Preliminary Analysis of Yeast Communities Associated with the Spontaneous Fermentation of Musalais, a Traditional Alcoholic Beverage of Southern Xinjiang, China

Musalais is a traditional alcoholic beverage made by the Uighur people in southern Xinjiang, China. Theinitial fermentation juice is obtained by prolonged boiling of local grape juice and grape residues. In thecurrent study, 242 yeast isolates were obtained from 18 samples (grapes, derived starting products, andprogressive stages of fermentation), and 20 phenotypes were distinguished, based on colony characteristicson WL nutrient agar. Fifty representative isolates were selected and found to belong to eight genera (basedon rRNA gene sequence analysis). Among the non-Saccharomyces species present on the grapes and relatedderived substrates, Hanseniaspora spp. was the dominant species. However, nearly all of these specieswere absent in early fermentation. Saccharomyces cerevisiae was not found until the onset of spontaneousfermentation and quickly became the dominant species. The identified yeast community could be used tofurther develop indigenous yeast strains to serve the traditional technology of Musalais. The productionof Musalais, from a starting substrate that has been boiled for 15 hours to kill all, or nearly all, yeast cells,provides fresh insights into the production of ethanol by the fermentation of grape juice

Association of gestational age at birth with subsequent suspected Developmental Coordination Disorder in early childhood

Importance. It remains unknown whether children born at different degrees of prematurity, early-term and post-term might have a higher risk of developing Developmental Coordination Disorder (DCD) compared to completely full-term children (39-40 gestational weeks). Objective. To differentiate between suspected DCD in children with different gestational ages based on a national representative sample in China. DESIGN, SETTING, AND PARTICIPANTS We conducted a retrospective cohort study in China from 2018 to 2019. A total of 152,433 children from 2,403 public kindergartens in 551 cities of China aged 3-5 years old were included in the final analysis. The association between gestational age and motor performance was investigated. A multi-level regression model was developed to determine the strength of association for different gestational ages associated with suspected DCD when considering kindergartens as clusters. Main outcomes and measures. Children’s motor performance was assessed using the Little Developmental Coordination Disorder Questionnaire (LDCDQ), completed by parents. Gestational age was determined according to the mother’s medical records. Results. Of the 152,433 children aged 3-5 years old, 80,370 (52.7%) were male, and 72,063 (47.3%) were female. There were 45,052 children aged 3 years old (29.6%), 59,796 aged 4 years old(39.2%), and 47,585 children aged 5 years old (31.2%). The LDCDQ total scores for very-preterm (β=-1.74, 95%CI: -1.98, 1.50; p<0.001), moderately-preterm (β=-1.24, 95%CI: -1.60, -0.89; p<0.001), late-preterm (β=-0.92, 95%CI: -1.08, -0.76; p<0.001), early-term (β=-0.36, 95%CI: -0.46, -0.25; p<0.001) and post-term children (β=-0.47, 95%CI: -0.67, -0.26; p<0.001) were significantly lower than full-term children when adjusting for child, family and maternal health characteristics. The very-preterm (OR=1.35, 95%CI: 1.23,1.48; p<0.001), moderately-preterm (OR=1.18, 95%CI: 1.02, 1.36; p<0.001), late-preterm (OR =1.24, 95%CI: 1.16,1.32; p<0.001), early-term (OR =1.11, 95%CI: 1.06,1.16; p<0.001) and post-term children (OR =1.167, 95%CI: 1.07, 1.27; p<0.001) were more likely to fall in the suspected Developmental Coordination Disorder (DCD) category on the LDCDQ compared with completely full-term children after adjusting for the same characteristics. The associations between different gestational ages and suspected DCD were stronger in boys and older (5 year old) children (each p<0.05). Conclusions and relevance. We found significant associations between every degree of prematurity at birth, early-term and post-term birth with suspected DCD when compared with full-term birth. Our findings have important implications for understanding motor development in children born at different gestational ages. Long-term follow-up and rehabilitation interventions should be considered for early- and post-term born children

Outcomes for Patients (Pts) with Low-/Int-1-Risk Myelodysplastic Syndromes (MDS) with del5q Aged < 65 Years Treated with Lenalidomide (LEN) in MDS-003 and MDS-004: A Retrospective Combined Analysis

Abstract Abstract 1723 Background: Two multicenter studies (MDS-003/-004) found LEN leads to RBC transfusion independence (TI) in > 50% of pts with RBC transfusion dependent Low-/Int-1-risk MDS with del5q (List A et al. NEJM 2006;355: 1456–65; Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). RBC-TI ≥ 8 wks with LEN was associated with significantly reduced risk of AML progression and death (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). Alternative therapy is required for pts failing LEN therapy. Aims: To assess predictive factors of LEN response and long term outcomes (especially after primary or secondary LEN failure) of pts < 65 yrs included in MDS-003/-004; ie, those in whom intensive therapies including allogeneic stem cell transplantation (ASCT) may be considered. Methods: LEN was administered as follows (all 28-d cycles): 5 mg/d on d 1–28 and 10 mg/d on d 1–21 or 1–28. RBC-TI ≥ 26 wks and cytogenetic response (CyR; IWG 2000) are reported. Overall survival (OS) and AML progression were assessed using Kaplan-Meier method. Response rates and outcomes in pts < 65 yrs were retrospectively compared with pts ≥ 65 yrs. Primary failure was defined as lack of RBC-TI with LEN treatment and secondary failure as relapse after achievement of RBC-TI ≥ 26 wks. Cox proportional hazards models were used to evaluate the effect of potential risk factors (ie, age, sex, time since diagnosis, FAB classification, LEN dose, IPSS risk, WPSS risk, cytogenetics, bone marrow blast %, transfusion burden, no. of cytopenias, hemoglobin level, platelet and neutrophil counts, RBC-TI ≥ 26 wks [time-dependent variable] and CyR [categorical variable]) on OS and AML progression. Logistic model was used to evaluate the effect of potential risk factors on achievement of RBC-TI ≥ 26 wks. Results: The trials included 97 (33.9%) pts < 65 yrs. Of these, 73.2% were female; 20.6% were IPSS Low-, 52.6% Int-1-, and 4.1% Int-2-risk; 30.9% had del5q with ≥ 1 additional cytogenetic abnormality (8.2% had complex cytogenetics). At baseline (BL), median time since diagnosis was 2.4 yrs (range 0.2–20.7) and median RBC transfusion requirement was 6 units/8 wks (range 1–15). In pts ≥ 65 yrs (n = 189) most BL characteristics were similar except IPSS risk, which was lower (36.5% Low-, 37.0% Int-1-, 5.8% Int-2-risk; p =.012). RBC-TI ≥ 26 wks was achieved by 54 (55.7%) pts < 65 yrs (vs 49.7% pts ≥ 65 yrs; p =.563). The median duration of RBC-TI ≥ 26 wks in responders was not estimable in pts < 65 yrs or ≥ 65 yrs (log-rank p =.879). None of the potential risk factors assessed was a significant predictor of RBC-TI ≥ 26 wks in pts < 65 yrs, possibly due to small pt number. In pts < 65 yrs with available follow-up cytogenetics (n = 71), CyR was achieved by 32 (45.1%) pts (vs 64.5% pts ≥ 65 yrs; p =.014). At time of data cutoff, 51 (52.6%) pts < 65 yrs were alive (vs 36.0% pts ≥ 65 yrs; p =.008); 29 (29.9%) pts progressed to AML (vs 20.1% pts ≥ 65 yrs; p =.077). The 1-, 2-, and 3-yr AML-progression rates were 9.7%, 15.4%, and 24.0% in pts < 65 yrs; and 6.0%, 17.9%, and 22.3% in pts ≥ 65 yrs (log-rank p =.308). The 1-, 2-, and 3-yr OS rates were 91.7%, 78.1%, and 66.4% in pts < 65 yrs; and 83.1%, 65.2%, and 49.9% in pts ≥ 65 yrs (log-rank p <.001). In pts < 65 yrs, RBC-TI ≥ 26 wks was the only factor associated with longer median OS (4.9 yrs in responders vs 2.0 yrs in non-responders) and lower BL ANC was the only factor associated with a reduced risk of AML-progression. A total of 43 (44.3% of total population) pts < 65 yrs experienced primary LEN failure and 9 (16.7% of responders) secondary failure. In pts < 65 yrs with primary failure after 16 wks (median follow up from primary failure 2.6 yrs), 13 (30.2%) pts progressed to AML (1- and 2-yr cumulative AML rates 7.9% and 16.8%) and median OS was 2.67 yrs. In pts < 65 yrs with secondary failure (median follow up from secondary failure 1.7 yrs), 3 (33.3%) pts progressed to AML and median OS was not reached (1-yr cumulative OS rate was 64.8%). Conclusions: LEN-treated pts < 65 yrs had greater incidence of IPSS Int-1-risk, had similar rates of RBC-TI ≥ 26 wks, but achieved CyR less often and more progressed to AML vs pts ≥ 65 yrs. In pts < 65 yrs, achievement of RBC-TI ≥ 26 wks was the only factor associated with longer OS. After primary or secondary LEN failure, AML progression rates were ∼30% each, and median OS 2.67 yrs and 1-yr OS 64.8%, respectively. Low-/Int-1-risk pts < 65 yrs with del5q and primary or secondary LEN failure have a relatively poor outcome and should be considered potential candidates for ASCT. Disclosures: Fenaux: Celgene Corporation: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Johnson & Johnson: Honoraria; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Consultancy, Honoraria, Research Funding. Hellström-Lindberg:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yu:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment. Shammo:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. del Cañizo:Celgene Corporation: Spanish advisory committee

Potential of lichen secondary metabolites againstplasmodiumliver stage parasites with fas-ii as the potential target

Chemicals targeting the liver stage (LS) of the malaria parasite are useful for causal prophylaxis of malaria. In this study, four lichen metabolites, evernic acid (1); vulpic acid (2), psoromic acid (3), and, (+)-usnic acid (4), were evaluated against LS parasites of Plasmodium berghei. Inhibition Of P. falciparum blood Stage (BS) parasites was also assessed to determine stage specificity. Compound 4 displayed the highest LS activity and stage specificity (LS IC50 value 2.3 mu M, BS IC50 value 47.3 mu M). The compounds 1 - 3 inhibited one Or more enzymes (Pf FabI, PfFabG, and pfFabZ), from the Plasmodial fatty acid biosynthesis (FAS-II) pathway, a potential drug. target for LS activity. To determine species specificity and to clarify the mechanism of reported antibacterial effects, 1-4 were also evaluated against FabI homologues and Whole cells of various pathogens -(S. aureus, E. coli M. tuberculosis). Molecular modeling studies suggest that lichen acids act indirectly via binding to allosteric sites on the protein surface of the FAS-II enzymes. Potential. toxicity, of compounds was assessed in human hepatocyte and cancer cells (in vitro) as well as in a zebrafish model (in vivo):. This study indicates the therapeutic and prophylactic potential of lichen metabolites as antibacterial and antiplasmodial agents.

Molecular Mechanisms of ARID5B-Mediated Genetic Susceptibility to Acute Lymphoblastic Leukemia.

BACKGROUND: There is growing evidence for the inherited basis of susceptibility to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified non-coding ALL risk variants at the ARID5B gene locus, but their exact functional effects and the molecular mechanism linking ARID5B to B-cell ALL leukemogenesis remain largely unknown. METHODS: We performed targeted sequencing of ARID5B in germline DNA of 5008 children with ALL. Variants were evaluated for association with ALL susceptibility using 3644 patients from the UK10K cohort as non-ALL controls, under an additive model. Cis-regulatory elements in ARID5B were systematically identified using dCas9-KRAB-mediated enhancer interference system enhancer screen in ALL cells. Disruption of transcription factor binding by ARID5B variant was predicted informatically and then confirmed using chromatin immunoprecipitation and coimmunoprecipitation. ARID5B variant association with hematological traits was examined using UK Biobank dataset. All statistical tests were 2-sided. RESULTS: We identified 54 common variants in ARID5B statistically significantly associated with leukemia risk, all of which were noncoding. Six cis-regulatory elements at the ARID5B locus were discovered using CRISPR-based high-throughput enhancer screening. Strikingly, the top ALL risk variant (rs7090445, P = 5.57 × 10-45) is located precisely within the strongest enhancer element, which is also distally tethered to the ARID5B promoter. The variant allele disrupts the MEF2C binding motif sequence, resulting in reduced MEF2C affinity and decreased local chromosome accessibility. MEF2C influences ARID5B expression in ALL, likely via a transcription factor complex with RUNX1. Using the UK Biobank dataset (n = 349 861), we showed that rs7090445 was also associated with lymphocyte percentage and count in the general population (P = 8.6 × 10-22 and 2.1 × 10-18, respectively). CONCLUSIONS: Our results indicate that ALL risk variants in ARID5B function by modulating cis-regulatory elements at this locus