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Nonlinear effects in a high-power laser amplification system based on thin-rod active elements are experimentally investigated. It is shown that the most important nonlinear effect is the Kerr effect leading to self-focusing and self-phase modulation of laser radiation. The observed luminescence in Yb : YAG crystals in the visible region of the spectrum is caused by the charge transfer luminescence effect, which, in turn, is due to multiphoton absorption of laser radiation. Second-order nonlinearity in the crystal is used to effectively convert femtosecond pulses to second harmonic and sum-frequency waves which exhibit radiations of green and UV spectra.

Uveitis caused by herpes simplex virus (HSV)‐1 is characterized by increased intraocular pressure (IOP) in the presence of anterior chamber inflammation. Despite their clinical significance, the pathogenic changes associated with HSV‐1 infection in trabecular meshwork (TM) cells, the key cell type regulating IOP, have not been completely elucidated. In this study, cytokine array analyses showed a significant stepwise increase in monocyte chemoattractant protein (MCP)‐1 expression upon HSV‐1 infection in TM cells (p

In mammalian cells, the bulky DNA adducts caused by ultraviolet radiation are mainly repaired via the nucleotide excision repair (NER) pathway; some defects in this pathway lead to a genetic disorder known as xeroderma pigmentosum (XP). Ribosomal protein S3 (rpS3), a constituent of the 40S ribosomal subunit, is a multi-functional protein with various extra-ribosomal functions, including a role in the cellular stress response and DNA repair-related activities. We report that rpS3 associates with transcription factor IIH (TFIIH) via an interaction with the xeroderma pigmentosum complementation group D (XPD) protein and complements its function in the NER pathway. For optimal repair of UV-induced duplex DNA lesions, the strong helicase activity of the TFIIH complex is required for unwinding damaged DNA around the lesion. Here, we show that XP-D cells overexpressing rpS3 showed markedly increased resistance to UV radiation through XPD and rpS3 interaction. Additionally, the knockdown of rpS3 caused reduced NER efficiency in HeLa cells and the overexpression of rpS3 partially restored helicase activity of the TFIIH complex of XP-D cells in vitro. We also present data suggesting that rpS3 is involved in post-excision processing in NER, assisting TFIIH in expediting the repair process by increasing its turnover rate when DNA is damaged. We propose that rpS3 is an accessory protein of the NER pathway and its recruitment to the repair machinery augments repair efficiency upon UV damage by enhancing XPD helicase function and increasing its turnover rate.

Accurate prediction of intended gait speed is crucial for facilitating volitional muscle activity during robot-assisted gait training. Considering that most patients find it difficult to perform gait at relatively high speeds, it is also imperative that the prediction model performs well at slow gait speed. Furthermore, ample time for signal processing should be given prior to robot assistance such that the patient is not subjected to unwanted resistance or lag. Here, the authors propose to predict the intended speed of the contralateral limb via kinematics of the current swing limb. Three lower-limb positions were evaluated using an inertial measurement unit sensor during treadmill gait sessions. The results suggest that the authors’ model performs well even during slow gait speeds ( ≤ 2 km / h ) with R 2 values as high as 0.86.

The lack of patient effort during robot-assisted gait training (RAGT) is thought to be the main factor behind unsatisfactory rehabilitative efficacy among hemiparetic stroke patients. A key milestone to implement patient-driven RAGT is to predict gait intent prior to actual joint movement. Here, the authors propose a method of predicting step speed intent via surface electromyogram (EMG) signals from the soleus. Six lower-limb muscles were initially evaluated on a treadmill, and the results suggest that the soleus EMG signals correlate well with step speed. The authors further propose a simple linear regression model which predicts subsequent step speed via current soleus EMG signals with over-ground gait sessions, R 2 of ∼0.6. The proposed experimental results and simple prediction model should be applicable for RAGT without significant modifications.

Fermented feeds are being considered as practical alternatives to antimicrobial growth promoters (AGP) supplemented in nursery pig diets. This study aimed to investigate health-promoting effects of fermented barley in weaned pigs challenged with Escherichia coli K88 +. A total of 37 piglets were weaned at 21 ± 1 day of age (6.41 ± 0.47 kg of BW) and assigned to either of the following five treatment groups: (1) unchallenged control (UCC; n = 7), (2) challenged control (CC; n = 7), (3) AGP (CC + 0.1% AGP; n = 7), (4) Ferm1 (challenged and fed homofermentative Lactobacillus plantarum (Homo)-fermented barley; n = 8) and (5) Ferm2 (challenged and fed heterofermentative L. buchneri (Hetero)-fermented barley; n = 8). The control diet included unfermented barley. Barley was fermented with either Homo or Hetero for 90 days under anaerobic conditions. On day 10, all pigs except those in UCC group were orally inoculated with E. coli K88 + (6 × 109 colony forming units/ml). The pre-planned orthogonal test was performed to compare (1) UCC and CC, (2) CC and AGP, (3) CC and Ferm1 + Ferm2, as well as (4) Ferm1 and Ferm2. Challenged control pigs showed shorter (P < 0.05) villus height (VH) in the duodenum and deeper (P < 0.05) crypt depth (CD) in the jejunum than UCC pigs. The AGP group had higher (P < 0.05) VH and lower (P < 0.05) IL-6 gene expression in the jejunum compared with CC group. Compared to CC, Ferm1 and Ferm2 had decreased (P < 0.05) CD in the duodenum, IL-6 gene expression in the jejunum and rectal temperature at 24 h post-challenge. Pigs fed fermented barley diets showed greater (P < 0.05) faecal abundance of Clostridium Cluster IV and Lactobacilli than those fed UCC diet. Ferm2-fed pigs showed lower (P < 0.05) concentrations of band cells, eosinophils and lymphocytes at 6, 24 and 48 h after challenge, respectively, and lower (P < 0.05) faecal abundance of Enterobacteriaceae 24 h after challenge than the Ferm1-fed pigs. In conclusion, the substitution of unfermented barley with fermented barley in a nursery diet showed similar results as those shown by AGP supplementation in terms of enhancing the intestinal morphology and modulating faecal microbiota composition, as well as down-regulating the pro-inflammatory cytokines; therefore, fermented barley can be a possible nutritional strategy for managing nursery pigs fed diets without in-feed AGP.

Background: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown. Patients and methods: We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death. Results: The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months [hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19]. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90). Conclusions: Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2-mutated patients with PSROC compared to patients not previously receiving poly (ADP-ribose) polymerase inhibitors (PARPi). The optimal strategy for patients who relapse after PARPi is an area of ongoing research.

Background Idiopathic pulmonary fibrosis is a progressive disease and antifibrotic therapies do not reverse existing fibrosis. There has been emerging evidence of potential role for statins in idiopathic pulmonary fibrosis. The aim of this review is to synthesise the evidence on the efficacy of statins in idiopathic pulmonary fibrosis, focusing on associations with all-cause mortality, disease-specific mortality and change in pulmonary function. Methods Medline and Embase were reviewed to identify relevant publications. Studies were selected if they examined disease-related outcomes including mortality, pulmonary function and adverse events in people with idiopathic pulmonary fibrosis receiving statin therapy. Results Five studies with a total of 3407 people with IPF were selected and analysed. The overall risk of bias of five included studies was moderate to serious. In the fixed effect meta-analysis, statin use was associated with a reduction in mortality (RR 0.8; 95% CI 0.72–0.99). However, in the random effects model, there was no longer any significant association between statin use and all-cause mortality (RR 0.87; 95% CI 0.68–1.12). There was no statistically significant association between statin use and decline in FVC % predicted. Conclusion There is currently insufficient evidence to conclude the effect of statin therapy on disease-related outcomes in idiopathic pulmonary fibrosis. Considering the limitations of available literature, we would recommend a prospective cohort study with capture of dosage and preparation of statin, statin adherence and use of concurrent antifibrotic treatment. PROSPERO registration number CRD42019122745.

The opportunistic human fungal pathogen Candida albicans has morphogenesis as a virulence factor. The morphogenesis of C. albicans is closely related to pathogenicity (1). Ras1 in C. albicans is an important switch in the MAPK pathway for morphogenesis (2, 3). The MAPK pathway is important for the virulence, such as cell growth, morphogenesis, and biofilm formation (4, 5). Ume6 is a well-known transcriptional factor for hyphal-specific genes (6). Despite numerous studies, as a recent issue, it is necessary to develop a new drug that uses a different pathway mechanism to inhibit resistant C. albicans strains caused by chronic prescription of azole or echinocandin drugs, which are mainly used. Here, we show that the small carbazole derivatives attenuated the pathogenicity of C. albicans through inhibition of the Ras1/MAPK pathway. We found that the small molecules inhibit morphogenesis through repressing protein and RNA levels in Ras/MAPK related genes including UME6 and NRG1. Furthermore, we found the antifungal effect of the small molecules in vivo using a candidiasis murine model. We anticipate our findings are that the small molecules are the promising compounds for the development of new antifungal agents for the treatment of systemic candidiasis and possibly for other fungal diseases.Author summaryThe infection by the opportunistic human fungal pathogen Candida albicans occurs mainly in immunocompetent and immunocompromised humans, such as AIDS patients, immunosuppressant-treated organ transplant patients, and recent COVID-19 patients. Morphogenesis which the ability to switch between yeast and hyphal growth forms is one of the representative virulence factors of C. albicans. Here, we describe novel small molecules that show antifungal effects such as the inhibition of the morphogenesis and the biofilm formation, and maintenance of biofilm. Moreover, we found that these small molecules had antifungal activity in mouse experiments, and confirmed that they were also effective in drug-resistant C. albicans strains. Studies of some small molecules with structures similar to ours have already been reported to exhibit growth inhibitory activity against bacteria and Candida species. However, the mechanism of action of these molecules has not been elucidated. In this study, we demonstrated, for the first time, the mechanism by which these two small molecules inhibit C. albicans pathogenicity through inhibition of specific pathways. Our study, through the research of the mechanism of action of novel small molecules, provides new insights into the development of drug candidates not only for wild-type C. albicans, but also for strains resistant to existing drugs.

In this Letter, the authors propose a face identification method using radar sensor data. They use a frequency-modulated continuous wave radar sensor that utilises a centre frequency of 61 GHz and a bandwidth of 6 GHz. Then, they accumulate radar data by transmitting and receiving radar signals on human faces. Finally, they use a convolutional neural network (CNN) to distinguish radar signals reflected from different human faces. In this network, signals received from multiple antenna elements are synthesised in parallel to make the radar signals into an image that is the input form of the CNN. The accuracy of face recognition through the CNN is > 98 % . In addition, they also collect radar data when the same subjects wear cotton masks. Within their entire dataset, wearing a mask does not significantly affect the accuracy of the radar-based face recognition method.

A chromatin immunoprecipitation (ChIP) assay is a method to identify how much a protein of interest binds to the DNA region. This method is indispensable to study the mechanisms of how the transcription factors or chromatin modifications regulate the gene expression. Candida albicans is a dimorphic pathogenic fungus, which can change its morphology very rapidly from yeast to hypha in response to the environmental signal. The morphological change of C. albicans is one of the critical factors for its virulence. Therefore, it is necessary to understand how to regulate the expression of genes for C. albicans to change its morphology. One of the essential methods for us to understand this regulation is a ChIP assay. There have been many efforts to optimize the protocol to lower the background signal and to analyze the results accurately because a ChIP assay can provide very different results even with slight differences in the experimental procedure. We have optimized the rapid and efficient ChIP protocol so that it could be applied equally for both yeast and hyphal forms of C. albicans. Our method in this protocol is also comparatively rapid to the method widely used. In this protocol, we described our rapid method for the ChIP assay in C. albicans in detail.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease thought to be caused by repetitive traumatic brain injury (TBI) and subconcussive injuries. While hyperphosphorylation of tau (p-Tau), which is attributed to astrocytic tangles (ATs) and neurofibrillary tangles, is known to be involved in CTE, there are limited neuropathological or molecular data. By utilizing repetitive mild TBI (rmTBI) mouse models, our aim was to examine the pathological changes of CTE-associated structures, specifically the ATs.Our rmTBI mouse models showed symptoms of depressive behavior and memory deficit, alongside an increased p-Tau expression in their neurons and astrocytes in both the hippocampus and cortex. rmTBI induced oxidative stress in endothelial cells and nitric oxide (NO) generation in astrocytes, which were mediated by hypoxia and increased hypoxia-inducible factor 1-α (HIF1α). There was also correlated decreased regional cerebral tissue perfusion units, mild activation of astrocytes and NFκB phosphorylation, increased expression of inducible nitric oxide synthase (iNOS), increased endothelial nitric oxide synthase (eNOS) uncoupling with decreased tetrahydrobiopterin, and increased expression of nitrotyrosine, NADPH oxidase 2 (Nox2)/nuclear factor (erythroid-derived 2) factor 2 (Nrf2) signaling proteins. Combined, these effects induced peroxynitrite formation and hyperphosphorylation of tau in the hippocampus and cortex toward the formation of ATs.Our model features molecular pathogenesis events of CTE with clinically relevant latency periods. In particular, this is the first demonstration of an increased astrocytic iNOS expression in an in vivo model.We propose a novel mechanism of uncoupled eNOS and NO contribution to Tau phosphorylation and AT formation in rmTBI brain, toward an increased molecular understanding of the pathophysiology of human CTE.

Patient selection for critical care admission must balance patient safety with optimal resource allocation. This study aimed to determine the relationship between critical care admission, and postoperative mortality after abdominal surgery.This prespecified secondary analysis of a multicentre, prospective, observational study included consecutive patients enrolled in the DISCOVER study from UK and Republic of Ireland undergoing major gastrointestinal and liver surgery between October and December 2014. The primary outcome was 30-day mortality. Multivariate logistic regression was used to explore associations between critical care admission (planned and unplanned) and mortality, and inter-centre variation in critical care admission after emergency laparotomy.Of 4529 patients included, 37.8% (n=1713) underwent planned critical care admissions from theatre. Some 3.1% (n=86/2816) admitted to ward-level care subsequently underwent unplanned critical care admission. Overall 30-day mortality was 2.9% (n=133/4519), and the risk-adjusted association between 30-day mortality and critical care admission was higher in unplanned [odds ratio (OR): 8.65, 95% confidence interval (CI): 3.51-19.97) than planned admissions (OR: 2.32, 95% CI: 1.43-3.85). Some 26.7% of patients (n=1210/4529) underwent emergency laparotomies. After adjustment, 49.3% (95% CI: 46.8-51.9%, P0.001) were predicted to have planned critical care admissions, with 7% (n=10/145) of centres outside the 95% CI.After risk adjustment, no 30-day survival benefit was identified for either planned or unplanned postoperative admissions to critical care within this cohort. This likely represents appropriate admission of the highest-risk patients. Planned admissions in selected, intermediate-risk patients may present a strategy to mitigate the risk of unplanned admission. Substantial inter-centre variation exists in planned critical care admissions after emergency laparotomies.

PURPOSE/OBJECTIVE(S) To evaluate the performance and clinical acceptability of the highest objective performing 3D convolutional neural network models developed to contour regions of interest (ROIs) in medical images. MATERIALS/METHODS Radiation treatment planning data from 582 HNC patients treated at a large tertiary cancer center were used for this study. Eleven open-source 3D segmentation models (6 UNETs, 3 DenseNets, 1 3D pyramid abstraction network, and 1 3D recurrent slice-wise attention network), originally engineered for medical image segmentation, were trained to segment 19 OARs. The same 80/10/10 split was used for training, validating and testing corresponding to 479, 44 and 59 scans. A model's performance was ranked by volumetric Dice similarity coefficient (DSC) and Hausdorff distance (HD). The best performing model was selected and re-trained on full-resolution patient scans and validated using sliding-window inference. With the best model, two radiation oncologists assessed clinical acceptability, using 5-scale ratings of 5 for "anatomically perfect, not requiring editing" and score 1 for "anatomically incorrect, unusable for planning purpose." At least 10 cases were randomly selected and deep learning-based (DLCs) and manual contours (MCs), for the entire range of the OAR, were presented to the blinded observers. The mean ratings between DLC and MC were compared using Wilcoxon signed rank test and Student's T-test for the groups where significant differences between the groups represented the ability to distinguish between the MC and DLC contours by the observers. RESULTS A simple 3D Unet performed the best among the 11 models when comparing average DSC (0.75 ± 0.12) and HD (mean HD 0.44 ± 0.09) for every OAR. Mandible (0.90 ± 0.03), brainstem (0.89 ± 0.04), and spinal cord (0.85 ± 0.05) received the highest mean DSC, and chiasm (0.38 ± 0.19), optic nerves (0.65 ± 0.15), and lips (0.70 ± 0.09) the lowest mean DSC. Lens (0.052 ± 0.019), optic nerve (0.069 ± 0.026), and chiasm (0.075 ± 0.02) received the lowest mean HD, and spinal cord (1.15 ± 0.15), mandible (1.11 ± 0.18), and brachial plexus (0.90 ± 0.12) the highest mean HD. For clinical acceptability, MC received a significantly higher rating than DLC (3.75 ± 0.77 vs. 3.23 ± 0.86) when all OARs were considered (P < 0.01). When evaluating OARs individually, MC showed significantly higher ratings for brainstem, esophagus, larynx, eyes, optic nerves, while lips, whereas parotids, acoustics, and lenses were indistinguishable. CONCLUSION Simple 3D architectures consistently outcompete more complex networks by quantitative measures. Qualitative assessment for clinical acceptability may not agree with quantitative performance, especially when the entire range of OARs is evaluated.

Background There is no clear consensus on the recommended second-line treatment for patients with metastatic pancreatic cancer who have disease progression following gemcitabine-based therapy. We retrospectively evaluated the clinical outcomes of liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (FL) and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) in patients who had failed on the first-line gemcitabine-based therapy. Patients and methods From January 2015 to August 2019, 378 patients with MPC who had received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as second-line treatment across 11 institutions were included in this retrospective study. Results There were no significant differences in baseline characteristics between groups, except age and first-line regimens. With a median follow-up of 6 months, the median progression-free survival (PFS) was 3.7 months with nal-IRI/FL versus 4.6 months with FOLFIRINOX (P = 0.44). Median overall survival (OS) was 7.7 months with nal-IRI/FL versus 9.7 months with FOLFRINOX (P = 0.13). There was no significant difference in PFS and OS between the two regimens in the univariate and multivariate analyses. The subgroup analysis revealed that younger age (, Highlights • This multicenter retrospective study investigated nal-IRI/FL and FOLFIRINOX outcomes after gemcitabine-based therapy. • We found no significant differences in outcome between nal-IRI/FL and FOLFIRINOX treatment. • Both regimens were well tolerated; however, neutropenia and peripheral neuropathy were more frequent with FOLFIRINOX. • Age (cut-off, 70 years) showed differential efficacy between chemotherapy regimens.