Butyrate limits inflammatory macrophage niche in NASH.

Immune cell infiltrations with lobular inflammation in the background of steatosis and deregulated gut-liver axis are the cardinal features of non-alcoholic steatohepatitis (NASH). An array of gut microbiota-derived metabolites including short-chain fatty acids (SCFA) multifariously modulates NASH pathogenesis. However, the molecular basis for the favorable impact of sodium butyrate (NaBu), a gut microbiota-derived SCFA, on the immunometabolic homeostasis in NASH remains elusive. We show that NaBu imparts a robust anti-inflammatory effect in lipopolysaccharide (LPS) stimulated or classically activated M1 polarized macrophages and in the diet-induced murine NASH model. Moreover, it impedes monocyte-derived inflammatory macrophage recruitment in liver parenchyma and induces apoptosis of proinflammatory liver macrophages (LM) in NASH livers. Mechanistically, by histone deactylase (HDAC) inhibition NaBu enhanced acetylation of canonical NF-κB subunit p65 along with its differential recruitment to the proinflammatory gene promoters independent of its nuclear translocation. NaBu-treated macrophages thus exhibit transcriptomic signatures that corroborate with a M2-like prohealing phenotype. NaBu quelled LPS-mediated catabolism and phagocytosis of macrophages, exhibited a differential secretome which consequently resulted in skewing toward prohealing phenotype and induced death of proinflammatory macrophages to abrogate metaflammation in vitro and in vivo. Thus NaBu could be a potential therapeutic as well as preventive agent in mitigating NASH.

Theragnostic application of nanoparticle and CRISPR against food-borne multi-drug resistant pathogens.

Foodborne infection is one of the leading sources of infections spreading across the world. Foodborne pathogens are recognized as multidrug-resistant (MDR) pathogens posing a significant problem in the food industry and healthy consumers resulting in enhanced economic burden, and nosocomial infections. The continued search for enhanced microbial detection tools has piqued the interest of the CRISPR-Cas system and Nanoparticles. CRISPR-Cas system is present in the bacterial genome of some prokaryotes and is repurposed as a theragnostic tool against MDR pathogens. Nanoparticles and composites have also emerged as an efficient tool in theragnostic applications against MDR pathogens. The diagnostic limitations of the CRISPR-Cas system are believed to be overcome by a synergistic combination of the nanoparticles system and CRISPR-Cas using nanoparticles as vehicles. In this review, we have discussed the diagnostic application of CRISPR-Cas technologies along with their potential usage in applications like phage resistance, phage vaccination, strain typing, genome editing, and antimicrobial. we have also elucidated the antimicrobial and detection role of nanoparticles against foodborne MDR pathogens. Moreover, the novel combinatorial approach of CRISPR-Cas and nanoparticles for their synergistic effects in pathogen clearance and drug delivery vehicles has also been discussed.

Automatic segmentation of high-risk clinical target volume for tandem-and-ovoids brachytherapy patients using an asymmetric dual-path convolutional neural network.

PURPOSES: Preimplant diagnostic magnetic resonance imaging is the gold standard for image-guided tandem-and-ovoids (T&O) brachytherapy for cervical cancer. However, high dose rate brachytherapy planning is typically done on postimplant CT-based high-risk clinical target volume (HR-CTVCT ) because the transfer of preimplant Magnetic resonance (MR)-based HR-CTV (HR-CTVMR ) to the postimplant planning CT is difficult due to anatomical changes caused by applicator insertion, vaginal packing, and the filling status of the bladder and rectum. This study aims to train a dual-path convolutional neural network (CNN) for automatic segmentation of HR-CTVCT on postimplant planning CT with guidance from preimplant diagnostic MR. METHODS: Preimplant T2-weighted MR and postimplant CT images for 65 (48 for training, eight for validation, and nine for testing) patients were retrospectively solicited from our institutional database. MR was aligned to the corresponding CT using rigid registration. HR-CTVCT and HR-CTVMR were manually contoured on CT and MR by an experienced radiation oncologist. All images were then resampled to a spatial resolution of 0.5 × 0.5 × 1.25 mm. A dual-path 3D asymmetric CNN architecture with two encoding paths was built to extract CT and MR image features. The MR was masked by HR-CTVMR contour while the entire CT volume was included. The network put an asymmetric weighting of 18:6 for CT: MR. Voxel-based dice similarity coefficient (DSCV ), sensitivity, precision, and 95% Hausdorff distance (95-HD) were used to evaluate model performance. Cross-validation was performed to assess model stability. The study cohort was divided into a small tumor group (<20 cc), medium tumor group (20-40 cc), and large tumor group (>40 cc) based on the HR-CTVCT for model evaluation. Single-path CNN models were trained with the same parameters as those in dual-path models. RESULTS: For this patient cohort, the dual-path CNN model improved each of our objective findings, including DSCV , sensitivity, and precision, with an average improvement of 8%, 7%, and 12%, respectively. The 95-HD was improved by an average of 1.65 mm compared to the single-path model with only CT images as input. In addition, the area under the curve for different networks was 0.86 (dual-path with CT and MR) and 0.80 (single-path with CT), respectively. The dual-path CNN model with asymmetric weighting achieved the best performance with DSCV of 0.65 ± 0.03 (0.61-0.70), 0.79 ± 0.02 (0.74-0.85), and 0.75 ± 0.04 (0.68-0.79) for small, medium, and large group. 95-HD were 7.34 (5.35-10.45) mm, 5.48 (3.21-8.43) mm, and 6.21 (5.34-9.32) mm for the three size groups, respectively. CONCLUSIONS: An asymmetric CNN model with two encoding paths from preimplant MR (masked by HR-CTVMR ) and postimplant CT images was successfully developed for automatic segmentation of HR-CTVCT for T&O brachytherapy patients.

An ERP study of cross-modal rhyming: Influences of phonology and orthography.

In a cross-modal rhyming study with visual pseudoword primes and auditory word targets, we found a typical ERP rhyming effect such that nonrhyming targets elicited a larger N400/N450 than rhyming targets. An orthographic effect was also apparent in the same 350- to 600-ms epoch as the phonological effect: The rhyming effect for targets with rime orthography that did not match their primes' (e.g., tain-"sane") was smaller over the left hemisphere than the rhyming effect for targets with rime orthography that did match their primes' (e.g., nain-"gain"), although the spellings of the auditory word targets were never explicitly shown. Our results indicate that this cross-modal ERP rhyming effect indexes both phonological and orthographic processing-for auditory stimuli for which no orthography is presented in the task. This pattern of findings is consistent with the notion of coactivation of sublexical orthography and phonology in fluent adult readers as they both read and listen.

Three kinds of rhymes: An ERP study.

In a simple prime-target visual rhyming paradigm, pairs of words, nonwords, and single letters elicited similar event-related potential (ERP) rhyming effects in young adults. Within each condition, primes elicited contingent negative variation (CNV) while nonrhyming targets elicited more negative waveforms than rhyming targets within the 320-500ms (N400/N450) time window. The target rhyming effect, apparently primarily an index of phonological processing, was similar across conditions but tended to be smaller in mean amplitude for letters. One of the first reports of such a letter rhyming effect in the ERP literature, these findings could be important developmentally because letter rhyme tasks simultaneously index the two best predictors of ease of learning to read: letter name knowledge and phonological awareness.

Intraoral manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) radioprotective gene therapy decreases ionizing irradiation-induced murine mucosal cell cycling and apoptosis.

BACKGROUND: Single or multiple intraoral administrations of manganese superoxide dismutase-plasmid/liposomes (MnSOD-PL) to C3H/HeNHsd mice receiving single fraction or fractionated ionizing irradiation to the head and neck region have been shown to significantly decrease mucosal ulceration, weight loss and to improve survival. MATERIALS AND METHODS: To elucidate the mechanism of irradiation protection by MnSOD-PL and explore possible additive or synergistic protective effects with Amifostine (WR2721), mice received a single fraction of 19, 22.5, 25 or 30 Gy, or 24 fractions of 3 Gy irradiation to the oral cavity and oropharynx. Multiple parameters of irradiation-induced toxicity were quantitated in subgroups of each irradiated group of mice treated with single or multiple administrations of intraoral MnSOD-PL and/or intravenous WR2721. RESULTS: In 19 Gy single fraction irradiated mice, MnSOD-PL treatment the day before irradiation alone or in combination with intravenous WR2721 significantly decreased the irradiation induction of mucosal cell cycling as measured by 5-bromo-2-deoxyuridine (BuDR) uptake in oral cavity mucosal cells at 48 hours and decreased ulceration of the tongue at nine days after irradiation compared to control, irradiated or irradiated, WR2721-treated mice. Mice treated in single fractions of 22.5, 25 or 30 Gy showed MnSOD-PL protection against irradiation-induced oral mucosal apoptosis and xerostomia measured in decreased saliva output. In fractionated irradiated mice, twice weekly hemagglutinin (HA) epitope-tagged MnSOD uptake in oral cavity and tongue mucosal cells was not detectably altered by daily WR2721 intravenous administration. Mice treated with both radioprotective agents (MnSOD-PL and WR2721) demonstrated a significant decrease in irradiation-induced xerostomia (measured as reduced salivary gland output volume), mucosal ulceration and improved survival. CONCLUSION: Enhanced salivary gland function in WR2721-treated mice in the absence of detectable mucosal protection, coupled with relatively low uptake of HA-MnSOD in the salivary glands of intraorally-treated mice, suggests that a combination of both radioprotective agents may prove optimally effective for the prevention of the acute and late normal tissue toxicities of fractionated radiotherapy for head and neck cancer.

Masked priming and ERPs dissociate maturation of orthographic and semantic components of visual word recognition in children.

This study examined the time-course of reading single words in children and adults using masked repetition priming and the recording of event-related potentials. The N250 and N400 repetition priming effects were used to characterize form- and meaning-level processing, respectively. Children had larger amplitude N250 effects than adults for both shorter and longer duration primes. Children did not differ from adults on the N400 effect. The difference on the N250 suggests that automaticity for form processing is still maturing in children relative to adults, while the lack of differentiation on the N400 effect suggests that meaning processing is relatively mature by late childhood. The overall similarity in the children's repetition priming effects to adults' effects is in line with theories of reading acquisition, according to which children rapidly transition to an orthographic strategy for fast access to semantic information from print.

Imagining the truth and the moon: an electrophysiological study of abstract and concrete word processing.

Previous event-related potential studies have indicated that both a widespread N400 and an anterior N700 index differential processing of concrete and abstract words, but the nature of these components in relation to concreteness and imagery has been unclear. Here, we separated the effects of word concreteness and task demands on the N400 and N700 in a single word processing paradigm with a within-subjects, between-tasks design and carefully controlled word stimuli. The N400 was larger to concrete words than to abstract words, and larger in the visualization task condition than in the surface task condition, with no interaction. A marked anterior N700 was elicited only by concrete words in the visualization task condition, suggesting that this component indexes imagery. These findings are consistent with a revised or extended dual coding theory according to which concrete words benefit from greater activation in both verbal and imagistic systems.

Multimodality approach to management of stage III non-small cell lung cancer.

Stage III non-small cell lung cancer represents a heterogeneous group of patients who are best managed with a multidisciplinary approach, including evaluation for surgical, radiation, and chemotherapeutic options.

Behavioral and ERP evidence of word and pseudoword superiority effects in 7- and 11-year-olds.

In groups of 7-year-olds and 11-year-olds, event-related potentials (ERPs) were recorded to briefly presented, masked letter strings that included real word (DARK/PARK), pronounceable pseudoword (DARL/PARL), unpronounceable nonword (RDKA/RPKA), and letter-in-xs (DXXX, PXXX) stimuli in a variant of the Reicher-Wheeler paradigm. Behaviorally, participants decided which of two letters occurred at a given position in each string (here, forced-choice alternatives D and P). Both groups showed evidence of behavioral word (more accurate choices for letters in words than in baseline nonwords or letter-in-xs) and pseudoword (more accurate choices for letters in pseudowords than in baseline nonwords or letter-in-xs) superiority effects. Electrophysiologically, 11-year-olds evidenced superiority effects on P150 and N400 peak amplitude, while 7-year-olds showed effects only on N400 amplitude. These findings suggest that the mechanisms underlying the observed behavioral superiority effects may be lexical in younger children but both sublexical and lexical in older children. These results are consistent with a lengthy developmental time course for automatic sublexical orthographic specialization, extending beyond the age of 11.

Letters rhyme: electrophysiological evidence from children and adults.

Event-related potentials (ERPs) and behavioral accuracy judgments were recorded in a letter name rhyming paradigm (e.g., A-J versus A-B) with 6- to 8-year-old beginning readers and adults. A typical N450 rhyming effect was evident for both children and adults, with few differences in mean amplitude or peak latency between groups. The size and timing of the electrophysiological effect were not correlated with standardized measures of phonological or reading ability, but accuracy in the ERP task was. Single letters elicit a similar ERP rhyming effect in young children and adults, suggesting the early establishment of neurocognitive systems used in the rhyme task.

Word and pseudoword superiority effects reflected in the ERP waveform.

A variant of the Reicher-Wheeler task was used to determine when in the event-related potential (ERP) waveform indices of word and pseudoword superiority effects might be present, and whether ERP measures of superiority effects correlated with standardized behavioral measures of orthographic fluency and single word reading. ERPs were recorded to briefly presented, masked letter strings that included real words (DARK/PARK), pseudowords (DARL/PARL), nonwords (RDKA/RPKA), and letter-in-xs (DXXX, PXXX) stimuli. Participants decided which of two letters occurred at a given position in the string (here, forced-choice alternatives D and P). Behaviorally, both word (more accurate choices for letters in words than in baseline nonwords or letter-in-xs) and pseudoword (more accurate choices for letters in pseudowords than in baseline conditions) superiority effects were observed. Electrophysiologically, effects of orthographic regularity and familiarity were apparent as early as the P150 time window (100-160ms), an effect of lexicality was observed as early as the N200 time window (160-200ms), and peak amplitude of the N300 and N400 also differentiated word and pseudoword as compared to baseline stimuli. Further, the size of the P150 and N400 ERP word superiority effects was related to standardized behavioral measures of fluency and reading. Results suggest that orthographic fluency is reflected in both lower-level, sublexical, perceptual processing and higher-level, lexical processing in fluently reading adults.

Clinical evaluation of soft tissue organ boundary visualization on cone-beam computed tomographic imaging.

PURPOSE: Cone-beam computed tomographic images (CBCTs) are increasingly used for setup correction, soft tissue targeting, and image-guided adaptive radiotherapy. However, CBCT image quality is limited by low contrast and imaging artifacts. This analysis investigates the detectability of soft tissue boundaries in CBCT by performing a multiple-observer segmentation study. METHODS AND MATERIALS: In four prostate cancer patients prostate, bladder and rectum were repeatedly delineated by five observers on CBCTs and fan-beam CTs (FBCTs). A volumetric analysis of contouring variations was performed by calculating coefficients of variation (COV: standard deviation/average volume). The topographical distribution of contouring variations was analyzed using an average surface mesh-based method. RESULTS: Observer- and patient-averaged COVs for FBCT/CBCT were 0.09/0.19 for prostate, 0.05/0.08 for bladder, and 0.09/0.08 for rectum. Contouring variations on FBCT were significantly smaller than on CBCT for prostate (p < 0.03) and bladder (p < 0.04), but not for rectum (p < 0.37; intermodality differences). Intraobserver variations from repeated contouring of the same image set were not significant for either FBCT or CBCT (p < 0.05). Average standard deviations of individual observers' contour differences from average surface meshes on FBCT vs. CBCT were 1.5 vs. 2.1 mm for prostate, 0.7 vs. 1.4 mm for bladder, and 1.3 vs. 1.5 mm for rectum. The topographical distribution of contouring variations was similar for FBCT and CBCT. CONCLUSION: Contouring variations were larger on CBCT than FBCT, except for rectum. Given the well-documented uncertainty in soft tissue contouring in the pelvis, improvement of CBCT image quality and establishment of well-defined soft tissue identification rules are desirable for image-guided radiotherapy.

A masked priming ERP study of letter processing using single letters and false fonts.

Previous event-related potential (ERP) research on letter processing has suggested that a P150 reflects low-level, featural processing, whereas a P260 reflects high-level, abstract letter processing. In order to investigate the specificity of these effects, ERPs were recorded in a masked priming paradigm using matching and nonmatching pairs of letters (e.g., g-g, g-j) and false fonts (e.g.,[SYMBOL: SEE TEXT], [SYMBOL: SEE TEXT]). If the P150 priming effect indexes featural processing, there should be no effect of condition on the P150, since the letters and false fonts shared visual features. If the P260 priming effect indexes the processing of abstract letter representations, it should be evident only in the letter condition. As was expected, the P150 priming effect was similar for letters and false fonts; however, the P260 priming effect was also similar between conditions. Thus, the P260 priming effect may not be sensitive to abstract letter processing per se, or such processing may be extremely abstract.