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IntroductionAbout half of all adolescents with major depressive disorder (MDD) have frequent suicidal thoughts and of those with suicidal ideations, about one-third attempt suicide. Identifying clinical characteristics associated with suicidal ideation and attempts is important for suicide prevention and clinical care.MethodsParticipants were four groups of adolescents diagnosed with MDD (n = 246, 180 females): (a) non-suicidal youths (n = 76), (b) ideators (n = 102; current suicidal ideation), (c) ideator-attempters (n = 56; current suicidal ideation and lifetime history of suicide attempt), and (d) lifetime attempters (n = 12; no current suicidal ideation but lifetime history of suicide attempt). Adolescents underwent clinical interviews and completed questionnaires assessing sociodemographic and clinical variables. Multivariate analyses of variance, logistic regression models, mediation and moderation analyses were run to assess which variables were associated with group membership.ResultsSuicidal ideators, irrespective of whether they had attempted suicide previously, had higher depression severity, higher anxiety and lower resilience compared to non-ideators. Hopelessness was associated with greater odds of being a suicidal ideator (p

Abstract Background In the era of targeted therapies, the influence of aging on cancer management varies from one patient to another. Assessing individual frailty using geriatric tools has its limitations, and is not appropriate for all patients especially the youngest one. Thus, assessing the complementary value of a potential biomarker of individual aging is a promising field of investigation. The chronic myeloid leukemia model allows us to address this question with obvious advantages: longest experience in the use of tyrosine kinase inhibitors, standardization of therapeutic management and response with minimal residual disease and no effect on age-related diseases. Therefore, the aim of the BIO-TIMER study is to assess the biological age of chronic myeloid leukemia or non-malignant cells in patients treated with tyrosine kinase inhibitors and to determine its relevance, in association or not with individual frailty to optimize the personalised management of each patient. Methods The BIO-TIMER study is a multi-center, prospective, longitudinal study aiming to evaluate the value of combining biological age determination by DNA methylation profile with individual frailty assessment to personalize the management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Blood samples will be collected at diagnosis, 3 months and 12 months after treatment initiation. Individual frailty and quality of life will be assess at diagnosis, 6 months after treatment initiation, and then annually for 3 years. Tolerance to tyrosine kinase inhibitors will also be assessed during the 3-year follow-up. The study plans to recruit 321 patients and recruitment started in November 2023. Discussion The assessment of individual frailty should make it possible to personalize the treatment and care of patients. The BIO-TIMER study will provide new data on the role of aging in the management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors, which could influence clinical decision-making. Trial registration ClinicalTrials.gov , ID NCT06130787; registered on November 14, 2023.

Lameness is an important health and welfare issue that causes considerable economic losses in dairy herds. The objective of this study was to investigate whether the hind feet position score (HFPS) can be used as an auxiliary trait for genetic evaluation of lameness. The HFPS is evaluated by visual scoring of the position of both the hind-digits to the mid-line of the cow's body. The higher the heel height of the lateral claw, the higher is the HFPS, and the higher is the risk for development of lameness. In total, 3,478 records from 1,064 Fleckvieh cows from 35 farms were obtained between September 1, 2021, and March 5, 2022. Data collection was carried out by the regional milk recording organizations. Hind feet position was scored visually by trained personnel during routine milk performance testing in the milking parlor using a 3-class scoring system: score 1 = 0° to 24°. After all cows had been milked, locomotion scoring was performed for each animal using a 5-class scoring system with locomotion scores ranging between 1 (normal) and 5 (severely lame). Using HFPS, sensitivity and specificity were 69.5% and 66.8%, respectively, for detecting lameness defined by locomotion score ≥2. For genetic analyses, a bivariate linear animal model was fitted with fixed effects of herd, parity, lactation stage, and classifier, and random effects of animal and permanent environment. Heritabilities for HFPS and locomotion score were 0.07 and 0.10, respectively, and the genetic correlation between the 2 traits studied was 0.80. These results suggest that the HFPS could be used for genetic evaluations to reduce lameness incidence in dairy cattle.

In chronic myeloid leukemia, the identification of early molecular predictors of stable treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation is challenging. The predictive values of residual disease (BCR::ABL1 quantification) at months 3 and 6 and more recently, BCR::ABL1 transcript halving time (HT) have been described, but no study compared the predictive value of different early parameters. Using a real-world cohort of 408 patients, we compared the performance of the ELTS score, BCR::ABL1 HT, and residual disease at month 3 and 6 to predict the molecular response, achievement of the TKI discontinuation criteria, and TFR maintenance. The performances of BCR::ABL1 HT and residual disease at month 3 were similar. Residual disease at month 6 displayed the best performance for predicting the optimal response (area under the ROC curve between 0.81 and 0.92; cut-off values: 0.11% for MR4 at month 24 and 0.12% for MR4.5 at month 48). Conversely, no early parameter predicted reaching the TKI discontinuation criteria and TFR maintenance. We obtained similar results when patients were divided in subgroups by first-line treatment (imatinib vs second generation TKI, 2G-TKI). We identified a relationship between ELTS score, earlier milestones and TFR maintenance only in the 2G-TKI group. In conclusion, this first comparative study of early therapeutic response parameters showed that they are excellent indicators of TKI efficacy (BCR::ABL1 transcript reduction) and best responders. Conversely, they did not predict the achievement of the TKI discontinuation criteria and TFR maintenance, suggesting that other parameters are involved in TFR maintenance.

The objective of this study was to assess the clinical impact and financial costs of next-generation sequencing (NGS) in 5 categories of pediatric and adult hematological cancers. NGS prescriptions were prospectively collected from 26 laboratories, with varied technical and reporting practice (all or only significant targets). Impact was defined by the identification of (1) an actionable mutation, (2) a mutation with prognostic and/or theranostic value, and/or (3) a mutation allowing nosological refinement, reported by local investigators. A microcosting study was undertaken in 4 laboratories, identifying the types and volumes of resources required for each procedural step. Individual index prescriptions for 3961 patients were available for impact analysis on the management of myeloid disorders (two thirds) and, mainly mature B, lymphoid disorders (one third). NGS results were considered to impact the management for 73.4% of prescriptions: useful for evaluation of prognostic risk in 34.9% and necessary for treatment adaptation (actionable) in 19.6%, but having no immediate individual therapeutic impact in 18.9%. The average overall cost per sample was 191 € for the restricted mature lymphoid amplicon panel. Capture panel costs varied from 369 € to 513 €. Unit costs varied from 0.5 € to 5.7 € per kb sequenced, from 3.6 € to 11.3 € per target gene/hot-spot sequenced and from 4.3 € to 73.8 € per target gene/hot-spot reported. Comparable costs for the Amplicon panels were 5–8 € per kb and 10.5–14.7 € per target gene/hot-spot sequenced and reported, demonstrating comparable costs with greater informativity/flexibility for capture strategies. Sustainable funding of precision medicine requires a transparent discussion of its impact on care pathways and its financial aspects.

Following the idea of a circular bioeconomy, the use of side streams as substitutes for cultivation media (components) in bioprocesses would mean an enormous economic and ecological advantage. Costly compounds in conventional media for the production of the triterpene squalene in thraustochytrids are the main carbon source and complex nitrogen sources. Among other side streams examined, extracts from the spent mycelium of the basidiomycete Pleurotus ostreatus were best-suited to acting as alternative nitrogen sources in cultivation media for thraustochytrids. The total nitrogen (3.76 ± 0.01 and 4.24 ± 0.04%, respectively) and protein (16.47 ± 0.06 and 18.57 ± 0.18%, respectively) contents of the fruiting body and mycelium were determined. The fungal cells were hydrolyzed and extracted to generate accessible nitrogen sources. Under preferred conditions, the extracts from the fruiting body and mycelium contained 73.63 ± 1.19 and 89.93 ± 7.54 mM of free amino groups, respectively. Cultivations of Schizochytrium sp. S31 on a medium using a mycelium extract as a complex nitrogen source showed decelerated growth but a similar squalene yield (123.79 ± 14.11 mg/L after 216 h) compared to a conventional medium (111.29 ± 19.96 mg/L, although improvable by additional complex nitrogen source).

Background: Common scabies can be difficult to diagnose and treat. There are limited data on the clinical characteristics of patients who may benefit from combined topical permethrin plus oral ivermectin. Postscabetic itch is common, but there is scant data describing its prognosis and management. Objective: This study describes the clinical characteristics and evaluates treatment outcomes of participants with common scabies treated with combined topical permethrin plus oral ivermectin and describes the prognosis and management of postscabetic itch. Methods: We conducted a single-center retrospective cohort study of participants with common scabies treated with combined topical permethrin plus oral ivermectin therapy and topical permethrin only. Participants previously treated with permethrin and/or ivermectin were excluded. The primary outcome was clinical outcome at follow-up, categorized as cure, worsening, or no change. Secondary outcomes included time from treatment initiation to cure, duration of follow-up after cure, recurrence rate, frequency of postscabetic itch, and duration of postscabetic itch. Results: Of 55 participants treated with combined topical permethrin plus oral ivermectin, 49 (89%) achieved cure, 5 (9%) had no change, and 1 (2%) had worsening disease. Of 48 participants treated with topical permethrin only, 46 (96%) achieved cure, 2 (4%) had no change, and 0 (0%) had worsening disease. Thirty-five participants (34%) experienced postscabetic itch for 52.5 days (interquartile range, 28–135). More participants in the older (mean: 55 years; standard deviation: 21 years; p = .002) combined treatment group experienced postscabetic itch than in the younger (mean: 42 years; standard deviation: 19 years) permethrin-only treatment group (42% vs. 25%; p = .072). Conclusion: These findings support the use of combined topical permethrin plus oral ivermectin therapy in treating common scabies, highlight that postscabetic itch can persist for longer than previously reported, and reveal a potential relationship between older age and postscabetic itch.

Abstract Accumulation in target cells is an essential pharmacokinetic step of targeted therapies. Tyrosine Kinase Inhibitors (TKI) against the BCR-ABL fusion protein in Chronic Phase-Chronic Myeloid Leukaemia (CP-CML) cells constitute a unique model in terms of efficacy, specificity, and in vivo demonstration of response heterogeneity by target cells. The overall therapeutic response to nilotinib is heterogeneous with no satisfactory explanation. To better understand the patients’ response heterogeneity, we quantified nilotinib uptake by primary CP-CML cells in standardized conditions using flow cytometry, which allowed also distinguishing mature (polymorphonuclear cells) from immature (CD34+) cells. Nilotinib was undetectable in 13.3% of PMN and 40% of CD34+ cells. Moreover, in CD34+ cells, intracellular nilotinib did not completely abolish BCR-ABL activity (monitored by CrkL phosphorylation inhibition), although nilotinib accumulated well in most CD34+ cell samples. Intracellular nilotinib concentration was inversely correlated with disease burden parameters, Sokal score, and early haematologic response at day 6 ± 1 only in PMN, suggesting an intrinsic ability to limit nilotinib entry in the forms with higher tumor cell burdenat diagnosis. These findings suggest that nilotinib accumulation in CP-CML cells is influenced by individual characteristics and intra-clonal heterogeneity, and might be used for pharmacokinetic studies and to assess the therapeutic response.

Three phenolic acids, p-coumaric, ferulic and caffeic acid as well as cinnamic acid were added to raw potatoes and sweet potatoes before frying. A distinct mitigation of acrylamide was not detected. Fried samples were analysed for postulated adducts of a direct reaction between acrylamide and these phenolic acids using LC-MS. In a model system with pure compounds (phenylacrylic acid and acrylamide) heated on 10% hydrated silica gel one specific adduct (respective m/z for M ​+ ​H+) was formed in each reaction. MS/MS-data suggested an oxa-Michael formation of 3-amino-3-oxopropyl-phenylacrylates, which was confirmed by de novo syntheses along an SN2 substitution of 3-chloropropanamide. Exemplarily, the structure of the ester was confirmed for p-coumaric acid by NMR-data. Standard addition revealed that 3-amino-(3-oxopropyl-phenyl)-acrylates occurred neither in fried potato nor in sweet potato, while a formation was shown in phenylacrylic acid plus acrylamide supplemented potatoes and sweet potatoes.

Abstract Background COPD exacerbations have negative impact on patients’ survival. Several risk factors for grave outcomes of such exacerbations have been descried. Muscle dysfunction and mass loss were shown to impact negatively on prognosis and survival. Low activity of the enzyme ALT (Alanine amino-transferase) in the blood is a known indicator for sarcopenia and frailty, however, no previous studies addressed the association of low ALT amongst patients hospitalized due to COPD exacerbation and long-term survival. Methods This is a historic prospective cohort study of patients hospitalized due to acute COPD exacerbation. Results Included were 232 consecutive COPD exacerbation patients. The median time of follow-up was 34.9 months (IQR 23.13–41.73 months). During this period 104 (44.8%) patients died. All patients were grouped to quartiles according to blood ALT levels (after exclusion of cases considered to have hepatic tissue damage (ALT > 40 IU)). The risk of long-term mortality increased, in a statistically significant manner, amongst patients with low ALT values: the median survival of patients with ALT 21 IU the mortality rates were 69%; 40.9%; 36.3 and 25% respectively (p

Abstract Background In patients with permanent pacemakers (PPM), physical activity (PA) can be monitored using embedded accelerometers to measure pacemaker detected active hours (PDAH), a strong predictor of mortality. We examined the impact of a PA Counseling (PAC) intervention on increasing activity as measured by PDAH and daily step counts. Methods Thirteen patients (average age 80 ± 6 years, 84.6% women) with implanted Medtronic PPMs with a ≤ 2 PDAH daily average were included in this study. Patients were randomized to Usual Care (UC, N = 6) or a Physical Activity Counseling Intervention (PACI, N = 7) groups. Step count and PDAH data were obtained at baseline, following a 12-week intervention, then 12 weeks after intervention completion. Data were analyzed using independent t-tests, Pearson’s r, chi-square, and general linear models for repeated measures. Results PDAH significantly differed by time point for all subject combined (P = 0.01) but not by study group. Subjects with baseline gait speeds of > 0.8 m/sec were responsible for the increases in PDAH observed. Step counts did not differ over time in the entire cohort or by study group. Step count and PDAH significantly correlated at baseline (r = 0.60, P = 0.03). This correlation disappeared by week 12. Conclusion(s) PDAH can be used to monitor PA and PA interventions and may be superior to hip-worn pedometers in detecting activity. A significant increase in PA, regardless of treatment group, suggests that patient awareness of the ability to monitor PA through a PPM increases PA in these patients, particularly in patients with gait speeds of

Discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia is feasible in clinical practice based on recently published international recommendations. Nevertheless, factors predictive of molecular recurrence have not been fully elucidated and long-term follow-up of patients enrolled in clinical studies are required in order to update knowledge on discontinuation attempts particularly in terms of the safety and durability of treatment-free remission (TFR). In the current study, we updated results from the STIM2 study in the light of the consensual criterion of molecular recurrence reported in different international recommendations. Among the 199 patients included in the perprotocol study, 108 patients lost a major molecular response. With a median follow-up of 40.8 months (5.5-111 months), the probability of treatment-free remission was 43.4% [36.3-50.4] at 5 years, 40.9% [32.8-47.3] at 7 years and 34.5% [25.6- 43.3] at 9 years. Molecular recurrence occurred between 0 to 6 months, 6 to 24 months and after 24 months in 75 patients (69%), 15 patients (14%) and 18 patients (17%), respectively. Notably, the kinetics of molecular recurrence differed significantly between these three subgroups with a median time from loss of MR4 (BCR::ABL1 IS≤0.01%) to loss of major molecular response of 1, 7 and 22 months, respectively. Predictive factors of molecular recurrence differed according to the time of occurrence of the molecular recurrence. Durations of imatinib treatment and deep molecular response as well as BCR::ABL1/ABL1 levels at cessation of tyrosine kinase inhibitor treatment, as quantified by reverse transcriptase droplet digital polymerase chain reaction, are involved in molecular recurrence occurring up to 24 months but not beyond. (ClinicalTrial. gov Identifier NCT#0134373).

The quality and harvest of essential oils depend on a large number of factors, most of which are hard to control in an open-field environment. Therefore, Basidiomycota have gained attention as a source for biotechnologically produced terpenoids. The basidiomycete Cerrena unicolor (Cun) was cultivated in submerged culture, and the production of sesquiterpenoids was analyzed via stir bar sorptive extraction (SBSE), followed by thermo-desorption gas chromatography coupled with mass spectrometry (TDS-GC-MS). Identification of aroma-active sesquiterpenoids was supported by GC, coupled with an olfactory detection port (ODP). Following the ideal of a circular bioeconomy, Cun was submerged (up-scalable) cultivated, and supplemented with a variety of food industrial side-streams. The effects of the different supplementations and of pure fatty acids were evaluated by liquid extraction and analysis of the terpenoids via GC-MS. As sesquiterpenoid production was enhanced by the most by lipid-rich side-streams, a cultivation with 13C-labeled acetate was conducted. Data confirmed that lipid-rich side-streams enhanced the sesquiterpene production through an increased acetyl-CoA pool.

Differences between seven authentic samples of Citrus sinensis var. Valencia peel (albedo and flavedo) and juices from Spain and Uruguay, in addition to a concentrate obtained from Brazil, were investigated by untargeted metabolic profiling. Sixty-six metabolites were detected by nano-liquid chromatography coupled to a high-resolution electrospray-ionization quadrupole time-of-flight mass spectrometer (nLC-ESI-qTOF-MS) belonging to phenolic acids, coumarins, flavonoid glycosides, limonoids, terpenes, and fatty acids. Eleven metabolites were detected for the first time in Citrus sinensis and identified as citroside A, sinapic acid pentoside, apigenin-C-hexosyl-O-pentoside, chrysoeriol-C-hexoside, di-hexosyl-diosmetin, perilloside A, gingerol, ionone epoxide hydroxy-sphingenine, xanthomicrol, and coumaryl alcohol-O-hexoside. Some flavonoids were completely absent from the juice, while present most prominently in the Citrus peel, conveying more industrial and economic prospects to the latter. Multivariate data analyses clarified that the differences among orange parts overweighed the geographical source. PCA analysis of ESI-(−)-mode data revealed for hydroxylinoleic acid abundance in flavedo peel from Uruguay the most distant cluster from all others. The PCA analysis of ESI-(+)-mode data provided a clear segregation of the different Citrus sinensis parts primarily due to the large diversity of flavonoids and coumarins among the studied samples.

Laetiporus sulphureus, a wood-decaying basidiomycete, produces yellow-orange pigments in fruiting bodies and, as was recently shown, in submerged cultivated mycelia. Out of four strains, the most potent laetiporic acid producer was identified and its yield compared in different media. The complex Moser b medium was replaced by potato dextrose broth, achieving higher yields at a lower cost. Cultivation was then scaled up from shake flask to a 7 L stirred tank bioreactor. Optimization of parameters led to increased product concentrations up to 1 g L−1, the highest yield reported so far. An in situ product recovery strategy with a biphasic system was established, increasing the yield by 19% on the shake flask scale. A crude ethanolic extract of the biomass was examined for color stability and application trials. In contrast to what has been suggested in the past, the pigment showed limited long-term stability to oxygen and light, but was stable under storage in the dark at 4 °C under nitrogen. The orange extract was successfully incorporated into different matrices like foods, cosmetics and textiles. Laetiporic acid can potentially replace petrochemical based synthetic dyes, and can thus support the development of a circular bioeconomy.

Hispidin (6-(3,4-dihydroxystyrl)-4-hydroxy-2-pyrone) production in submerged cultured mycelia of the basidiomycete Inonotus hispidus was doubled in shake flasks through irradiation with white light. The daily addition of 1 mM hydrogen peroxide as a chemical stressor and a repeated supplementation of the shake flask cultures with 2 mM caffeic acid, a biogenetic precursor, further increased the hispidin synthesis. These cultivation conditions were combined and applied to parallel fermentation trials on the 4 L scale using a classical stirred tank bioreactor and a wave bag bioreactor. No significant differences in biomass yield and colorant production were observed. The hispidin concentration in both bioreactors reached 5.5 g·L−1, the highest ever published. Textile dyeing with hispidin was successful, but impeded by its limited light stability in comparison to industrial dyes. However, following the idea of sustainability and the flawless toxicity profile, applications in natural cosmetics, other daily implements, or even therapeutics appear promising.

Evapotranspiration (ET) is a key process in hydrological systems and, consequently, in agroecosystems. It can be measured or derived with a large variety of models at scales ranging from leaf to catchment. MODIS16A2 is a satellite ET product with 500 meters / 8-day spatio-temporal resolution worldwide. It is based on the Penman-Monteith equation and considers the effect of vegetation dynamics, albedo and land cover. This technical paper compares the ET estimated from MODIS16A2 against the ET estimated at different scales from three reference methods: (1) the INIA-GRAS Water Balance on a country-scale, (2) the SWAT model of the Santa Lucia basin on the catchment scale, and (3) the Eddy Covariance Flux located in Colonia on a farmer scale. The analysis shows similarities between MODIS16A2 and the reference methods depending on seasonality, geographic location and scale of ET estimation. The assumptions about vegetation cover, vegetation dynamics, meteorological forcing and soil characteristics of the reference methods compared with MODIS16A2 ones could explain some deviations in the ET estimations. The results of this work contribute with a first approximation towards the quantification of the uncertainty of MODIS16A2 in Uruguay.

Edible mushrooms are widely appreciated for their appealing flavours, low caloric values and high content of presumably health-protecting metabolites. Their long history of safe use together with the looming worldwide food crisis have revived the idea of generating meat analogues and protein isolates by the controlled fermentation of mycelia of these edible fungi as a dietary option. The occurrence of proteins, polysaccharides, smaller metabolites, metal ions and toxins in mycelia and fruiting bodies is compared among the three most popular species, Agaricus bisporus (button mushroom), Pleurotus ostreatus (oyster mushroom), Lentinus edodes (shiitake) and some closely related species. Large effects of substrate chemistry, strain, developmental stage and ecological interactions result in a wide variation of the concentrations of some metabolites in both mycelial cells and fruiting bodies. This is obviously a result of the high adaptation abilities required to survive in natural habitats. Fungal bioprocesses are decoupled from agricultural production and can be operated anytime, anywhere, and on any scale according to demand. It is concluded that fungal biomass, if produced under food-grade conditions and on an industrial scale, could provide a safe and nutritious meat substitute and protein isolates with a high biological value for future vegan foods.

The biocatalytic system comprised of RizA and acetate kinase (AckA) combines the specific synthesis of bioactive arginyl dipeptides with efficient ATP regeneration. Immobilization of this coupled enzyme system was performed and characterized in terms of activity, specificity and reusability of the immobilisates. Co-immobilization of RizA and AckA into a single immobilisate conferred no disadvantage in comparison to immobilization of only RizA, and a small addition of AckA (20:1) was sufficient for ATP regeneration. New variants of RizA were constructed by combining mutations to yield variants with increased biocatalytic activity and specificity. A selection of RizA variants were co-immobilized with AckA and used for the production of the salt-taste enhancers Arg-Ser and Arg-Ala and the antihypertensive Arg-Phe. The best variants yielded final dipeptide concentrations of 11.3 mM Arg-Ser (T81F_A158S) and 11.8 mM Arg-Phe (K83F_S156A), the latter of which represents a five-fold increase in comparison to the wild-type enzyme. T81F_A158S retained more than 50% activity for over 96 h and K83F_S156A for over 72 h. This study provides the first example of the successful co-immobilization of an l-amino acid ligase with an ATP-regenerating enzyme and paves the way towards a bioprocess for the production of bioactive dipeptides.

Despite the high efficiency of tyrosine kinase inhibitors (TKI), some patients with chronic myeloid leukemia (CML) will display residual disease that can become resistant to treatment, indicating intraclonal heterogeneity in chronic‐phase CML (CP‐CML). To determine the basis of this heterogeneity, we conducted the first exhaustive characterization of the DNA methylation pattern of sorted CP‐CML CD34+CD15− (immature) and CD34−CD15+ (mature) cells at diagnosis (prior to any treatment) and compared it to that of CD34+CD15− and CD34−CD15+ cells isolated from healthy donors (HD). In both cell types, we identified several hundreds of differentially methylated regions (DMRs) showing DNA methylation changes between CP‐CML and HD samples, with only a subset of them in common between CD34+CD15− and CD34−CD15+ cells. This suggested DNA methylation variability within the same CML clone. We also identified 70 genes that could be aberrantly repressed upon hypermethylation and 171 genes that could be aberrantly expressed upon hypomethylation of some of these DMRs in CP‐CML cells, among which 18 and 81, respectively, were in CP‐CML CD34+CD15− cells only. We then validated the DNA methylation and expression defects of selected candidate genes. Specifically, we identified GAS2, a candidate oncogene, as a new example of gene the hypomethylation of which is associated with robust overexpression in CP‐CML cells. Altogether, we demonstrated that DNA methylation abnormalities exist at early stages of CML and can affect the transcriptional landscape of malignant cells. These observations could lead to the development of combination treatments with epigenetic drugs and TKI for CP‐CML.

Abstract Recent epidemiological evidence suggests that exposure to antibiotics in early‐to‐middle adulthood is associated with an increased risk of colorectal adenoma. However, mechanistic studies in established preclinical cancer to examine these claims are extremely limited. Therefore, we investigated the effect of long‐term exposure of an antibiotic cocktail composed of Vancomycin, Neomycin, and Streptomycin, on tumor development and progression in the ApcMin/+ mouse, an established genetic model for familial adenomatous polyposis. Clinical pathologies related to tumor development as well as intestinal and colon tissue histopathology were studied at ages 8, 12, and 16 weeks of age, which correspond to the approximate ages of development of neoplasia, gut inflammation with polyposis, and cancer progression, respectively, in this animal model. We show that the antibiotics significantly increase the severity of clinical symptoms, including effects on intestinal histology and goblet cell numbers. In addition, they promote small intestinal polyposis. Finally, metagenomic analysis of fecal samples demonstrated that antibiotic exposure is associated with a significant but nonuniform depletion of the animal's natural gut flora. Overall, these findings support the premise that long‐term antibiotic exposure mediates the selected depletion of gut microbial communities and the concomitant thinning of the protective mucus layer, resulting in an increase in tumor development.

Wheat is the most widely grown food crop, with 761 Mt produced globally in 2020. To meet the expected grain demand by mid-century, wheat breeding strategies must continue to improve upon yield-advancing physiological traits, regardless of climate change impacts. Here, the best performing doubled haploid (DH) crosses with an increased canopy photosynthesis from wheat field experiments in the literature were extrapolated to the global scale with a multi-model ensemble of process-based wheat crop models to estimate global wheat production. The DH field experiments were also used to determine a quantitative relationship between wheat production and solar radiation to estimate genetic yield potential. The multi-model ensemble projected a global annual wheat production of 1050 ± 145 Mt due to the improved canopy photosynthesis, a 37% increase, without expanding cropping area. Achieving this genetic yield potential would meet the lower estimate of the projected grain demand in 2050, albeit with considerable challenges.

The production of natural flavors by means of microorganisms is of great interest for the food and flavor industry, and by-products of the agro-industry are particularly suitable as substrates. In the present study, Citrus side streams were fermented using monokaryotic strains of the fungus Pleurotus sapidus. Some of the cultures exhibited a pleasant smell, reminiscent of woodruff and anise, as well as herbaceous notes. To evaluate the composition of the overall aroma, liquid/liquid extracts of submerged cultures of a selected monokaryon were prepared, and the volatiles were isolated via solvent-assisted flavor evaporation. Aroma extract dilution analyses revealed p-anisaldehyde (sweetish, anisic- and woodruff-like) with a flavor dilution factor of 218 as a character impact compound. The coconut-like, herbaceous, and sweetish smelling acyloin identified as (2S)-hydroxy-1-(4-methoxyphenyl)-1-propanone also contributed to the overall aroma and was described as an aroma-active substance with an odor threshold in air of 0.2 ng L−1 to 2.4 ng L−1 for the first time. Supplementation of the culture medium with isotopically substituted l-tyrosine elucidated this phenolic amino acid as precursor of p-anisaldehyde as well as of (2S)-hydroxy-1-(4-methoxyphenyl)-1-propanone. Chiral analysis via HPLC revealed an enantiomeric excess of 97% for the isolated product produced by P. sapidus.

The paper examines the problem of forensic examination of doppelgängers' portraits for dominant matching features. The authors outline the types of forensic objectives addressed in the course of such examination, and offer an algorithm for the selection of matching group, individualizing and dominant characteristics (features) in doppelgängers' facial images. The relationship between individualizing and dominant features is analyzed, and the concept of a dominant set of features is introduced. Recommendations are offered for the best methods of dominant feature identification.

Recent clinical studies found a strong association of colonic inflammation and Inflammatory bowel disease (IBD)-like phenotype with NonAlcoholic Fatty liver Disease (NAFLD) yet the mechanisms remain unknown. The present study identifies high mobility group box 1 (HMGB1) as a key mediator of intestinal inflammation in NAFLD and outlines a detailed redox signaling mechanism for such a pathway. NAFLD mice showed liver damage and release of elevated HMGB1 in systemic circulation and increased intestinal tyrosine nitration that was dependent on NADPH oxidase. Intestines from NAFLD mice showed higher Toll like receptor 4 (TLR4) activation and proinflammatory cytokine release, an outcome strongly dependent on the existence of NAFLD pathology and NADPH oxidase. Mechanistically intestinal epithelial cells showed the HMGB1 activation of TLR-4 was both NADPH oxidase and peroxynitrite dependent with the latter being formed by the activation of NADPH oxidase. Proinflammatory cytokine production was significantly blocked by the specific peroxynitrite scavenger phenyl boronic acid (FBA), AKT inhibition and NADPH oxidase inhibitor Apocynin suggesting NADPH oxidase-dependent peroxynitrite is a key mediator in TLR-4 activation and cytokine release via an AKT dependent pathway. Studies to ascertain the mechanism of HMGB1-mediated NADPH oxidase activation showed a distinct role of Receptor for advanced glycation end products (RAGE) as the use of inhibitors targeted against RAGE or use of deformed HMGB1 protein prevented NADPH oxidase activation, peroxynitrite formation, TLR4 activation and finally cytokine release. Thus, in conclusion the present study identifies a novel role of HMGB1 mediated inflammatory pathway that is RAGE and redox signaling dependent and helps promote ectopic intestinal inflammation in NAFLD.

Background: Student satisfaction with key aspects of a medical school program plays a major role in an institution's accreditation in the United States (US). There is limited evidence regarding how to best engage students in responding to areas of lower student satisfaction that are identified through the national Liaison Committee on Medication Education (LCME) accreditation self-study process. Methods: We present a student-led innovation to promote greater levels of student engagement throughout Harvard Medical School's re-accreditation experience, which we refer to as the Independent Student Analysis Action (ISA2) process. This innovation built directly upon the Independent Student Analysis (ISA) survey, which is expected by the LCME for accreditation. The ISA2 process allowed medical student leaders to leverage ISA results to identify 11 priority areas that had relatively lower levels of satisfaction and subsequently coordinate focused, time-limited ISA2 working groups to address these problematic areas. These working groups then presented their solutions to the student body, and a follow-up survey gauged satisfaction with these areas in light of the changes made. Results: The ISA2 process engaged over 110 students, faculty, and staff. The majority of the student body completed the follow-up survey, which demonstrated higher levels of satisfaction with these previously problematic areas as identified in the original ISA survey. Further, 96% of students reported being satisfied with the ISA2 process as a mechanism for utilizing student feedback in the ISA to create meaningful institutional changes. Conclusions: The ISA2 served as a powerful convening mechanism for engaging a large number of students in our institution's re-accreditation efforts. Other medical schools looking to involve students in their continuous quality improvement systems and accreditation experience may benefit from reviewing and customizing this model to their institution's needs.

Traditional smoke flavours bear the risk of containing a multitude of contaminating carcinogenic side-products. Enzymatic decarboxylation of ferulic acid released from agro-industrial side-streams by ferulic acid esterases (FAE) enables the sustainable generation of pure, food grade 4-vinylguaiacol (4-VG), the impact compound of smoke flavour. The first basidiomycetous ferulic acid decarboxylase (FAD) was isolated from Schizophyllum commune (ScoFAD) and heterologously produced by Komagataella phaffii. It showed a molecular mass of 21 kDa, catalytic optima at pH 5.5 and 35°C, and a sequence identity of 63.6% to its next relative, a FAD from the ascomycete Cordyceps farinosa. The ScoFAD exhibited a high affinity to its only known substrate ferulic acid (FA) of 0.16 mmol L-1 and a turnover number of 750 s-1. The resulting catalytic efficiency kcat KM-1 of 4,779 L s-1 mmol-1 exceeded the next best known enzyme by more than a factor of 50. Immobilised on AminoLink Plus Agarose, ScoFAD maintained its activity for several days. The combination with FAEs and agro-industrial side-streams paves the way for a new generation of sustainable, clean, and safe smoke flavours.

Chitotriosidase activity and CCL18 concentration are interchangeably used for monitoring Gaucher disease (GD) activity, together with clinical assessment. However, comparative studies of these two biomarkers are scarce and of limited sample size. The aim of this systematic review with meta-analysis of individual participant data (IPD) was to compare the accuracy of chitotriosidase activity and CCL18 concentration for assessing type I GD severity. We identified cross-sectional and prospective cohort studies by searching Medline, EMBASE, and CENTRAL from 1995 to June 2017, and by contacting research groups. The primary outcome was a composite of liver volume >1.25 multiple of normal (MN), spleen volume >5 MN, hemoglobin concentration

Suspicion of myelodysplastic syndromes (MDS) is one of the commonest reasons for bone marrow aspirate in elderly patients presenting with persistent peripheral blood (PB) cytopenia of unclear etiology. A PB assay that accurately rules out MDS would have major benefits. The diagnostic accuracy of the intra-individual robust coefficient of variation (RCV) for neutrophil myeloperoxidase (MPO) expression measured by flow cytometric analysis in PB was evaluated in a retrospective derivation study (44 MDS cases and 44 controls) and a prospective validation study (68 consecutive patients with suspected MDS). Compared with controls, MDS cases had higher median RCV values for neutrophil MPO expression (40.2% vs. 30.9%; P