Characterization of mesenchymal stem cells in pre-B acute lymphoblastic leukemia

Components of the bone marrow microenvironment (BMM) have been shown to mediate the way in which leukemia develops, progresses and responds to treatment. Increasing evidence shows that leukemic cells hijack the BMM, altering its functioning and establishing leukemia-supportive interactions with stromal and immune cells. While previous work has highlighted functional defects in the mesenchymal stem cell (MSC) population from the BMM of acute leukemias, thorough characterization and molecular profiling of MSCs in pre-B cell acute lymphoblastic leukemia (B-ALL), the most common cancer in children, has not been conducted. Here, we investigated the cellular and transcriptome profiles of MSCs isolated from the BMM of an immunocompetent BCR-ABL1+ model of B-ALL. Leukemia-associated MSCs exhibited reduced self-renewal capacity in vitro and significant changes in numerous molecular signatures, including upregulation of inflammatory signaling pathways. Additionally, we found downregulation of genes involved in extracellular matrix organization and osteoblastogenesis in leukemia-associated MSCs. This study provides cellular and molecular insights into the role of MSCs during B-ALL progression

Methodology for Development of a 600-Year Tree-Ring Multi-Element Record for Larch from the Taymir Peninsula, Russia

We developed a long (600-year) dataset for the concentrations of 26 elements in tree rings of larch from the Taymir Peninsula, the northernmost region in the world (ca. 72°N) where trees grow. Tree rings corresponding to the time period from 1300 to 1900 A.D. were studied. Eleven wood strips, each from a different larch tree, were cut into ca. 100 mg samples usually consisting of ten consecutive tree rings (but occasionally five). Between 19 and 40 consecutive samples resulted from each tree, yielding a total of 277 samples. The replication of each time interval ranged from three (for periods 1300-1400 A.D. and 1600-1700 A.D.) to six (for 1450-1600 A.D.). Wood samples were digested with concentrated HNO 3 for measurement of Li, B, Na, Mg, Al, Si, P, Cl, K, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Rb, Sr, Y, Zr, Nb, Mo, Ag, Cd, Sn, Sb, I, Ba, La, Ce, Nd, W, Au, Pb, Bi, Th, and U using solution Inductively Coupled Plasma Mass Spectrometry (ICPMS). Fourteen elements (V, Co, As, Y, Nb, Mo, Sb, La, Ce, Nd, W, Au, Th, and U) with extremely low concentrations were eliminated from consideration as unreliable. Here we report our sample preparation and measurement procedure, as well as the observed concentrations in tree rings, emphasizing considerations for developing representative and reliable denrodochemical datasets.Нами был получен длительный массив данных (600 лет) концентраций 26 элементов в годичных кольцах лиственницы с полуострова Таймыр, самого северного региона в мире (около 72° с.ш.), где возможен рост деревьев. Изучались годичные кольца, соответствующие промежутку времени с 1300 по 1900 год н.э. Одиннадцать древесных выпилов, по одному для каждой лиственницы, нарезались на образцы массой около 100 мг, которые, как правило, состояли из десяти годичных колец (но в некоторых случаях из пяти). Из каждого дерева было получено от 19 до 40 последовательных образцов, что дало в общей сложности 277 образцов. Повторность для каждого временного интервала варьировала от трех (для периодов 1300-1400 г.н.э. и 1600-1700 г.н.э.) до шести (для периода 1450-1600 г.н.э.). Древесные образцы растворяли в концентрированной HNO 3 для последующего измерения Li, B, Na, Mg, Al, Si, P, Cl, K, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Rb, Sr, Y, Zr, Nb, Mo, Ag, Cd, Sn, Sb, I, Ba, La, Ce, Nd, W, Au, Pb, Bi, Th и U при помощи масс-спектрометрии с индуктивно связанной плазмой (ICP-MS) для растворов. Четырнадцать элементов (V, Co, As, Y, Nb, Mo, Sb, La, Ce, Nd, W, Au, Th и U) с очень низкими концентрациями были исключены из рассмотрения как недостоверные. В данной статье, основной целью которой являлась отработка методики получения репрезентативных и достоверных дендрохимических данных, приводится использованная нами процедура пробоподготовки и измерений, а также полученные концентрации в годичных кольцах

Development and Initial Validation of a Self-Scored COPD Population Screener Questionnaire (COPD-PS)

COPD has a profound impact on daily life, yet remains underdiagnosed and undertreated. We set out to develop a brief, reliable, self-scored questionnaire to identify individuals likely to have COPD. COPD-PS™ development began with a list of concepts identified for inclusion using expert opinion from a clinician working group comprised of pulmonologists (n = 5) and primary care clinicians (n = 5). A national survey of 697 patients was conducted at 12 practitioner sites. Logistic regression identified items discriminating between patients with and without fixed airflow obstruction (AO, postbronchodilator FEV1/FVC < 70%). ROC analyses evaluated screening accuracy, compared scoring options, and assessed concurrent validity. Convergent and discriminant validity were assessed via COPD-PS and SF-12v2 score correlations. For known-groups validation, COPD-PS differences between clinical groups were tested. Test-retest reliability was evaluated in a 20% sample. Of 697 patients surveyed, 295 patients met expert review criteria for spirometry performance; 38% of these (n = 113) had results indicating AO. Five items positively predicted AO (p < 0.0001): breathlessness, productive cough, activity limitation, smoking history, and age. COPD-PS scores accurately classified AO status (area under ROC curve = 0.81) and reliable (r = 0.91). Patients with spirometry indicative of AO scored significantly higher (6.8, SD = 1.9; p < 0.0001) than patients without AO (4.0, SD = 2.3). Higher scores were associated with more severe AO, bronchodilator use, and overnight hospitalization for breathing problems. With the prevalence of COPD in the studied cohort, a score on the COPD-PS of greater than five was associated with a positive predictive value of 56.8% and negative predictive value of 86.4%. The COPD-PS accurately classified physician-reported COPD (AUC = 0.89). The COPD-PS is a brief, accurate questionnaire that can identify individuals likely to have COPD

A Systems Biology Approach Reveals the Role of a Novel Methyltransferase in Response to Chemical Stress and Lipid Homeostasis

Using small molecule probes to understand gene function is an attractive approach that allows functional characterization of genes that are dispensable in standard laboratory conditions and provides insight into the mode of action of these compounds. Using chemogenomic assays we previously identified yeast Crg1, an uncharacterized SAM-dependent methyltransferase, as a novel interactor of the protein phosphatase inhibitor cantharidin. In this study we used a combinatorial approach that exploits contemporary high-throughput techniques available in Saccharomyces cerevisiae combined with rigorous biological follow-up to characterize the interaction of Crg1 with cantharidin. Biochemical analysis of this enzyme followed by a systematic analysis of the interactome and lipidome of CRG1 mutants revealed that Crg1, a stress-responsive SAM-dependent methyltransferase, methylates cantharidin in vitro. Chemogenomic assays uncovered that lipid-related processes are essential for cantharidin resistance in cells sensitized by deletion of the CRG1 gene. Lipidome-wide analysis of mutants further showed that cantharidin induces alterations in glycerophospholipid and sphingolipid abundance in a Crg1-dependent manner. We propose that Crg1 is a small molecule methyltransferase important for maintaining lipid homeostasis in response to drug perturbation. This approach demonstrates the value of combining chemical genomics with other systems-based methods for characterizing proteins and elucidating previously unknown mechanisms of action of small molecule inhibitors

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant