean CRA size significantly increased after an average of 4.83 years of follow-up with progression rate of 0.69 mm2/year. Moreover, we had identified the axial length and initial PIC lesion number as significant risk factors for CRA progression. CONCLUSION: Significant CRA enlargement is noted in PIC/MFC patients after 5 years of follow-up. The progression rate is associated with axial length and initial PIC numbers. Aggressive treatment is suggested for eyes with more initial lesion numbers and longer axial length to control the faster CRA progression.

Therapeutic efficacy of nivolumab plus sorafenib therapy in patients with unresectable hepatocellular carcinoma.

BACKGROUND: Immune checkpoint inhibitor therapy is the backbone of numerous combination regimens for improving the therapeutic response of patients with hepatocellular carcinoma (HCC). We aimed to investigate the therapeutic efficacy of nivolumab plus sorafenib therapy in patients with unresectable HCC. METHODS: Patients with unresectable HCC who received sorafenib and followed at Taipei Tzu Chi Hospital from January 2016 to May 2022 were selected for this study, and those treated with nivolumab plus sorafenib and those with sorafenib alone were propensity score matched. The primary outcome was overall survival (OS) presented as a hazard ratio calculated using Cox proportional hazards regression models. RESULTS: In the analysis, 36 patients receiving nivolumab plus sorafenib and 36 receiving sorafenib alone were propensity score matched. The median OS for those receiving nivolumab plus sorafenib and sorafenib alone were 3.6 years and 1.2 years, respectively (p = 0.031). The hazard ratio of OS for nivolumab plus sorafenib compared to sorafenib alone was 0.36 (95 %CI, 0.19-0.70; p = 0.003). Furthermore, patients receiving nivolumab plus sorafenib with a baseline α-fetoprotein(AFP) < 10 ng/mL and early reduction in AFP had a 100 % objective response rate and disease control rate. CONCLUSION: In patients with unresectable HCC, nivolumab plus sorafenib resulted in better OS outcomes than sorafenib.

A novel DNA selection and direct extraction process and its application in DNA recombination.

In the conventional bench-top approach, the DNA recombination process is time- and effort-consuming due to laborious procedures lasting from several hours to a day. A novel DNA selection and direct extraction process has been proposed, integrated and tested on chip. The integrative microfluidic chip can perform the whole procedure of DNA recombination, including DNA digestion, gel electrophoresis, DNA extraction and insert-vector ligation within 1 h. In this high-throughput design, the manual gel cutting was replaced by an automatic processing system that performed high-quality and high-recovery efficiency in DNA extraction process. With no need of gel-dissolving reagents and manipulation, the application of selection and direct extraction process could significantly eliminate the risks from UV and EtBr and also facilitate DNA recombination. Reliable output with high success rate of cloning has been achieved with a significant reduction in operational hazards, required materials, efforts and time.

Do alternate bacterial indicators and pathogens increase after centrifuge dewatering of anaerobically digested biosolids?

The objectives of this research were to evaluate the potential for sudden increase and/or regrowth of alternative bacteria as either indicators or pathogens after dewatering of thermophilic and mesophilically digested biosolids. The results showed that, in general, for thermophilic processes, even when a statistically significant (p < 0.05) sudden increase and regrowth occurred for fecal coliforms, Escherichia coli, and Enterococci, it did not occur for Salmonella or Aeromonas. For the mesophilic process evaluated, sudden increase did not occur, but regrowth occurred for fecal coliforms, E. coli, Enterococci, and Salmonella. The results have implications for Class A and B biosolids regulations, as both fecal coliform and Salmonella are part of the regulatory limits. The results also suggest that the public health risks are minimal, as a result of the potential sudden increase and regrowth that may occur.

The effect of digestion and dewatering on sudden increases and regrowth of indicator bacteria after dewatering.

Several investigators have reported higher densities of indicator bacteria after dewatering of anaerobically digested biosolids. The increases appear to occur at two points in the biosolids process: the first, referred to as "sudden increase", occurs immediately after dewatering; the second, "regrowth", occurs during storage over longer periods. The objectives of this study were to examine the effect of digestion and dewatering processes on sudden increase and regrowth of fecal coliform and E. coli. Samples were collected from five thermophilic and five mesophilic digestion processes, with either centrifuge or belt filter press dewatering. Sudden increase typically was observed in the thermophilic processes with centrifuge dewatering and was not observed in the mesophilic processes with either centrifuge or belt filter press dewatering. Regrowth was observed in both thermophilic and mesophilic processes with centrifuge dewatering but not belt filter press dewatering.

Human amniotic membrane grafts for retinal breaks in diabetic tractional retinal detachment and combined tractional and rhegmatogenous retinal detachment.

To describe the surgical outcomes of using human amniotic membrane (hAM) grafts in the management of retinal breaks in diabetic tractional detachment (TRD) and combined tractional and rhegmatogenous retinal detachment (CTRRD). A retrospective case series of 10 eyes with TRD or CTRRD receiving pars plana vitrectomy with hAM grafts implantation, compared with 13 controls receiving the same surgery without hAM grafts. Best-corrected visual acuity (BCVA) and re-detachment rate were compared between two groups. Postoperatively, all eyes in the hAM group had retina attachment without recurrence, while 9 eyes in the control group had retina re-detachment and required additional surgery (0% vs 69.2%, p = 0.003). The BCVA significantly improved in the hAM group (from 1.96 ± 0.95 to 1.44 ± 0.77 in log MAR, p = 0.03), but not improved in control group (p = 0.20). Postoperative optical coherence tomography of the eyes receiving hAM grafts demonstrated glial tissue regeneration and restoration of ellipsoid zone. In diabetic TRD or CTRRD, hAM grafts could be an effective method, with promising outcome. Compared to standard surgery, it could result in higher retina reattachment rate and significant visual improvement. Moreover, it may offer the adjunctive benefit in tissue regeneration and fasten ellipsoid zone restoration.

Isolated Central Epiretinal Membrane: A Rare Complication of Fovea-Sparing Internal Limiting Membrane Peeling Technique.

PURPOSE: To report a rare complication presenting as an isolated central epiretinal membrane (ERM) related to fovea-sparing internal limiting membrane (ILM) peeling technique. METHODS: Five patients who received fovea-sparing ILM peeling were enrolled. Postoperatively, an isolated central ERM developed. Optical coherence tomography (OCT) was used to evaluate the serial anatomic change. RESULTS: Among the five included patients, one patient had high myopia with foveoschisis, two patients had vitreomacular traction, and two patients had proliferative diabetic retinopathy with tractional retinal detachment and a fovea cyst. With an average of 5.80 months, OCT showed the gradual development of the isolated central ERM with severe fovea distortion. Four patients received secondary revision surgery, with improvement of the fovea contour and visual acuity. CONCLUSION: The fovea-sparing ILM peeling technique may cause a rare but serious complication as the isolated central ERM, which would cause significant fovea distortion as well as visual deterioration. Timely detection and intervention is recommended to prevent further visual loss. This trial is registered with NCT04445142.

3-year follow-up of half-dose verteporfin photodynamic therapy for central serous chorioretinopathy with OCT-angiography detected choroidal neovascularization.

To assess the 3-year outcome of half-dose verteporfin photodynamic therapy (PDT) in central serous chorioretinopathy (CSC) with optical coherence tomography angiography (OCT-A) detected choroidal neovascularization (CNV), we performed a retrospective, interventional study. Patients were divided into 2 groups according to the fluorescein angiography: point source leakage in group 1 and diffuse oozing in group 2. Data were collected from patients including changes of best-corrected visual acuity (BCVA), size of CNV, central macular thickness (CMT), choroidal thickness (CT), reabsorption of subretinal fluid (SRF), sessions of half-dose PDT, and the number of intravitreal injections (IVI) of anti-vascular endothelial growth factor (anti-VEGF). There was a total of 34 eyes in 32 patients included. The mean sessions of half-dose PDT was 1.50 ± 0.75. The mean number of IVI of anti-VEGF was 1.38 ± 3.34. BCVA improved from 0.38 ± 0.33 to 0.20 ± 0.22 (p < 0.001). Mean CMT was significantly reduced along with reduced CT and increased size of CNV. SRF was totally reabsorbed in 31 eyes. Patients in group 1 had significant less sessions of PDT and better final BCVA. In conclusion, half-dose PDT treatment was effective for CSC with CNV. Patients with diffuse oozing in FA may fare less well with half-dose PDT.

Metformin inhibits gastric cancer cell proliferation by regulation of a novel Loc100506691-CHAC1 axis.

Long noncoding RNAs (lncRNAs) are a group of nonprotein coding transcripts that play a critical role in cancer progression. However, the role of lncRNA in metformin-induced inhibition of cell growth and its biological function in gastric cancer remain largely unknown. In this study, we identified an oncogenic lncRNA, Loc100506691, the expression of which was decreased in gastric cancer cells with metformin treatment. Moreover, Loc100506691 was significantly overexpressed in gastric cancer compared with adjacent normal tissues (p < 0.001), and high Loc100506691 expression was significantly correlated with poor survival of patients with gastric cancer. Additionally, Loc100506691 knockdown could significantly suppress gastric cancer cell growth in vitro, and ectopic Loc100506691 expression accelerated tumor growth in an in vivo mouse model. Analysis of the cell cycle revealed that Loc100506691 knockdown induced cell cycle arrest at the G2/M phase by impairing cell entry from the G2/M to G1 phase. Loc100506691 negatively regulated CHAC1 expression by modulating miR-26a-5p/miR-330-5p expression, and CHAC1 knockdown markedly attenuated Loc100506691 knockdown-induced gastric cancer cell growth and motility suppression. We concluded that anti-proliferative effects of metformin in gastric cancer may be partially caused by suppression of the Loc100506691-miR-26a-5p/miR-330-5p-CHAC1 axis.