A challenging diagnosis of alpha-1-antitrypsin deficiency: identification of a patient with a novel F/Null phenotype

Alpha-1-antitrypsin (A1AT) deficiency is a genetic disease characterized by low levels and/or function of A1AT protein. A1AT deficiency can result in the development of COPD, liver disease, and certain skin conditions. The disease can be diagnosed by demonstrating a low level of A1AT protein and genotype screening for S and Z mutations, which are the most common. However, there are many genetic variants in A1AT deficiency, and this screening may miss rarer cases, such as those caused by dysfunctional protein. We identified a patient with a previously unreported F/null phenotype that was missed by routine screening. This case highlights the wide variation in possible mutations, limitations in diagnostics, and the importance of combining clinical suspicion with measurement of protein levels, phenotypic analysis, and in appropriate cases expanded genetic analysis

Late-stage tectonic evolution of the Al-Hajar Mountains, Oman: New constraints from Palaeogene sedimentary units and low-temperature thermochronometry

Mountain building in the Al-Hajar Mountains (NE Oman) occurred during two major shortening stages, related to the convergence between Africa-Arabia and Eurasia, separated by nearly 30 Ma of tectonic quiescence. Most of the shortening was accommodated during the Late Cretaceous, when northward subduction of the Neo-Tethys Ocean was followed by the ophiolites obduction on top of the former Mesozoic margin. This shortening event lasted until the latest Santonian - early Campanian. Maastrichtian to Eocene carbonates unconformably overlie the eroded nappes and seal the Cretaceous foredeep. These neo-autochthonous post-nappe sedimentary rocks were deformed, along with the underlying Cretaceous tectonic pile, during the second shortening event, itself including two main exhumation stages. In this study we combine remotely sensed structural data, seismic interpretation, field-based structural investigations and apatite (U-Th)/He (AHe) cooling ages to obtain new insights into the Cenozoic deformation stage. Seismic interpretation indicates the occurrence of a late Eocene flexural basin, later deformed by an Oligocene thrusting event, during which the post-nappe succession and the underlying Cretaceous nappes of the internal foredeep were uplifted. This stage was followed by folding of the post-nappe succession during the Miocene. AHe data from detrital siliciclastic deposits in the frontal area of the mountain chain provide cooling ages spanning from 17.3 to 42 Ma, consistent with available data for the structural culminations of Oman. Our work points out how renewal of flexural subsidence in the foredeep and uplift of the mountain belt were coeval processes, followed by layer-parallel shortening preceding final fold amplification

Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity

POLE driver mutations in the exonuclease domain (ExoD driver) are prevalent in several cancers, including colorectal cancer and endometrial cancer, leading to dramatically ultra-high tumor mutation burden (TMB). To understand whether POLE mutations that are not classified as drivers (POLE Variant) contribute to mutagenesis, we assessed TMB in 447 POLE-mutated colorectal cancers, endometrial cancers, and ovarian cancers classified as TMB-high >= 10 mutations/Mb (mut/Mb) or TMB-low <10 mut/Mb. TMB was significantly highest in tumors with POLE ExoD driver plus POLE Variant (colorectal cancer and endometrial cancer, P < 0.001; ovarian cancer, P < 0.05). TMB increased with additional POLE variants (P < 0.001), but plateaued at 2, suggesting an association between the presence of these variants and TMB. Integrated analysis of AlphaFold2 POLE models and quantitative stability estimates predicted the impact of multiple POLE variants on POLE functionality. The prevalence of immunogenic neoepitopes was notably higher in the POLE ExoD driver plus POLE Variant tumors. Overall, this study reveals a novel correlation between POLE variants in POLE ExoD-driven tumors, and ultra-high TMB. Currently, only select pathogenic ExoD mutations with a reliable association with ultra-high TMB inform clinical practice. Thus, these findings are hypothesis-generating, require functional validation, and could potentially inform tumor classification, treatment responses, and clinical outcomes. Significance: Somatic POLE ExoD driver mutations cause proofreading deficiency that induces high TMB. This study suggests a novel modifier role for POLE variants in POLE ExoD-driven tumors, associated with ultra-high TMB. These data, in addition to future functional studies, may inform tumor classification, therapeutic response, and patient outcomes

The significance of the F variant of alpha-1-antitrypsin and unique case report of a PiFF homozygote

BackgroundInheritance of the F variant of alpha-1-antitrypsin is associated with normal circulating protein levels, but it is believed to be dysfunctional in its ability to inhibit neutrophil elastase and therefore has been implicated as a susceptibility factor for the development of emphysema. In this study, its functional characteristics were determined following the identification of a unique patient with the PiFF phenotype, and the implications as a susceptibility factor for emphysema are considered both in homozygotes and heterozygotes.MethodsSecond order association rate constants were measured for M, Z, S and F variants of alpha-1-antitrypsin with neutrophil elastase and proteinase 3. Clinical characteristics of the PiFF homozygote and six PiFZ heterozygote subjects were studied.ResultsThe F variant had a reduced association rate constant with neutrophil elastase (5.60???0.83 ? 106 M-1?s-1) compared to the normal M variant (1.45???0.02 ? 107 M-1?s-1), indicating an increased time to inhibition that was comparable to that of the Z variant (7.34???0.03 ? 106 M-1?s-1). The association rate constant for the F variant and proteinase 3 (1.06???0.22 ? 106 M-1?s-1) was reduced compared to that with neutrophil elastase, but was similar to that of other alpha-1-antitrypsin variants. Of the six PiFZ heterozygotes, five had airflow obstruction and radiological evidence of emphysema. The PiFF homozygote had airflow obstruction but no emphysema. None of the patients had clinical evidence of liver disease.ConclusionsThe F variant may increase susceptibility to elastase-induced lung damage but not emphysema, whereas co-inheritance with the Z deficiency allele may predispose to emphysema despite reasonable plasma concentrations of alpha-1-antitrypsin

Alternating thin versus thick-skinned decollements, example in a fast tectonic setting: The Misool–Onin–Kumawa Ridge (West Papua)

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Mechanisms of basin contraction and reactivation in the basement involved Malargue fold-and thrust-belt, Central Andes (34°S-36°S)

ACLInternational audienc

Evaporitic minibasins of the Sivas basin (Turkey)

AFFInternational audienc

Detection and discrimination of complex thrust and salt tectonics structures using field data and RASAT images around the Emirhan region (Sivas, Turkey) [Emirhan (Sivas) Civarinda Karmasik Bindirme ve Tuz Tektonigi Yapilarinin Arazi Verileri ve RASAT Görüntüleriyle Ortaya Çikarilmasi ve Ayrimi]

ACTInternational audienceRASAT L2 visible and panchromatic images were used to detect both thrust and salt tectonics structures as a reliable geologic mapping tool in this research. As a geographical transition plateau between Inner and Eastern Anatolian region, Sivas Basin doesn't show hampering vegetation on geologic outcroppings for remote sensing analyses. This feature also allow healthy interpretation possibilities. Salt structures in Sivas Basin can be counted in worldwide well-known examples (e.g. La Popa Mexico, Great Kavir Iran and Axel Heiberg Canada) conveniently. In this research, a detailed geological map was prepared in the field. The results show that both of visual interpretations and digital image processing methods spectrally could provide healthy discrimination power between different rock lithologies. Image fusion method was contributed to reveal these subtle tectonic and geomorphologic evidences that developed in and between salt and clastic lithologies. In addition, specifically chosen Landsat ETM+ bands such as 5 and 7 images together with RASAT visible bands were also used to create RGB combinations for geological studies. © 2016 IEEE

Deformation zone ‘jumps’ in a young convergent setting; the Lengguru fold-and-thrust belt, New Guinea Island

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Mechanisms of basin contraction and reactivation in the basement-involved Malargüe fold-and-thrust belt, Central Andes (34-36°S)

ACLInternational audienceWe have conducted a structural study of both the basement-involved Malargüe fold-andthrust belt (MFTB) and the active San Rafael Block (SRB), which are located in the Central Andes at latitude 34-36° S. Based on several field examples located both in the inner and frontal part of belt and from the distal foreland zone, we focus on the relationships between basement and cover deformation with respect to the known palaeogeography and structural inheritance. In several zones, we point out similarities in the structural and sedimentary responses to Andean shortening. The recent morphologic response has also been investigated through the analysis of active deformation along the eastern border of the SRB. We show that these structural and sedimentary processes are continuous in time and space since they can be applied in the various parts of the fold belt and also at different stages of fold-and-thrust-belt building as well. Finally, we propose the illustration of those mechanisms by complete cross-section along the Rio Grande valley and a possible kinematic scenario of deformation propagation. © 2016 Cambridge University Press