Origin and Evolution of Prebiotic Organic Matter as Inferred from the Tagish Lake Meteorite

The complex suite of organic materials in carbonaceous chondrite meteorites probably originally formed in the interstellar medium and/or the solar protoplanetary disk, but was subsequently modified in the meteorites' asteroidal parent bodies. The mechanisms of formation and modification are still very poorly understood. We carried out a systematic study of variations in the mineralogy, petrology, and soluble and insoluble organic matter in distinct fragments of the Tagish Lake meteorite. The variations correlate with indicators of parent body aqueous alteration and at least some molecules of pre-biotic importance formed during the alteration

Type I Interferons Link Viral Infection to Enhanced Epithelial Turnover and Repair

The host immune system functions constantly to maintain chronic commensal and pathogenic organisms in check. The consequences of these immune responses on host physiology are as yet unexplored, and may have long-term implications in health and disease. We show that chronic viral infection increases epithelial turnover in multiple tissues, and the antiviral cytokines type I interferons (IFNs) mediate this response. Using a murine model with persistently elevated type I IFNs in the absence of exogenous viral infection, the Irgm1−/− mouse, we demonstrate that type I IFNs act through nonepithelial cells, including macrophages, to promote increased epithelial turnover and wound repair. Downstream of type I IFN signaling, the highly related IFN-stimulated genes Apolipoprotein L9a and b activate epithelial proliferation through ERK activation. Our findings demonstrate that the host immune response to chronic viral infection has systemic effects on epithelial turnover through a myeloid-epithelial circuit

Duration of Exclusive Breastfeeding for Preterm or Low Birth Weight Infants: A Systematic Review and Meta-analysis

BACKGROUND AND OBJECTIVES: Cessation of exclusive breastfeeding (EBF) with early introduction of complementary food provides additional calories for catch-up growth but may also increase the risk of adverse outcomes. The objective of this study was to assess effects of exclusive breastfeeding for less than 6 months compared with 6 months in preterm and low birth weight infants. METHODS: Data sources include Medline, Scopus, Web of Science, CINAHL, and Index Medicus through June 30, 2021. Study selection includes randomized trials and observational studies. Primary outcomes were mortality, morbidity, growth, and neurodevelopment. Data were extracted and pooled using random-effects models. The Cochrane Risk of Bias 2 tool was used to assess the risk of bias of included studies. RESULTS: A total of 2 studies of 307 preterm or low birth weight infants were included. None of the study results could be pooled. Both studies compared EBF for 4 months to 6 months. Growth was similar between the 4-month and 6-month EBF groups for the following outcomes: weight-for-age z-score at corrected age 12 months (mean [standard deviation], 4-month group: -1.7 [1.1], 6-month group: -1.8 [1.2], 1 study, 188 participants, low certainty evidence), absolute weight gain (gram) from 16 to 26 weeks of age (4-month group: 1004 [366], 6-month group: 1017 [350], 1 study, 119 participants, very low certainty evidence), and linear growth gain (cm) from 16 to 26 weeks of age (4-month group: 4.3 [0.9], 6-month group: 4.5 [1.2], 1 study, 119 participants, very low certainty evidence). There were no apparent differences in reported morbidity symptoms. No difference in the timing to achieve motor development milestones between the 2 groups was found (1 study; 119 participants, very low certainty evidence). A limited number of studies prevented data pooling. CONCLUSIONS: The evidence is very uncertain about the effect of exclusive breastfeeding for less than 6 months for preterm and low birth weight infants. Further studies are warranted to better answer this question

Fast Feed Advancement for Preterm and Low Birth Weight Infants: A Systematic Review and Meta-analysis

BACKGROUND AND OBJECTIVES: Fast feed advancement may reduce hospital stay and infection but may increase adverse outcomes in preterm and low birth weight infants. The objective of this study was to assess effects of fast feed advancement (≥30 ml/kg per day) compared with slow feed advancement (\u3c30 ml/kg per day) in preterm and low birth weight infants. METHODS: Data sources include Medline, Scopus, Web of Science, CINAHL, and Index Medicus through June 30, 2021. Randomized trials were selected. Primary outcomes were mortality, morbidity, growth, and neurodevelopment. Data were extracted and pooled using random-effects models. The Cochrane Risk of Bias 2 tool was used. RESULTS: A total of 12 RCTs with 4291 participants were included. At discharge, there was moderate certainty evidence that fast advancement likely slightly reduces the risk of: mortality (relative risk [RR] 0.93, 95% confidence interval [95% CI] 0.73 to 1.18, I2 = 18%, 11 trials, 4132 participants); necrotizing enterocolitis (RR 0.89, 95% CI 0.68 to 1.15, I2 = 0%, 12 trials, 4291 participants); sepsis (RR 0.92, 95% CI 0.83 to 1.03, I2 = 0%, 9 trials, 3648 participants); and feed intolerance (RR 0.92, 95% CI 0.77 to 1.10, I2 = 0%, 8 trials, 1114 participants). Fast feed advancement may also reduce the risk of apnea (RR 0.72, 95% CI 0.47 to 1.12, I2 = 0%, low certainty, 2 trials, 153 participants). Fast feed advancement decreases time to regain birth weight (mean difference [MD] -3.69 days, 95% CI -4.44 to -2.95, I2 = 70%, high certainty, 6 trials, 993 participants,) and likely reduces the duration of hospitalization (MD -3.08 days, 95% CI -4.34 to -1.81, I2 = 77%, moderate certainty, 7 trials, 3864 participants). Limitations include heterogeneity between studies and small sample sizes. CONCLUSIONS: Fast feed advancement reduces time to regain birth weight and likely reduces the length of hospital stay; it also likely reduces the risk of neonatal morbidity and mortality slightly. However, it may increase the risk of neurodevelopmental disability slightly. More studies are needed to understand the long-term effects of fast feed advancement

L1CAM in Early-Stage Type I Endometrial Cancer: Results of a Large Multicenter Evaluation

Contains fulltext : 124525.pdf (publisher's version ) (Closed access)BACKGROUND: Despite the excellent prognosis of Federation Internationale de Gynecologie et d'Obstetrique (FIGO) stage I, type I endometrial cancers, a substantial number of patients experience recurrence and die from this disease. We analyzed the value of immunohistochemical L1CAM determination to predict clinical outcome. METHODS: We conducted a retrospective multicenter cohort study to determine expression of L1CAM by immunohistochemistry in 1021 endometrial cancer specimens. The Kaplan-Meier method and Cox proportional hazard model were applied for survival and multivariable analyses. A machine-learning approach was used to validate variables for predicting recurrence and death. RESULTS: Of 1021 included cancers, 17.7% were rated L1CAM-positive. Of these L1CAM-positive cancers, 51.4% recurred during follow-up compared with 2.9% L1CAM-negative cancers. Patients bearing L1CAM-positive cancers had poorer disease-free and overall survival (two-sided Log-rank P < .001). Multivariable analyses revealed an increase in the likelihood of recurrence (hazard ratio [HR] = 16.33; 95% confidence interval [CI] = 10.55 to 25.28) and death (HR = 15.01; 95% CI = 9.28 to 24.26). In the L1CAM-negative cancers FIGO stage I subdivision, grading and risk assessment were irrelevant for predicting disease-free and overall survival. The prognostic relevance of these parameters was related strictly to L1CAM positivity. A classification and regression decision tree (CRT)identified L1CAM as the best variable for predicting recurrence (sensitivity = 0.74; specificity = 0.91) and death (sensitivity = 0.77; specificity = 0.89). CONCLUSIONS: To our knowledge, L1CAM has been shown to be the best-ever published prognostic factor in FIGO stage I, type I endometrial cancers and shows clear superiority over the standardly used multifactor risk score. L1CAM expression in type I cancers indicates the need for adjuvant treatment. This adhesion molecule might serve as a treatment target for the fully humanized anti-L1CAM antibody currently under development for clinical use

Identification and characterization of novel PDYN mutations in dominant cerebellar ataxia cases

<p>We have recently identified missense mutations in prodynorphin (PDYN), the precursor to dynorphin opioid peptides, as the cause for spinocerebellar ataxia (SCA23) in Dutch ataxia cases. We report a screen of PDYN for mutations in 371 cerebellar ataxia cases, which had a positive family history; most are of French origin. Sequencing revealed three novel putative missense mutations and one heterozygous two-base pair deletion in four independent SCA patients. These variants were absent in 400 matched controls and are located in the highly conserved dynorphin domain. To resolve the pathogenicity of the heterozygous variants, we assessed the peptide production of the mutant PDYN proteins. Two missense mutations raised dynorphin peptide levels, the two-base pair deletion terminated dynorphin synthesis, and one missense mutation did not affect PDYN processing. Given the outcome of our functional analysis, we may have identified at least two novel PDYN mutations in a French and a Moroccan SCA patient. Our data corroborates recent work that also showed that PDYN mutations only account for a small percentage (similar to 0.1 %) of European SCA cases.</p>

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases