Non-rigid image registration to reduce beam-induced blurring of cryo-electron microscopy images

Microscopic imaging and technolog

Tectonic influences on the preservation of marine terraces: Old and new evidence from Santa Catalina Island, California

The California Channel Islands contain some of the best geologic records of past climate and sea-level changes, recorded in uplifted, fossil-bearing marine terrace deposits. Among the eight California Channel Islands and the nearby Palos Verdes Hills, only Santa Catalina Island does not exhibit prominent emergent marine terraces, though the same terrace-forming processes that acted on the other Channel Islands must also have occurred on Santa Catalina. We re-evaluated previous researchers\u27 field evidence and examined new topographic, bathymetric, and stream-profile data in order to find possible explanations for the lack of obvious marine terrace landforms or deposits on the island today. The most likely explanation is associated with the island\u27s unresolved tectonic history, with evidence for both recent uplift and subsidence being offered by different researchers. Bathymetric and seismic reflection data indicate the presence of submerged terrace-like landforms from a few meters below present sea level to depths far exceeding that of the lowest glacial lowstand, suggesting that the Catalina Island block may have subsided, submerging marine terraces that would have formed in the late Quaternary. Similar submerged marine terrace landforms exist offshore of all of the other California Channel Islands, including some at anomalously great depths, but late Quaternary uplift is well documented on those islands. Therefore, such submarine features must be more thoroughly investigated and adequately explained before they can be accepted as definitive evidence of subsidence. Nevertheless, the striking similarity of the terrace-like features around Santa Catalina Island to those surrounding the other, uplifting, Channel Islands prompted us to investigate other lines of evidence of tectonic activity, such as stream profile data. Recent uplift is suggested by disequilibrium stream profiles on the western side of the island, including nickpoints and profile convexities. Rapid uplift is also indicated by the island\u27s highly dissected, steep topography and abundant landslides. A likely cause of uplift is a restraining bend in the offshore Catalina strike-slip fault. Our analysis suggests that Santa Catalina Island has recently experienced, and may still be experiencing, relatively rapid uplift, causing intense landscape rejuvenation that removed nearly all traces of marine terraces by erosion. A similar research approach, incorporating submarine as well as subaerial geomorphic data, could be applied to many tectonically active coastlines in which a marine terrace record appears to be missing

The molecular basis for apolipoprotein E4 as the major risk factor for late onset Alzheimer's disease

Apolipoprotein E4 (ApoE4) is one of three (E2, E3 and E4) human isoforms of an -helical, 299-amino acid protein. Homozygosity for the ε4 allele is the major risk factor for developing late onset Alzheimer’s disease (AD). ApoE2, ApoE3 and ApoE4 differ at amino acid positions 112 and 158 and these sequence variations may confer conformational differences that underlie their participation in the risk of developing AD. Here, we compared the shape, oligomerisation state, conformation and stability of ApoE isoforms using a range of complementary biophysical methods including small angle X-ray scattering, analytical ultracentrifugation, circular dichroism, X-ray fibre diffraction and transmission electron microscopy We provide an in-depth and definitive study demonstrating that all three proteins are similar in stability and conformation. However, we show that ApoE4 has a propensity to polymerise to form wavy filaments which do not share the characteristics of cross- amyloid fibrils. Moreover, we provide evidence for the inhibition of ApoE4 fibril formation by ApoE3. This study shows that recombinant ApoE isoforms show no significant differences at the structural or conformational level. However, self-assembly of the ApoE4 isoform may play a role in pathogenesis and these results open opportunities for uncovering new triggers for AD onset

The MLL-Menin Interaction is a Therapeutic Vulnerability in <em>NUP98</em>-rearranged AML

\ua9 2023 Wolters Kluwer Health. All rights reserved. Chromosomal translocations involving the NUP98 locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with NUP98 fusions is characterized by high expression of HOXA and MEIS1 genes and is associated with poor clinical outcome. NUP98 fusion proteins are recruited to their target genes by the mixed lineage leukemia (MLL) complex, which involves a direct interaction between MLL and Menin. Here, we show that therapeutic targeting of the Menin-MLL interaction inhibits the propagation of NUP98-rearrranged AML both ex vivo and in vivo. Treatment of primary AML cells with the Menin inhibitor revumenib (SNDX-5613) impairs proliferation and clonogenicity ex vivo in long-term coculture and drives myeloid differentiation. These phenotypic effects are associated with global gene expression changes in primary AML samples that involve the downregulation of many critical NUP98 fusion protein-target genes, such as MEIS1 and CDK6. In addition, Menin inhibition reduces the expression of both wild-type FLT3 and mutated FLT3-ITD, and in combination with FLT3 inhibitor, suppresses patient-derived NUP98-r AML cells in a synergistic manner. Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that NUP98-rearranged AMLs are highly susceptible to inhibition of the MLL-Menin interaction and suggest the inclusion of AML patients harboring NUP98 fusions into the clinical evaluation of Menin inhibitors

Revealing low-dose radiation damage using single-crystal spectroscopy

Data on the rapid reduction of haem proteins in the X-ray beam at synchrotron sources are presented. The use of single-crystal spectroscopy to detect these changes and their implication for diffraction data collection from oxidized species is also discussed