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Among amniotic skin appendages, avian feathers and mammalian hairs protect their stem cells in specialized niches, located in the collar bulge and hair bulge, respectively. In chickens and alligators, label retaining cells (LRCs), which are putative stem cells, are distributed in the hinge regions of both avian scutate scales and reptilian overlapping scales. These LRCs take part in scale regeneration. However, it is unknown whether other types of scales, for example, symmetrically shaped reticulate scales, have a similar way of preserving their stem cells. In particular, the foot sole represents a special interface between animal feet and external environments, with heavy mechanical loading. This is different from scutate-scale-covered metatarsal feet that function as protection. Avian reticulate scales on foot soles display specialized characteristics in development. They do not have a placode stage and lack β-keratin expression. Here, we explore the molecular and cellular characteristics of avian reticulate scales. RNAscope analysis reveals different molecular profiles during surface and hinge determination compared with scutate scales. Furthermore, reticulate scales express Keratin 15 (K15) sporadically in both surface- and hinge-region basal layer cells, and LRCs are not localized. Upon wounding, the reticulate scale region undergoes repair but does not regenerate. Our results suggest that successful skin appendage regeneration requires localized stem cell niches to guide regeneration.

Staphylococcal scalded skin syndrome (SSSS) in premature infants is a rare condition. We present SSSS in a preterm infant, who developed all signs and symptoms of SSSS at birth, with a fatal outcome due to fungemia caused by Candida parapsilosis. The clinical presentation was challenging to differential diagnosis. SSSS diagnosis was

Esophagitis dissecans superficialis (EDS) is a rare but benign disease of the esophagus often identified endoscopically by sloughing of the superficial esophageal mucosa. We present an asymptomatic 66-year-old patient found to have EDS in the setting of Barrett's esophagus. The association of EDS with Barrett's esophagus has not been previously reported. He was initiated on proton pump inhibitor therapy with rapid and complete resolution of the endoscopic abnormality. This case illustrates the importance of identification of EDS as prognosis relies on prompt diagnosis and treatment.

Fraser's dolphins (

This study employs fMRI to examine the neural substrates of response to cognitive training in healthy old adults. Twenty Japanese healthy elders participated in a 4-week program and practiced a verbal articulation task on a daily basis. Functional connectivity analysis revealed that in comparison to age- and education-matched controls, elders who received the cognitive training demonstrated increased connectivity in the frontotemporal regions related with language and memory functions and showed significant correlations between the behavioral change in a linguistic task and connectivity in regions for goal-oriented persistence and lexical processing. The increased hippocampal connectivity was consistent with previous research showing efficacious memory improvement and change in hippocampal functioning. Moreover, the increased intra-network connectivity following cognitive training suggested an improved neural differentiation, in contrast to the inter-network activation pattern typical in the aging brain. This research not only validates the relationship of functional change in the frontal and temporal lobes to age-associated cognitive decline but also shows promise in turning neural change toward the right direction by cognitive training.

Fraser’s dolphins (Lagenodelphis hosei) possess great healing abilities. Their skin composition can be restored after wounding, including collagen spacing, orientation, and bundle thickness. However, it remains unclear how collagens are involved in the wound-healing process and eventually regain normality in Fraser’s dolphins. Learned from the other two scarless healing animals, changes in type III/I collagen composition are believed to modulate the wound healing process and influence the scarring or scarless fate determination in human fetal skin and spiny mouse skin. In the current study, Herovici’s, trichrome, and immunofluorescence staining were used on normal and wounded skin samples in Fraser’s dolphins. The results suggested that type I collagens were the main type of collagens in the normal skin of Fraser’s dolphins, while type III collagens were barely seen. During the wound healing process, type III collagens showed at early wound healing stages, and type I collagen increased in the mature healed wound. In an early healed wound, collagens were organized in a parallel manner, showing a transient hypertrophic-like scar, and eventually restored to normal collagen configuration and adipocyte distribution in the mature healed wound. The remarkable ability to remove excessive collagens merits further investigation to provide new insights into clinical wound management.

Cetaceans are tight-skinned mammals that exhibit an extraordinary capacity to heal deep soft tissue injuries. However, essential information of large full-thickness wound healing in cetaceans is still lacking. Here, the stages of full-thickness wound healing were characterized in Fraser’s dolphins (Lagenodelphis hosei). The skin samples were collected from normal skin and full-thickness cookiecutter shark (Isistius brasiliensis)-bite wounds of stranded carcasses. We defined five stages of wound healing according to macroscopic and histopathological examinations. Wounds in Stage 1 and 2 were characterized by intercellular and intracellular edema in the epidermal cells near the wound edge, mixed inflammatory cell infiltration, and degradation of collagen fibers. In Stage 3 wounds, melanocytes, melanin granules, rete and dermal ridges were noticed in the neo-epidermis, and the adipose tissue in adjacent blubber was replaced by cells and fibers. Wounds in Stage 4 and 5 were characterized by gradual restoration of the normal skin architecture including rete and dermal ridges, collagen bundles, and adipose tissue. These phenomena were quite different from previous studies in terrestrial tight-skinned mammals, and therefore, further in-depth research into the mechanisms of dolphin wound healing would be needed to gain new insights into veterinary and human regenerative medicine.

Cetaceans are tight-skinned mammals that exhibit an extraordinary capacity to heal deep soft tissue injuries. However, essential information of large full-thickness wound healing in cetaceans is still lacking. Here, the stages of full-thickness wound healing were characterized in Fraser's dolphins (

Wearable cuffless photoplethysmographic blood pressure monitors have garnered widespread attention in recent years; however, the long-term performance values of these devices are questionable. Most cuffless blood pressure monitors require initial baseline calibration and regular recalibrations with a cuffed blood pressure monitor to ensure accurate blood pressure estimation, and their estimation accuracy may vary over time if left uncalibrated. Therefore, this study assessed the accuracy and long-term performance of an upper-arm, cuffless photoplethysmographic blood pressure monitor according to the ISO 81060-2 standard. This device was based on a nonlinear machine-learning model architecture with a fine-tuning optimized method. The blood pressure measurement protocol followed a validation procedure according to the standard, with an additional four weekly blood pressure measurements over a 1-month period, to assess the long-term performance values of the upper-arm, cuffless photoplethysmographic blood pressure monitor. The results showed that the photoplethysmographic signals obtained from the upper arm had better qualities when compared with those measured from the wrist. When compared with the cuffed blood pressure monitor, the means ± standard deviations of the difference in BP at week 1 (baseline) were −1.36 ± 7.24 and −2.11 ± 5.71 mmHg for systolic and diastolic blood pressure, respectively, which met the first criterion of ≤5 ± ≤8.0 mmHg and met the second criterion of a systolic blood pressure ≤ 6.89 mmHg and a diastolic blood pressure ≤ 6.84 mmHg. The differences in the uncalibrated blood pressure values between the test and reference blood pressure monitors measured from week 2 to week 5 remained stable and met both criteria 1 and 2 of the ISO 81060-2 standard. The upper-arm, cuffless photoplethysmographic blood pressure monitor in this study generated high-quality photoplethysmographic signals with satisfactory accuracy at both initial calibration and 1-month follow-ups. This device could be a convenient and practical tool to continuously measure blood pressure over long periods of time.

Simple Summary Feeding restriction (FR) is essential to reduce excessive fat deposits caused by overfeeding in hens and to ensure their reasonable nutritional requirements for egg production. Effective FR is particularly crucial for raising hens in the late phase of laying; because hens require lower energy at this stage, overfeeding reduces their feed efficiency and increase feed costs. The gut microbiota is involved in various metabolic pathways of laying hens, including in late-phase age. Thus, changes in feeding interventions can alter the presence of gut microorganisms and the structure of the microbial community, resulting in altered metabolic regulation. In this study, we investigate the microbiota and metabolome responses of late-phase laying hens under FR. Our results provide data to access the profile of the cecal bacteria community, their relevance to cecal and serum metabolites, and their FR biosynthetic pathways related to host nutritional requirements and intestinal nutrient availability. Moreover, understanding the principles of host-microbial interaction is essential for developing cost-effective strategies to improve laying hens’ production. Abstract This study investigated cecal bacterial community profile, cecal and serum metabolites, and its biosynthesis pathway in late-phase laying hens during 6 weeks feeding restriction (FR), using 16S rDNA as gene sequencing and non-targeted LC-MS/MS as metabolomics approach. We used three groups (ad libitum, FR20, and FR40). FR can reduce excessive fat in late-phase laying hens, while egg production rate is not affected, except for the FR40 group. In phylum level, FR20 had more population of Bacteriodetes and Firmicutes amongst groups. The same result is at genus level, FR20 were higher of the predominant genus (Bacteroides and Rikenellaceae_RC9_gut_group). Both of FR20 and FR40 reduced Proteobacteria as potential pathogenic bacteria. Non-targeted metabolomic analysis revealed that FR20 modified 20 metabolites in cecal and 10 metabolites in serum of laying hens, whereas 48 cecal metabolites and 31 serum metabolites has revealed in FR40. KEGG assay showed FR20 and FR40 upregulated lipid, carbohydrate, amino acid, nucleic acid pathway, and FR40 modified steroid metabolism in cecal analysis. In serum, only FR40 modified lipid, amino acid pathway, and carbohydrate biosynthesis were shown. This study showed that FR during late-phase laying hens altered the microbiome composition, modified metabolites profile and biosynthesis of the cecal as well as serum.

Endoscopy with sedation is a common inpatient procedure. "NPO after midnight" remains the prevailing fasting practice despite ASA guidelines indicating specific fasting times. This quality improvement project aims to assess patient discomfort with the "NPO after midnight" order versus implementation of specific NPO times.Patients in the inpatient wards scheduled for endoscopy after 1 pm the following day were recruited. The gastroenterology services designated specific NPO times per ASA guidelines for the post-intervention group. Each participant completed a survey qualifying hunger, thirst, and discomfort levels. Pearson's chi-squared analysis was performed.NPO duration was reduced in the post-intervention group with significant improvement in thirst, hunger, and discomfort levels. A shortened preoperative fasting period did not lead to increase in procedural complications.Despite ASA guidelines, the practice of keeping patients NPO after midnight remains pervasive, resulting in unnecessarily prolonged fasting and patient discomfort. Implementing specific diet recommendations reduces duration of NPO and improves patient comfort and overall satisfaction.

This study aimed to investigate whether weekend admissions to psychiatric wards in Taiwan were associated with different patient characteristics or worse clinical outcomes.Patients with acute psychiatric admissions between 1996 and 2012 were included based on the National Health Insurance Research Database. The patients' baseline characteristics were recorded. The study outcomes included inpatient mortality, length of stay, and readmission within 30 days. Multivariable linear regression and multivariable logistic regression with adjustment for age, sex, diagnosis, and compulsory hospitalization status were performed.Among 661,709 acute psychiatric admissions, there were 82,450 weekend admissions. The patients with weekend admissions tended to be younger and the proportion of patients with schizophrenia, bipolar affective disorder, substance use disorder, and compulsory hospitalization were higher. Weekend admissions were associated with a shorter length of stay (30.3 days vs. 33.3 days, p 0.001), lower inpatient morality rate (0.07% vs. 0.11%, p = 0.007), but higher readmission rate (26.8% vs. 25.3%, p 0.001).The impact of weekend admission on clinical outcomes was relatively small compared to the differences in demographic and clinical characteristics. Despite the small influence of weekend admission, evaluation of the quality of care provided at weekends requires further attention and research to improve mental health care.

Low-temperature co-fired ceramics (LTCCs) have been attracting attention due to rapid advances in wireless telecommunications. Low-dielectric-constant (Dk) and low-dissipation-factor (Df) LTCCs enable a low propagation delay and high signal quality. However, the wide ranges of glass, ceramic filler compositions, and processing features in fabricating LTCC make property modulating difficult via experimental trial-and-error approaches. In this study, we explored Dk and Df values of LTCCs using a machine learning method with a Gaussian kernel ridge regression model. A principal component analysis and k-means methods were initially performed to visually analyze data clustering and to reduce the dimension complexity. Model assessments, by using a five-fold cross-validation, residual analysis, and randomized test, suggest that the proposed Dk and Df models had some predictive ability, that the model selection was appropriate, and that the fittings were not just numerical due to a rather small data set. A cross-plot analysis and property contour plot were performed for the purpose of exploring potential LTCCs for real applications with Dk and Df values less than 10 and 2 × 10−3, respectively, at an operating frequency of 1 GHz. The proposed machine learning models can potentially be utilized to accelerate the design of technology-related LTCC systems.

Purpose:To assess the predictive validity of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive scores at 6 months of corrected age (CA) for cognitive outcomes at 24 months of CA in very-low-birth-weight (VLBW) infants and investigate the predictors of change in cognitive outcomes.Methods:We retrospectively evaluated VLBW children enrolled in the Taiwan Premature Infant Follow-up Network between 2010 and 2015 and completed the Bayley-III at CA of 6 and 24 months. The predictive validity of the cognitive performance at 6-month CA for the cognitive outcomes at 24-month CA was analyzed. The positive and negative predictive factors were also evaluated using logistic regression. Cut-off scores of Results:A total of 2,972 VLBW children, born with a mean weight of 1116.4 ± 257.5 g and mean gestational age of 29.0 ± 2.8 weeks, were evaluated. A cognitive score of Conclusion:Subnormal Bayley-III cognitive scores at 6-month CA were not predictive of subnormal cognitive function at 24-month CA. In children with normal cognition during early infancy, abnormal muscle tone and lower maternal socioeconomic status may influence the cognitive developing process; this highlighted the importance of early identification of high risk infants and complete preterm infant-associated public health policies to promote an improved neurodevelopmental outcome.

Fraser’s dolphins (Lagenodelphis hosei) exhibit the capability to restore nearly normal pigmentation after full-thickness wounding. However, the association among melanocytes, melanin and skin pigmentation during wound healing in cetaceans has yet to be addressed. Here, the number of melanocytes and the distribution of melanocytes and melanin in different-colored skin and different wound-healing stages in Fraser’s dolphins were analyzed by using Fontana–Masson staining, immunofluorescence staining and immunohistochemical staining. It was noticed that there was the highest number of melanocytes in dark skin and the lowest number of melanocytes in white skin. The appearance of functional melanocytes and full-melanized neoepidermis was observed in the early stage of wound healing in Fraser’s dolphins. Furthermore, the melanocyte number and skin pigmentation and pattern in healed wounds recovered to a similar condition of unwounded skin. This study provides fundamental knowledge of skin repigmentation in cetaceans for further research, and it will be warranted to elucidate the mechanisms of the replenishment of melanocytes and the regulation of melanocyte activity that contribute to the successful repigmentation in cetacean skin wounds.

Simple Summary Photoperiods can affect sexual maturity, body weight, and body composition. In this work, we provided male mule ducks with a one-hour lighting from 20:00 to 21:00, in addition to the natural photoperiod, and evaluated its effects on their body weight, organ mass, gonadal function, and plasma levels of metabolites. The results indicate that the nocturnal lighting stimulated gonadal development and function and reduced fat deposition. This implies that nocturnal lighting is able to shorten the feeding period for the marketing of mature ducks. Abstract In this study, the effects of a nocturnal light pulse on body weight, organ mass, gonadal function, and plasma levels of metabolites were determined in male mule ducks. In total, 32 15-week-old mule ducks were randomly allocated to either Group C (control group) or L+ (lighting group). Group C was exposed to the natural photoperiod, whereas Group L+ was provided with a 1-h lighting over 20:00–21:00 every day, in addition to the natural photoperiod. At the end of the 42-day experiment, Group L+ had significantly lower relative weights (% of live weight) of the digestive tract and abdominal fat and higher relative weights of the breast meat and testes than Group C. Moreover, Group L+ had significantly higher plasma testosterone and lower plasma glucose levels. However, no between-group differences were observed in the triacylglycerol and uric acid levels. Histological examination demonstrated that the seminiferous tubule diameter was larger in Group L+ than in Group C. Moreover, the meiosis stage in spermatogenesis had begun in Group L+ but not in Group C. In conclusion, the supplemented 1-h lighting at 20:00 stimulated gonadal development and function and reduced fat deposition.

Objective Palladin is a ubiquitous phosphoprotein expressed in vertebrate cells that works as a scaffolding protein. Several isoforms deriving from alternative splicing are originated from the palladin gene and involved in mesenchymal and muscle cells formation, maturation, migration, and contraction. Recent studies have linked palladin to the invasive spread of cancer and myogenesis. However, since its discovery, the promoter region of the palladin gene has never been studied. The objective of this study was to predict, identify, and measure the activity of the promoter regions of palladin gene. Results By using promoter prediction programs, we successfully identified the transcription start sites for the Palld isoforms and revealed the presence of a variety of transcriptional regulatory elements including TATA box, GATA, MyoD, myogenin, MEF, Nkx2-5, and Tcf3 upstream promoter regions. The transcriptome profiling approach confirmed the active role of predicted transcription factors in the mouse genome. This study complements the missing piece in the characterization of palladin gene and certainly contributes to understanding the complexity and enrollment of palladin regulatory factors in gene transcription.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with an overall five-year survival rate of 11%. Potential curative resection is possible if the tumor is detected at an early stage, with a five-year survival rate of 42%. The only current FDA-cleared biomarker for PDAC is the carbohydrate antigen 19-9 (CA19-9), which is intended for monitoring response to therapy but not for early detection. CA19-9 blood tests have varying sensitivity to detect PDAC and are prone to false positives in the presence of other underlying pancreatic conditions and to false negatives in subpopulations unable to express CA19-9. The goal of our pilot study was to determine if a multiomics approach using cell-free DNA and CA19-9 would be better than CA19-9 alone in detecting PDAC. In this retrospective study of 75 participants, we performed targeted methylation profiling of circulating cell-free DNA and quantitation of plasma CA19-9 abundance. Participants with PDAC (n=39) were 51% male with a mean age of 74.9 years, and consisted of stage II (n=9), stage III (n=11) and stage IV (n=19) pancreatic cancer. Controls (n=36) were 33% male with a mean age of 74.2 years, and included both healthy control/normal pancreas (n=17) and various benign abnormalities of the pancreas or biliary system (n=19). We developed a novel machine learning model that combines CA19-9 and methylation signals to build a joint multiomics prediction. We compared the joint predictions to those based on methylation or CA19-9 alone. Five resamplings of three-fold cross-validation were performed, and sensitivity was calculated for decision thresholds that achieved the desired test set specificity. Across all stages, the multiomics approach achieved a sensitivity of 93% at a specificity of 96%, which was greater than methylation or CA19-9 alone. At 96% specificity, methylation alone achieved a sensitivity of 74% while CA19-9 alone achieved a sensitivity of 87%. In stages II, III and IV, the multiomics approach achieved a sensitivity of 82%, 89%, and 100%, respectively and was also more sensitive than either methylation or CA19-9 alone. These proof-of-concept data demonstrate the promise of using a multiomics approach to develop a highly sensitive and specific test for the early detection of pancreatic cancer. Additional studies are underway, focusing on early-stage disease (stage I/II), to validate these results. Citation Format: Teng-Kuei Hsu, Tzu-Yu Liu, Billie Gould, Christine Decapite, Amer Zureikat, Alessandro Paniccia, Eric Ariazi, Marvin Bertin, Richard Bourgon, Kaitlyn Coil, Hayley Donnella, Adam Drake, Julie M. Granka, Preet Kaur, Maggie C. Louie, Shivani Mahajan, Amit Pasupathy, Ofer Shapira, Peter Ulz, Chun Yang, C. Jimmy Lin, Randall Brand. Plasma-based detection of pancreatic cancer: A multiomics approach [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-007.

For this study, we designed learning activities in which students applied newly acquired knowledge to solve meaningful daily life problems in their local community – a real, familiar, and relevant environment for students. For example, students learned about signs and rules in class and then applied this new knowledge to create their own rules for a location in their community (e.g., playground rules that tell visitors what is or is not allowed to do in a local playground) to make it more environmentally friendly. To facilitate this, we developed a mobile learning system equipped with a dictionary as well as textual annotation, recording, and sharing functions. This mobile learning system enables students to take pictures of objects, describe them verbally or in writing, and share their work with peers. Our goal was to study the effectiveness of learning activities supported by a mobile learning system on the cognitive learning process by examining the changes in students’ cognitive processes and the distribution of students who reach a certain level of cognition before and after learning. Fifty-seven junior high school students participated in the research, and their views of the mobile learning system and interest in continuing use were also explored. Students were divided into one control $({{\mathrm{n}} = 26})$ group and one experimental $({{\mathrm{n}} = 31})$ group. The control group completed learning activities using a traditional approach while the experimental group used a learning system installed in tablet PCs. The effectiveness of the mobile PC system on students’ cognitive processes was tested by comparing the control and experimental groups’ pre-test and post-test outcomes. Changes in students’ cognitive processes were measured by calculating the differences in student scores among three tasks. The distribution of students who reached a certain level of cognition was derived based on their learning performance. Students’ perceptions were evaluated using a questionnaire survey. The mobile learning system kept records of how students used it. Our results show that the experimental students significantly outperformed the control students on test items related to high cognitive levels. Students made clear cognitive progress from the second topic to the third one. Most students rated the learning system highly and want to use it in the future. Finally, the results show that creating text annotations is the best indicator of learning. Based on these results, we recommend applying appropriate learning activities supported by a mobile learning system to facilitate students’ cognitive processes when they are studying English as a foreign language in an authentic environment.

Additional file 2: Table S2. Transcription start sites (TSS) prediction by Promoter 2.0 Prediction Server.

Background The present study aimed to develop a new scale to evaluate the level of difficulty in treating major depressive disorder with antidepressants based on the lifetime treatment profile. Methods In addition to evaluating the difficulty of treatment with antidepressants (A subscale), the Treatment Resistance to Antidepressants Evaluation Scale (TRADES) is comprised of a subscale to account for the attributes that compromise the efficacy of treatment (B subscale). One hundred and six participants aged 18 to 65 years with remitted major depressive disorder were enrolled. Eligible cases were those with at least 2 years from disease onset until the scoring date of the TRADES (the index date), with a complete treatment record. Various psychosocial and clinical features, such as neuroticism, harm avoidance, and utilization of psychiatric services, were used to validate the TRADES. Results The mean duration of the course before and after the index date were 5.5 ± 3.5 and 3.1 ± 1.7 years, respectively. In a multiple regression analysis, the final total scores of the TRADES independently correlated with higher levels of neuroticism and harm avoidance. Total scores were also associated with a higher utilization of psychiatric outpatient and admission services before the index date. Furthermore, it is thought that total scores could predict a higher number of visits to psychiatric outpatient, emergency, and admission services following the index date. Conclusions The TRADES has acceptable validity and could help to quantify the level of treatment difficulty with antidepressants in major depressive disorder.

Additional file 3: Figure S1. Transcription factors general expression.

Additional file 4: Figure S2. Expression of palladin isoforms and myogenic genes.

Additional file 1: Table S1. Oligonucleotides used for qPCR.

Emergency usage intention and behavior are crucial to business service success for m-Health providers and patient healthcare service. This study aimed to identify the factors that influence m-Health acceptance and the effect of emergency use intentions on usage behavior among Taiwanese m-Health users by adopting and extending the Unified Theory of Acceptance and Use of Technology (UTAUT). This study also examines the moderating role of gender and age in the effects of the independent variables on satisfaction with m-Health services. An online questionnaire was used to collect data from 371 participants. The results revealed that performance expectancy, facilitating conditions, and trust had positive effects on user satisfaction. Additionally, m-Health knowledge and user satisfaction had positive effects on emergency use intentions. However, social influence and effort expectancy did not have a significant effect on satisfaction. Moreover, age and gender significantly moderated the effects of some predictors.

For this study the researchers designed learning activities to enhance students’ high level cognitive processes. Students learned new information in a classroom setting and then applied and analyzed their new knowledge in familiar authentic contexts by taking pictures of objects found there, describing them, and sharing their homework with peers. An experiment was carried out in which 58 junior high school students were divided into a control (n = 30) and an experimental (n = 28) group. The control group studied and completed learning activities with traditional textbooks while the experimental group used electronic textbooks and a learning system, Virtual Pen for Tablet PC (VPenTPC), in order to gauge the feasibility of the proposed approach. The post-test results show a significant difference between the control and experimental groups. In our analysis of the various approaches students took to complete the task, we were able to identify thirty cognitive and metacognitive strategies for using mobile technology, from which we selected the ten most frequently used ones. The results show that low ability students make better use of strategies than their high ability peers, resulting in significant learning gains. The results also show that most students perceive VPenTPC positively. Based on these results, we suggest some implications along with conclusions and directions for future research.

Motivation: Ribosome profiling is a useful technique for studying translational dynamics and quantifying protein synthesis. Applications of this technique have shown that ribosomes are not uniformly distributed along mRNA transcripts. Understanding how each transcript-specific distribution arises is important for unraveling the translation mechanism. Results: Here, we apply kernel smoothing to construct predictive features and build a sparse model to predict the shape of ribosome footprint profiles from transcript sequences alone. Our results on Saccharomyces cerevisiae data show that the marginal ribosome densities can be predicted with high accuracy. The proposed novel method has a wide range of applications, including inferring isoform-specific ribosome footprints, designing transcripts with fast translation speeds and discovering unknown modulation during translation. Availability and implementation: A software package called riboShape is freely available at https://sourceforge.net/projects/riboshape Contact: yss@berkeley.edu

ObjectivesThe primary aim is to provide a summary of evidence for the diagnostic accuracies of multiplex PCR gastrointestinal (GI) panels—BioFire FilmArray and Luminex xTAG on the detection of gastroenteritis pathogens. The secondary aim is to compare the performance of these GI panels head to head.MethodsA comprehensive search up to 1 December 2019 was conducted on PubMed, Embase, Ovid Medline and Web of Science for studies that used FilmArray or Luminex xTAG Gastrointestinal Pathogen Panel (GPP) for diagnosis of acute gastroenteritis. A summary of diagnostic accuracies for the 16 pathogens were calculated by comparing the GI panels to the current gold standards (conventional standard microbiology techniques such as culture or PCR for bacteria, PCR or enzyme immunoassay (EIA) for viruses, microscopy or EIA for parasite). Hierarchical summary receiver operating characteristic (HSROC) curve analysis, pretest and post-test probabilities were used for estimating the pathogen detection performance.ResultsA total of 11 studies with 7085 stool samples were eligible for analysis. Multiplex PCRs demonstrated high diagnostic accuracy, with specificity ≧0.98 and area under the ROC curve (AUROC) ≧0.97 for all the pathogens except for Yersinia enterocolitica (AUROC 0.91). The FilmArray panel demonstrated a higher sensitivity than xTAG GPP for most of the pathogens with the exception of Rotavirus A (xTAG GPP and FilmArray were both 0.93).ConclusionsThis is the first meta-analysis that is a head-to-head comparison examining the performance of the novel multiplex PCR-based tests Luminex xTAG GPP and FilmArray GI panel in detecting each pathogen. Point estimates calculated from eligible studies showed that both GI panels are highly accurate and may provide important diagnostic information for early identification of gastroenteritis. In addition, although FilmArray has higher sensitivity and post-test probability than xTAG GPP for most of the pathogens, how this will translate to a clinical setting remains unclear.

43 Background: Blood-based screening tests for colorectal cancer (CRC) with high sensitivity and specificity are needed to improve adherence, facilitate early detection, and ultimately reduce mortality from CRC. Current stool-based tests have a sensitivity of 24-42% for colorectal advanced adenomas (AAs), while blood tests that rely on tumor-derived cell-free DNA (cfDNA) methylation signatures have shown limited sensitivity for AAs. Here we demonstrate the ability to detect AAs from blood using a multiomics test that incorporates both tumor- and immune-derived signatures, and compare it to the performance of a cfDNA methylation-only test. Methods: Participants enrolled in a prospective study (NCT03688906) were included in this analysis. The multiomics test includes signatures for cell-free nucleic acids based on next-generation sequencing, and for plasma proteins based on high-throughput multiplexed assays. Signatures are integrated computationally with a combination of convolutional neural networks and regularized logistic regression. We compared the multiomics test with one based on cfDNA methylation only. Results: This sub-study included 542 participants (AA: n = 122; colonoscopy-confirmed negative controls: n = 420). Participants with AA were 56% male with a mean age of 63 years, and colonoscopy-confirmed negative controls were 54% male with a mean age of 61 years. The multiomics test achieved a sensitivity of 41% (n = 50/122, 95% CI 34-48%) at 90% specificity (377/420). By contrast, the cfDNA methylation-only test achieved a sensitivity of 20% (24/122, 95% CI 15-25%) at 91% specificity (383/420). Performance was also analyzed by histological subtype and location, and superiority of the multiomics test to the cfDNA-methylation-only test was consistently observed. Conclusions: A novel multiomics blood test can detect colorectal AAs at a sensitivity and specificity comparable to existing stool-based tests. Combining signatures from both tumor- and immune-derived sources resulted in AA sensitivity greater than that of cfDNA-methylation alone.

Blood-based markers can be used to non-invasively predict cancer progression after treatment. Here, cell-free DNA (cfDNA) and plasma proteins were evaluated to explore biological signatures of progression in non-small cell lung cancer (NSCLC). Baseline plasma samples (n=24; 16 progressors, 8 non-progressors) were from patients diagnosed in 2004 with stage I-III NSCLC, collected prior to surgical resection, and retrospectively analyzed. Six patients were treated with neoadjuvant therapies, one with adjuvant therapy, and 17 with surgery alone. Progression was defined as a relapse event or death by any cause. Whole-genome sequencing was performed to characterize cfDNA fragments, which reflect nucleosome protection and chromatin state. Transcriptional activation for protein-coding genes was inferred by modeling fragment distribution around each transcription start site. Univariate comparisons of gene activation between progressors and non-progressors and Cox proportional hazard ratios (HRs) were calculated by grouping patients above or below the median of the marker of interest. This analysis revealed IL-1RN, the gene encoding for the IL-1RA antagonist to the IL-1 receptor complex, as the gene most negatively correlated with progression-free survival (PFS) (r = -0.76, p < 0.0001; Cox HR = 13.77, p < 0.001). This gene was also significantly more active in progressors than in non-progressors (p < 0.005). The binding activity of ~500 transcription factors was also inferred by measuring chromatin accessibility across the genome, revealing SOX-9 to be significantly associated with progression (p < 0.0001, FDR = 1.1%) and the factor most negatively correlated with PFS (r = -0.72, p < 0.001, FDR = 16.9%). Both IL-1RN and SOX-9 have been previously reported to affect survival in NSCLC patients.In addition, the abundances of ~450 proteins including cytokines, receptors, and enzymes were measured. Six proteins were identified as differentially abundant between progression groups. Among these, IL-1α was more abundant in progressors vs. non-progressors (effect size = 0.92, p < 0.05). Notably, IL-1RA abundance did not differ between these groups. Both IL-1α (r = -0.61, p < 0.01; Cox HR = 3.78, p < 0.05) and IL-1RA (r = -0.75, p < 0.001; Cox HR = 1.13, p = 0.78) were negatively correlated with PFS in progressors. Finally, all features and analytes were integrated to identify biological signatures that may be shared among proteins and cfDNA. These signatures differed significantly (p < 0.05) between progressors and non-progressors, suggesting differences in cytokine signaling. The multiomics platform described here integrates biological signals with computational featurization to reveal clinically relevant signatures. Specifically, findings from a small cohort of early-stage NSCLC patients demonstrated the potential of this platform to reveal signatures of progression in NSCLC. Citation Format: Francesco Vallania, Hayley Warsinske, Peter Ulz, Tzu-Yu Liu, Karen Assayag, Krishnan K. Palaniappan, Mitch Bailey, Irving Wang, David E. Weinberg, Riley Ennis, C Jimmy Lin, Anne-Marie Martin, Nancy Krunic. Multiomic plasma profiling identifies potential signatures of disease progression in early-stage NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2433.

BackgroundBlood-based methods using cell-free DNA (cfDNA) are under development as an alternative to existing screening tests. However, early-stage detection of cancer using tumor-derived cfDNA has proven challenging because of the small proportion of cfDNA derived from tumor tissue in early-stage disease. A machine learning approach to discover signatures in cfDNA, potentially reflective of both tumor and non-tumor contributions, may represent a promising direction for the early detection of cancer.MethodsWhole-genome sequencing was performed on cfDNA extracted from plasma samples (N=546 colorectal cancer and 271 non-cancer controls). Reads aligning to protein-coding gene bodies were extracted, and read counts were normalized. cfDNA tumor fraction was estimated using IchorCNA. Machine learning models were trained using k-fold cross-validation and confounder-based cross-validation to assess generalization performance.ResultsIn a colorectal cancer cohort heavily weighted towards early-stage cancer (80% stage I/II), we achieved a mean AUC of 0.92 (95% CI 0.91-0.93) with a mean sensitivity of 85% (95% CI 83-86%) at 85% specificity. Sensitivity generally increased with tumor stage and increasing tumor fraction. Stratification by age, sequencing batch, and institution demonstrated the impact of these confounders and provided a more accurate assessment of generalization performance.ConclusionsA machine learning approach using cfDNA achieved high sensitivity and specificity in a large, predominantly early-stage, colorectal cancer cohort. The possibility of systematic technical and institution-specific biases warrants similar confounder analyses in other studies. Prospective validation of this machine learning method and evaluation of a multi-analyte approach are underway.

Figure S1. Performance of confounding variable in k-fold and target CV procedure (ROC curves) for: a) Age and binned-age CV b) Batch and k-batch CV c) Processing date and ordered k-batch CV d) Institution and balanced k-batch CV. Note that stratification CVs (i.e., binned-age, k-batch, and ordered k-batch) perform at chance (mean AUC of 0.50) when the distribution of labels in the test covariate is even and would result in an ROC that is just a diagonal line. The variance seen in some of the target procedures is due to class imbalance in the test data. (DOCX 420 kb)

Figure S2. Percentage of colorectal cancer samples by stage and non-cancer controls in each range of estimated TF (based on observed CNV using an IchorCNA-based estimate). (DOCX 74 kb)

Figure S3. IchorCNA-based estimated TF alone to predict case status (i.e., cancer or control) achieved an AUC of 0.67 in the IU age range, meaningfully lower than results from the ML model under any analyzed CV procedure. (DOCX 101 kb)

Figure S4. Non-linear relationship between the total number of samples used for training and sensitivity at 85% specificity for colorectal cancer detection. The method was trained again with k-fold, except the number of training samples per fold was downsampled. The lower numbers are comparable to those available for balanced k-batch and were used to investigate decreased classifier performance due to smaller sample sizes in training. (DOCX 60 kb)

Conjugation of multiple peptides by their N-termini is a promising technique to produce branched multiantigenic vaccines. We established a double conjugation strategy that combines a mercapto-acryloyl Michael addition and a copper-catalysed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction to synthesise self-adjuvanting branched multiantigenic vaccine candidates. These vaccine candidates aim to treat cervical cancer and include two HPV-16 derived epitopes and a novel self-adjuvanting moiety. This is the first report of mercapto-acryloyl conjugation applied to the hetero conjugation of two unprotected peptides by their N-termini followed by a CuAAC reaction to conjugate a novel synthetic lipoalkyne self-adjuvanting moiety. In vivo experiments showed that the most promising vaccine candidate completely eradicated tumours in 46% of the mice (6 out of 13 mice).

Human papillomaviruses (HPVs) are associated with various cancers, with HPV16 linked to more than half of cervical cancer cases. Vaccines to prevent HPV infection and cancer development have proven effective, but are not useful in individuals with prior HPV exposure. Treatment vaccines to eradicate or control HPV-associated lesions are therefore desirable for these patients. Herein we describe the development of a process to enable the production of semisynthetic vaccines based on the site-specific attachment of synthetic bacterial lipid analogs (e.g., Pam2Cys) to a non-oncogenic mutant HPV16 E7 protein to generate molecularly defined vaccines. Many cytotoxic lymphocyte (CTL) epitopes from E7 are delivered by this approach; potentially ensuring that large numbers of immunized individuals can generate CTLs to clear HPV infected cells. Delivery of this construct reduced the growth of HPV16-associated tumors in a TC1 mouse model, the effects of which were better than the potent CTL epitope HPV16 E7(44-57) administered with Montanide ISA51 adjuvant.

Glyoxalase 1 (GLO1) and HMG-CoA reductase (HMGCR) are highly expressed in most tumor cells and little in normal cells. In this study, treatment of HL-60 cells with lovastatin induced characteristic apoptosis in a dose-dependent manner. We demonstrated that lovastatin treatment inhibited Ras and Raf protein translocation to cell membrane and eliminated the phosphorylation of the downstream effectors Akt and ERK, and the subsequent NF-κB translocation into nucleus. Specific inhibitors and γ-tocotrienol confirmed the Ras/Raf/ERK/NF-κB/GLO1 and Ras/Akt/NF-κB/GLO1 pathways. Data revealed that lovastatin induced HL-60 cell death was attenuated by mevalonate treatment. We demonstrated also that γ-tocotrienol showed its apoptotic effect on the HL-60 cell through the same pathway. γ-Tocotrienol enhanced the apoptotic effect of lovastatin through the down-regulation of GLO1 and HMGCR resulting in an increase of methylglyoxal and a decrease of cholesterol and led to the apoptosis of HL-60 cells. Data also revealed that both lovastatin and gamma-tocotrienol induced significant HL-60 cell differentiation. These results suggest that both lovastatin and gamma-tocotrienol could induce differentiation and followed by apoptosis.

We designed learning activity in which language learning was combined with physical exercise. Our participants applied new knowledge to solve real life problems in their local community. Walking around the community during the learning activity enabled participants to be physically active. We provided students with smart watches to support their learning and monitor physical activities. We aimed to explore (1) whether our learning activity supported by smart watches can be useful for learning, make it healthy, and bring positive emotions to students.

International audience; Modern developments in light microscopy have allowed the observation of cell deformation with remarkable spatiotemporal resolution and reproducibility. Analyzing such phenomena is of particular interest for the signal processing and computer vision communities due to the numerous computational challenges involved, from image acquisition all the way to shape analysis and pattern recognition and interpretation. This article aims at providing an up-to-date overview of the problems, solutions, and remaining challenges in deciphering the morphology of living cells via computerized approaches, with a particular focus on shape description frameworks and their exploitation using machine-learning techniques. As a concrete illustration, we use our recently acquired data on amoeboid cell deformation, motivated by its direct implication in immune responses, bacterial invasion, and cancer metastasis.