Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma

PR domain containing 1 with zinc finger domain (PRDM1)/B lymphocyte–induced maturation protein 1 (BLIMP1) is a transcriptional repressor expressed in a subset of germinal center (GC) B cells and in all plasma cells, and required for terminal B cell differentiation. The BLIMP1 locus lies on chromosome 6q21-q22.1, a region frequently deleted in B cell lymphomas, suggesting that it may harbor a tumor suppressor gene. We report here that the BLIMP1 gene is inactivated by structural alterations in 24% (8 out of 34) activated B cell–like diffuse large cell lymphoma (ABC-DLBCL), but not in GC B cell–like (n = 0/37) or unclassified (n = 0/21) DLBCL. BLIMP1 alterations included gene truncations, nonsense mutations, frameshift deletions, and splice site mutations that generate aberrant transcripts encoding truncated BLIMP1 proteins. In all cases studied, both BLIMP1 alleles were inactivated by deletions or mutations. Furthermore, most non–GC type DLBCL cases (n = 20/26, 77%) lack BLIMP1 protein expression, despite the presence of BLIMP1 mRNA. These results indicate that a sizable fraction of ABC-DLBCL carry an inactive BLIMP1 gene, and suggest that the same gene is inactivated by epigenetic mechanisms in an additional large number of cases. These findings point to a role for BLIMP1 as a tumor suppressor gene, whose inactivation may contribute to lymphomagenesis by blocking post–GC differentiation of B cells toward plasma cells

Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache

Cefalea; Estudio de asociación del genoma completoCefalea; Estudi de l'associació del genoma completHeadache; Genomewide Association StudyObjective Identifying common genetic variants that confer genetic risk for cluster headache. Methods We conducted a case–control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. Results An association was found with cluster headache for 4 independent loci (r2 < 0.1) with genomewide significance (p < 5 × 10−8), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33–1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37–1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26–1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54–0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r2 = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients. Interpretation This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90:203–21

Inversion of provenance data and sediment load into spatially varying erosion rates

Sediment fingerprinting methods aim to determine the relative contribution of different source areas in detrital sediments based on natural properties – fingerprints – of the source areas. Here, we use U/Th–Pb age signatures as fingerprints, assuming that the age signal is not altered during erosion–transportation–deposition events, and given that recent technological advances enable precise dating of large amounts of grains. We introduce a formal inversion method that allows to disentangle the amalgamation of source contributions in detrital zircon data and enables to convert this information into an erosion rate map starting from the spatial distribution of zircon age signatures. Relying on the least‐squares method and using prior and covariance information to deal with non‐uniqueness, we show, using synthetic and natural examples, that we are able to retrieve erosion rate patterns of a catchment when the age distribution and zircon fertility for each source area are well known. Moreover, we show that not only zircon age fingerprints but also other tracers such as mineral content can be used. Furthermore, we found that adding data from samples taken at the outlet of tributaries improves the estimation of erosion rate patterns. We conclude that the least squares inverse model applied to detrital data has great potential for investigating erosion rates

Podoconiosis and soil-transmitted helminths (STHs): double burden of neglected tropical diseases in Wolaita zone, rural southern Ethiopia

Background Both podoconiosis and soil-transmitted helminth (STH) infections occur among barefoot people in areas of extreme poverty; however, their co-morbidity has not previously been investigated. We explored the overlap of STH infection and podoconiosis in Southern Ethiopia and quantified their separate and combined effects on prevalent anemia and hemoglobin levels in podoconiosis patients and health controls from the same area. Methods and Principal Findings A two-part comparative cross-sectional study was conducted in Wolaita zone, southern Ethiopia. Data were collected from adult patients presenting with clinically confirmed podoconiosis, and unmatched adult neighborhood controls living in the same administrative area. Information on demographic and selected lifestyle factors was collected using interviewer-administered questionnaires. Stool samples were collected and examined qualitatively using the modified formalin-ether sedimentation method. Hemoglobin level was determined using two different methods: hemoglobinometer and automated hematology analyzer. A total of 913 study subjects (677 podoconiosis patients and 236 controls) participated. The prevalence of any STH infection was 47.6% among patients and 33.1% among controls (p<0.001). The prevalence of both hookworm and Trichuris trichiura infections was significantly higher in podoconiosis patients than in controls (AOR 1.74, 95% CI 1.25 to2.42, AOR 6.53, 95% CI 2.34 to 18.22, respectively). Not wearing shoes and being a farmer remained significant independent predictors of infection with any STH. There was a significant interaction between STH infection and podoconiosis on reduction of hemoglobin level (interaction p value = 0.002). Conclusions Prevalence of any STH and hookworm infection was higher among podoconiosis patients than among controls. A significant reduction in hemoglobin level was observed among podoconiosis patients co-infected with hookworm and ‘non-hookworm STH’. Promotion of consistent shoe-wearing practices may have double advantages in controlling both podoconiosis and hookworm infection in the study area

Core binding factors are necessary for natural killer cell development, and cooperate with Notch signaling during T cell specification

CBF{beta} is the non-DNA binding subunit of the core binding factors (CBFs). Mice with reduced CBF{beta} levels display profound, early defects in T but not B cell development. Here we show that CBF{beta} is also required at very early stages of natural killer (NK) cell development. We also demonstrate that T cell development aborts during specification, as the expression of Gata3 and Tcf7, which encode key regulators of T lineage specification, is substantially reduced, as are functional thymic progenitors. Constitutively active Notch or IL-7 signaling cannot restore T cell expansion or differentiation of CBF{beta} insufficient cells, nor can overexpression of Runx1 or CBF{beta} overcome a lack of Notch signaling. Therefore the ability of the prethymic cell to respond appropriately to Notch is dependent on CBF{beta}, and both signals converge to activate the T cell developmental program

Изменения ледника Чалаати (Грузинский Кавказ) с малого ледникового периода по данным космогенных изотопов (10Be) и дендрохронологии

Glacier variations over the past centuries are still poorly documented on the southern slope of the Greater Caucasus. In this paper, the change of Chalaati Glacier in the Georgian Caucasus from its maximum extent during the Little Ice Age has been studied. For the first time in the history of glaciological studies of the Georgian Caucasus, 10Be in situ Cosmic Ray Exposure (CRE) dating was applied. The age of moraines was determined by tree-ring analysis. Lichenometry was also used as a supplementary tool to determine the relative ages of glacial landforms. In addition, the large-scale topographical maps (1887, 1960) were used along with the satellite imagery – Corona, Landsat 5 TM, and Sentinel 2B. Repeated photographs were used to identify the glacier extent in the late XIX and early XX centuries. 10Be CRE ages from the oldest lateral moraine of the Chalaati Glacier suggest that the onset of the Little Ice Age occurred ~0.73±0.04 kyr ago (CE ~1250–1330), while the dendrochronology and lichenometry measurements show that the Chalaati Glacier reached its secondary maximum extent again about CE ~1810. From that time through 2018 the glacier area decreased from 14.9±1.5 km2 to 9.9±0.5 km2 (33.8±7.4% or ~0.16% yr−1), while its length retreated by ~2280 m. The retreat rate was uneven: it peaked between 1940 and 1971 (~22.9 m yr−1), while the rate was slowest in 1910– 1930 (~4.0 m yr−1). The terminus elevation rose from ~1620 m to ~1980 m above sea level in ~1810–2018.Для реконструкции колебаний ледника Чалаати в Грузии использовались космические снимки, старые карты, повторные фотографии, дендрохронология, лихенометрия и анализ космогенных изотопов. Максимальное наступание ледника в начале малого ледникового периода произошло в ~1250–1330 гг., второй максимум, когда ледник достиг почти такой же длины, датируется примерно 1810 г. С этого времени до 2018 г. площадь ледника уменьшилась с 14,9±1,5 до 9,9±0,5 км2 (33,8±7,4%, или ~0,16% год−1), а его длина сократилась на ~2280 м

Single-cell RNA sequencing identifies a paracrine interaction that may drive oncogenic notch signaling in human adenoid cystic carcinoma

Salivary adenoid cystic carcinoma (ACC) is a rare, biologically unique biphasic tumor that consists of malignant myoepithelial and luminal cells. MYB and Notch signaling have been implicated in ACC pathophysiology, but in vivo descriptions of these two programs in human tumors and investigation into their active coordination remain incomplete. We utilize single-cell RNA sequencing to profile human head and neck ACC, including a comparison of primary ACC with a matched local recurrence. We define expression heterogeneity in these rare tumors, uncovering diversity in myoepithelial and luminal cell expression. We find differential expression of Notch ligands DLL1, JAG1, and JAG2 in myoepithelial cells, suggesting a paracrine interaction that may support oncogenic Notch signaling. We validate this selective expression in three published cohorts of patients with ACC. Our data provide a potential explanation for the biphasic nature of low- and intermediate-grade ACC and may help direct new therapeutic strategies against these tumors