AID Overlapping and Polη Hotspots Are Key Features of Evolutionary Variation Within the Human Antibody Heavy Chain (IGHV) Genes

© Copyright © 2020 Tang, Bagnara, Chiorazzi, Scharff and MacCarthy. Somatic hypermutation (SHM) of the immunoglobulin variable (IgV) loci is a key process in antibody affinity maturation. The enzyme activation-induced deaminase (AID), initiates SHM by creating C → U mismatches on single-stranded DNA (ssDNA). AID has preferential hotspot motif targets in the context of WRC/GYW (W = A/T, R = A/G, Y = C/T) and particularly at WGCW overlapping hotspots where hotspots appear opposite each other on both strands. Subsequent recruitment of the low-fidelity DNA repair enzyme, Polymerase eta (Polη), during mismatch repair, creates additional mutations at WA/TW sites. Although there are more than 50 functional immunoglobulin heavy chain variable (IGHV) segments in humans, the fundamental differences between these genes and their ability to respond to all possible foreign antigens is still poorly understood. To better understand this, we generated profiles of WGCW hotspots in each of the human IGHV genes and found the expected high frequency in complementarity determining regions (CDRs) that encode the antigen binding sites but also an unexpectedly high frequency of WGCW in certain framework (FW) sub-regions. Principal Components Analysis (PCA) of these overlapping AID hotspot profiles revealed that one major difference between IGHV families is the presence or absence of WGCW in a sub-region of FW3 sometimes referred to as “CDR4.” Further differences between members of each family (e.g., IGHV1) are primarily determined by their WGCW densities in CDR1. We previously suggested that the co-localization of AID overlapping and Polη hotspots was associated with high mutability of certain IGHV sub-regions, such as the CDRs. To evaluate the importance of this feature, we extended the WGCW profiles, combining them with local densities of Polη (WA) hotspots, thus describing the co-localization of both types of hotspots across all IGHV genes. We also verified that co-localization is associated with higher mutability. PCA of the co-localization profiles showed CDR1 and CDR2 as being the main contributors to variance among IGHV genes, consistent with the importance of these sub-regions in antigen binding. Our results suggest that AID overlapping (WGCW) hotspots alone or in conjunction with Polη (WA/TW) hotspots are key features of evolutionary variation between IGHV genes

Ureteroscopic lithotripsy for ureteral stones in children using holmium: yag laser energy: results of a multicentric survey

BACKGROUND: Holmium:YAG (Ho:YAG) laser lithotripsy has broadened the indications for ureteroscopic stone managements in adults, but few evidence are currently available in the pediatric population. OBJECTIVE: This article aimed to assess the outcome of Ho:YAG laser lithotripsy during retrograde ureteroscopic management of ureteral stones in different locations in children. STUDY DESIGN: The medical records of 149 patients (71 boys and 78 girls; median age 9.2 years) treated with Ho:YAG laser ureteroscopic lithotripsy in five international pediatric urology units over the last 5 years were retrospectively reviewed. Exclusion criteria included patients with renal calculi and/or with a history of ipsilateral stricture, renal failure, active urinary tract infection, or coagulation disorder. RESULTS: Stones were treated with dusting technique in all cases. The median stone size was 10.3 mm (range 5-17). Stones were located in the distal ureter in 77 cases (51.7%), in the middle ureter in 23 cases (15.4%), and in the proximal ureter in 49 cases (32.9%). The median operative time was 29.8 min (range 20-95). Intra-operative complications included five bleedings (3.3%) and seven stone retropulsions (4.7%). Overall stone-free rate was 97.3%. Overall postoperative complications rate was 4.0% and included two cases of stent migration (1.3%) (Clavien II) and four residual stone fragments (2.7%) that were successfully treated using the same technique (Clavien IIIb). On multivariate analysis, re-operation rate was significantly dependent on the proximal stone location and presence of residual fragments >2 mm (P = 0.001). DISCUSSION: This study is one of the largest pediatric series among those published until now. The study series reported a shorter operative time, a higher success rate, and a lower postoperative complications rate compared with previous series. A limitation of this study is that stone-free rates may be somewhat inaccurate using ultrasonography and plain X-ray compared with computed tomography (CT); the study's 97.3% success rate may be overestimated because no CT scan was done postoperatively to check the stone-free rate. Other limitations of this article include its retrospective nature, the multi-institutional participation, and the heterogeneous patient collective. CONCLUSION: The Ho:YAG laser ureteroscopic lithotripsy seems to be an excellent first-line treatment for children with ureteral stones, independently from primary location and size. However, patients with proximal ureteral stones and residual fragments >2 mm reported a higher risk to require a secondary procedure to become stone-free. Combination of techniques as well as appropriate endourologic tools are key points for the success of the procedure regardless of stones' size and location

Enforcing Termination of Interprocedural Analysis

Interprocedural analysis by means of partial tabulation of summary functions may not terminate when the same procedure is analyzed for infinitely many abstract calling contexts or when the abstract domain has infinite strictly ascending chains. As a remedy, we present a novel local solver for general abstract equation systems, be they monotonic or not, and prove that this solver fails to terminate only when infinitely many variables are encountered. We clarify in which sense the computed results are sound. Moreover, we show that interprocedural analysis performed by this novel local solver, is guaranteed to terminate for all non-recursive programs --- irrespective of whether the complete lattice is infinite or has infinite strictly ascending or descending chains

Resolving Stellar Populations outside the Local Group: MAD observations of UKS2323-326

We present a study aimed at deriving constraints on star formation at intermediate ages from the evolved stellar populations in the dwarf irregular galaxy UKS2323-326. These observations were also intended to demonstrate the scientific capabilities of the multi-conjugated adaptive optics demonstrator (MAD) implemented at the ESO Very Large Telescope as a test-bench of adaptive optics (AO) techniques. We perform accurate, deep photometry of the field using J and Ks band AO images of the central region of the galaxy. The near-infrared (IR) colour-magnitude diagrams clearly show the sequences of asymptotic giant branch (AGB) stars, red supergiants, and red giant branch (RGB) stars down to ~1 mag below the RGB tip. Optical-near-IR diagrams, obtained by combining our data with Hubble Space Telescope observations, provide the best separation of stars in the various evolutionary stages. The counts of AGB stars brighter than the RGB tip allow us to estimate the star formation at intermediate ages. Assuming a Salpeter initial mass function, we find that the star formation episode at intermediate ages produced ~6x10^5 M_sun of stars in the observed region.Comment: 4 pages, 4 figures, Accepted for publication in A&A Letter

Alternating runtime and size complexity analysis of integer programs

We present a modular approach to automatic complexity analysis. Based on a novel alternation between finding symbolic time bounds for program parts and using these to infer size bounds on program variables, we can restrict each analysis step to a small part of the program while maintaining a high level of precision. Extensive experiments with the implementation of our method demonstrate its performance and power in comparison with other tools

Generation of Functional CLL-Specific Cord Blood CTL Using CD40-Ligated CLL APC

PMCID: PMC3526610This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Multivariant Assertion-based Guidance in Abstract Interpretation

Approximations during program analysis are a necessary evil, as they ensure essential properties, such as soundness and termination of the analysis, but they also imply not always producing useful results. Automatic techniques have been studied to prevent precision loss, typically at the expense of larger resource consumption. In both cases (i.e., when analysis produces inaccurate results and when resource consumption is too high), it is necessary to have some means for users to provide information to guide analysis and thus improve precision and/or performance. We present techniques for supporting within an abstract interpretation framework a rich set of assertions that can deal with multivariance/context-sensitivity, and can handle different run-time semantics for those assertions that cannot be discharged at compile time. We show how the proposed approach can be applied to both improving precision and accelerating analysis. We also provide some formal results on the effects of such assertions on the analysis results.Comment: Pre-proceedings paper presented at the 28th International Symposium on Logic-Based Program Synthesis and Transformation (LOPSTR 2018), Frankfurt am Main, Germany, 4-6 September 2018 (arXiv:1808.03326

A Fluorescent Chromatophore Changes the Level of Fluorescence in a Reef Fish

Body coloration plays a major role in fish ecology and is predominantly generated using two principles: a) absorbance combined with reflection of the incoming light in pigment colors and b) scatter, refraction, diffraction and interference in structural colors. Poikilotherms, and especially fishes possess several cell types, so-called chromatophores, which employ either of these principles. Together, they generate the dynamic, multi-color patterns used in communication and camouflage. Several chromatophore types possess motile organelles, which enable rapid changes in coloration. Recently, we described red fluorescence in a number of marine fish and argued that it may be used for private communication in an environment devoid of red. Here, we describe the discovery of a chromatophore in fishes that regulates the distribution of fluorescent pigments in parts of the skin. These cells have a dendritic shape and contain motile fluorescent particles. We show experimentally that the fluorescent particles can be aggregated or dispersed through hormonal and nervous control. This is the first description of a stable and natural cytoskeleton-related fluorescence control mechanism in vertebrate cells. Its nervous control supports suggestions that fluorescence could act as a context-dependent signal in some marine fish species and encourages further research in this field. The fluorescent substance is stable under different chemical conditions and shows no discernible bleaching under strong, constant illumination

Seletividade de herbicidas à cultura da erva-mate.

A erva-mate (Ilex paraguariensis St. Hil.) é uma espécie florestal arbórea nativa da América do Sul. Dentre os fatores que afetam o desenvolvimento das plantas, a interferência por plantas daninhas é um dos mais importantes. Nesse sentido o objetivo desse trabalho foi avaliar a seletividade de herbicidas em plantas de erva-mate de um e dois anos de idade. O experimento foi desenvolvido em casa de vegetação, com delineamento inteiramente casualizado, com arranjo fatorial 2 x 18, com quatro repetições. O fator A foi composto por plantas de erva-mate com 1 e 2 anos de idade, enquanto o fator B era composto por testemunha; clethodim+haloxifop (72+36); imazethapyr (100); chlorimuron (17,5); metsulfuron (6); nicosulfuron (45); nicosulfuron safener (60); diclosulam (25,2); atrazine+s-metalochlor (1295+805); bentazone (720); diquat (400); saflufenacil (24,5); fomesafen (250); oxyfluorfen (720); glyphosate (1440); glufosinate (420); florpyrauxifen (15,93); e fluroxypyr (149,8 g de i.a. ou e.a. ha-1). Foram avaliadas as variáveis fitotoxicidade e altura de plantas. Para a variável altura de plantas os tratamentos não apresentaram diferença estatisticamente significativa. As plantas de 1 ano apresentaram menores níveis de fitotoxicidade quando comparadas às plantas de 2 anos (exceto para glufosinate). Os herbicidas clethodim + haloxifop, imazethapyr e diclosulam apresentaram baixa fitotoxicidade e são uma possibilidade para o uso em erva-mate. Em plantas de 1 ano, todos os inibidores da ALS testados apresentaram baixa fitotoxicidade