Emerging Role of Plasma Microbial Cell-free DNA in the Diagnosis of Pediatric Mucormycosis.

Mucormycosis is a rare and devastating angioinvasive infection that can be challenging to diagnose due to the low sensitivity of current noninvasive diagnostics and the lack of a "gold standard" reference test. We describe a retrospective case series of children with suspected mucormycosis where plasma microbial cell-free DNA testing was utilized in the diagnostic evaluation to illustrate the ways in which microbial cell-free DNA testing can noninvasively contribute to the evaluation and management of at-risk, immunosuppressed patients suspected of mucormycosis.

Social Emotional Learning Competencies in Belize Children: Psychometric Validation Through Exploratory Structural Equation Modeling.

In the nation of Belize, and in particular the south side of Belize City, the main metropolitan area of the nation, significant economic disparities have led to child and adolescent exposure to high rates of violent crime, gang activity, unsafe neighborhoods, sexual, and physical violence. Problems associated with poor Social-Emotional Character Development are especially prevalent among boys. Consequently, valid culture-relevant measures are required that identify problematic behavior for policy-based intervention and evaluation of educational programs designed to ameliorate this problem. The present study demonstrates the application of Exploratory Structural Equation Modeling to existing measures through the investigation of structural validity and generalizability of the Social-Emotional and Character Development Scale with a large sample of children from schools in Belize (N = 1,877, Ages 10-13). Exploratory structural equation modeling results demonstrate the original factor correlations were reduced, providing less biased estimates than confirmatory factor analysis (CFA). Moreover, a multi-group Exploratory Structural Equation Modeling analysis illuminates significant differences between latent factor scores of males and females for most factors. Using this newer factor analytic procedure, original factors are reconceptualized to better situate the Social Emotional Character Development Scales into the larger body of Social-Emotional Learning (SEL) competencies literature.

Accelerated long-term forgetting in healthy older adults predicts cognitive decline over 1 year.

BACKGROUND: Here, we address a pivotal factor in Alzheimer's prevention-identifying those at risk early, when dementia can still be avoided. Recent research highlights an accelerated forgetting phenotype as a risk factor for Alzheimer's disease. We hypothesized that delayed recall over 4 weeks would predict cognitive decline over 1 year better than 30-min delayed recall, the current gold standard for detecting episodic memory problems which could be an early clinical manifestation of incipient Alzheimer's disease. We also expected hippocampal subfield volumes to improve predictive accuracy. METHODS: Forty-six cognitively healthy older people (mean age 70.7 ± 7.97, 21/46 female), recruited from databases such as Join Dementia Research, or a local database of volunteers, performed 3 memory tasks on which delayed recall was tested after 30 min and 4 weeks, as well as Addenbrooke's Cognitive Examination III (ACE-III) and CANTAB Paired Associates Learning. Medial temporal lobe subregion volumes were automatically measured using high-resolution 3T MRI. The ACE-III was repeated after 12 months to assess the change in cognitive ability. We used univariate linear regressions and ROC curves to assess the ability of tests of delayed recall to predict cognitive decline on ACE-III over the 12 months. RESULTS: Fifteen of the 46 participants declined over the year (≥ 3 points lost on ACE-III). Four-week verbal memory predicted cognitive decline in healthy older people better than clinical gold standard memory tests and hippocampal MRI. The best single-test predictor of cognitive decline was the 4-week delayed recall on the world list (R2 = .123, p = .018, ß = .418). Combined with hippocampal subfield volumetry, 4-week verbal recall identifies those at risk of cognitive decline with 93% sensitivity and 86% specificity (AUC = .918, p < .0001). CONCLUSIONS: We show that a test of accelerated long-term forgetting over 4 weeks can predict cognitive decline in healthy older people where traditional tests of delayed recall cannot. Accelerated long-term forgetting is a sensitive, easy-to-test predictor of cognitive decline in healthy older people. Used alone or with hippocampal MRI, accelerated forgetting probes functionally relevant Alzheimer's-related change. Accelerated forgetting will identify early-stage impairment, helping to target more invasive and expensive molecular biomarker testing.

Suppression of stress induction of the 78-kilodalton glucose regulated protein (GRP78) in cancer by IT-139, an anti-tumor ruthenium small molecule inhibitor.

In many cancers, combination therapy regimens are successfully improving response and survival rates, but the challenges of toxicity remain. GRP78, the master regulator of the unfolded protein response, is emerging as a target that is upregulated in tumors, specifically following treatment, and one that impacts tumor cell survival and disease recurrence. Here, we show IT-139, an antitumor small molecule inhibitor, suppresses induction of GRP78 from different types of endoplasmic reticulum (ER) stress in a variety of cancer cell lines, including those that have acquired therapeutic resistance, but not in the non-cancer cells being tested. We further determined that IT-139 treatment exacerbates ER stress while at the same time suppresses GRP78 induction at the transcriptional level. Our studies revealed a differential effect of IT-139 on chaperone protein family expression at multiple levels in different cancer cell lines. In xenograft studies, IT-139 decreased BRAF inhibitor upregulation of GRP78 expression in the tumor, while having minimal effect on GRP78 expression in the adjacent normal cells. The preferential decrease in GRP78 levels in tumor cells over normal cells, supported by the manageable safety profile seen in the Phase 1 clinical trial, reinforce the value IT-139 brings to combination therapies as it continues its clinical development.

Taq DNA Polymerase Mutants and 2'-Modified Sugar Recognition.

Chemical modifications to DNA, such as 2' modifications, are expected to increase the biotechnological utility of DNA; however, these modified forms of DNA are limited by their inability to be effectively synthesized by DNA polymerase enzymes. Previous efforts have identified mutant Thermus aquaticus DNA polymerase I (Taq) enzymes capable of recognizing 2'-modified DNA nucleotides. While these mutant enzymes recognize these modified nucleotides, they are not capable of synthesizing full length modified DNA; thus, further engineering is required for these enzymes. Here, we describe comparative biochemical studies that identify useful, but previously uncharacterized, properties of these enzymes; one enzyme, SFM19, is able to recognize a range of 2'-modified nucleotides much wider than that previously examined, including fluoro, azido, and amino modifications. To understand the molecular origins of these differences, we also identify specific amino acids and combinations of amino acids that contribute most to the previously evolved unnatural activity. Our data suggest that a negatively charged amino acid at 614 and mutation of the steric gate residue, E615, to glycine make up the optimal combination for modified oligonucleotide synthesis. These studies yield an improved understanding of the mutational origins of 2'-modified substrate recognition as well as identify SFM19 as the best candidate for further engineering, whether via rational design or directed evolution.

The camp management toolkit

Le Camp Managment Toolkit présente les questions essentielles de protection et de prestation de services dans les camps et fournit des conseils pratiques pour le personnel de la gestion des camps. Il permet de travailler sur la meilleure façon dÆassurer la coordination globale, la gestion des camps et défendre les droits des personnes déplacées. Ce document est applicable pour les camps de refugiés et de personnes déplacées, dans les situations humanitaires liées à des conflits ou catastrophes naturelles.

Le toolkit de gestion de camp

Le toolkit de gestion de camp présente les questions essentielles de protection et de prestation de services dans les camps et fournit des conseils pratiques pour le personnel de la gestion des camps. Il permet de travailler sur la meilleure façon dÆassurer la coordination globale, la gestion des camps et défendre les droits des personnes déplacées. Ce document est applicable pour les camps de refugiés et de personnes déplacées, dans les situations humanitaires liées à des conflits ou catastrophes naturelles.