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Abstract Actin mediates insulin secretion in pancreatic β-cells through remodeling. Hampered by limited resolution, previous studies have offered an ambiguous depiction as depolymerization and repolymerization. We report the in situ structure of actin remodeling in INS-1E β-cells during glucose-stimulated insulin secretion at nanoscale resolution. After remodeling, the actin filament network at the cell periphery exhibits three marked differences: 12% of actin filaments reorient quasi-orthogonally to the ventral membrane; the filament network mainly remains as cell-stabilizing bundles but partially reconfigures into a less compact arrangement; actin filaments anchored to the ventral membrane reorganize from a “netlike” to a “blooming” architecture. Furthermore, the density of actin filaments and microtubules around insulin secretory granules decreases, while actin filaments and microtubules become more densely packed. The actin filament network after remodeling potentially precedes the transport and release of insulin secretory granules. These findings advance our understanding of actin remodeling and its role in glucose-stimulated insulin secretion.

Abstract Background Perinatal outcomes vary for women with gestational diabetes mellitus (GDM). The precise factors beyond glycemic status that may refine GDM diagnosis remain unclear. We conducted a systematic review and meta-analysis of potential precision markers for GDM. Methods Systematic literature searches were performed in PubMed and EMBASE from inception to March 2022 for studies comparing perinatal outcomes among women with GDM. We searched for precision markers in the following categories: maternal anthropometrics, clinical/sociocultural factors, non-glycemic biochemical markers, genetics/genomics or other -omics, and fetal biometry. We conducted post-hoc meta-analyses of a subset of studies with data on the association of maternal body mass index (BMI, kg/m2) with offspring macrosomia or large-for-gestational age (LGA). Results A total of 5905 titles/abstracts were screened, 775 full-texts reviewed, and 137 studies synthesized. Maternal anthropometrics were the most frequent risk marker. Meta-analysis demonstrated that women with GDM and overweight/obesity vs. GDM with normal range BMI are at higher risk of offspring macrosomia (13 studies [n = 28,763]; odds ratio [OR] 2.65; 95% Confidence Interval [CI] 1.91, 3.68), and LGA (10 studies [n = 20,070]; OR 2.23; 95% CI 2.00, 2.49). Lipids and insulin resistance/secretion indices were the most studied non-glycemic biochemical markers, with increased triglycerides and insulin resistance generally associated with greater risk of offspring macrosomia or LGA. Studies evaluating other markers had inconsistent findings as to whether they could be used as precision markers. Conclusions Maternal overweight/obesity is associated with greater risk of offspring macrosomia or LGA in women with GDM. Pregnancy insulin resistance or hypertriglyceridemia may be useful in GDM risk stratification. Future studies examining non-glycemic biochemical, genetic, other -omic, or sociocultural precision markers among women with GDM are warranted.

Abstract In Chronic Myeloid Leukemia, the transition from drug sensitive to drug resistant disease is poorly understood. Here, we used exploratory sequencing of gene transcripts to determine the mechanisms of drug resistance in a dasatinib resistant cell line model. Importantly, cell samples were collected sequentially during drug exposure and dose escalation, revealing several resistance mechanisms which fluctuated over time. BCR::ABL1 overexpression, BCR::ABL1 kinase domain mutation, and overexpression of the small molecule transporter ABCG2, were identified as dasatinib resistance mechanisms. The acquisition of mutations followed an order corresponding with the increase in selective fitness associated with each resistance mechanism. Additionally, it was demonstrated that ABCG2 overexpression confers partial ponatinib resistance. The results of this study have broad applicability and help direct effective therapeutic drug usage and dosing regimens and may be useful for clinicians to select the most efficacious therapy at the most beneficial time.

The authors developed a computational approach to probe the stability of amyloid fibrils and discover networks of hotspot interactions. Understanding the mechanisms of amyloid folding will help identify novel methods to treat protein (mis)folding diseases.

Abstract A definitive diagnosis of Alzheimer’s disease (AD), even in the presence of co-morbid neuropathology (occurring in > 50% of AD cases), is a significant unmet medical need that has obstructed the discovery of effective AD therapeutics. An AD-biomarker, the Morphometric Imaging (MI) assay on cultured skin fibroblasts, was used in a double-blind, allcomers (ages 55–90) trial of 3 patient cohorts: AD dementia patients, N = 25, all autopsy confirmed, non-AD dementia patients, N = 21—all autopsy or genetically confirmed; and non-demented control (AHC) patients N = 27. Fibroblasts cells isolated from 3-mm skin punch biopsies were cultured on a 3-D Matrigel matrix with movement dynamics quantified by image analysis. From counts of all aggregates (N) in a pre-defined field image and measures of the average area (A) of aggregates per image, the number-to-area ratios in a natural logarithmic form Ln(A/N) were determined for all patient samples. AD cell lines formed fewer large aggregates (cells clustered together) than non-AD or AHC cell lines. The cut-off value of Ln(A/N) = 6.98 was determined from the biomarker values of non-demented apparently healthy control (AHC) cases. Unequivocal validation by autopsy, genetics, and/or dementia criteria was possible for all 73 patient samples. The samples were collected from multiple centers—four US centers and one center in Japan. The study found no effect of center-to-center variation in fibroblast isolation, cell growth, or cell aggregation values (Ln(A/N)). The autopsy-confirmed MI Biomarker distinguished AD from non-AD dementia (non-ADD) patients and correctly diagnosed AD even in the presence of other co-morbid pathologies at autopsy (True Positive = 25, False Negative = 0, False Positive = 0, True Negative = 21, and Accuracy = 100%. Sensitivity and specificity were calculated as 100% (95% CI = 84 to 100.00%). From these findings, the MI assay appears to detect AD with great accuracy—even with abundant co-morbidity.

Abstract This study compared different approaches to measuring breast density and breast tissue composition (BTC) in adolescent girls (n = 42, aged 14–16 years) and their mothers (n = 39, aged 36–61 years) from a cohort in Santiago, Chile. Optical spectroscopy (OS) was used to measure collagen, water, and lipid concentrations, which were combined into a percent breast density index (%BDI). A clinical dual-energy X-ray absorptiometry (DXA) system calibrated to measure breast density provided percent fibroglandular volume (%FGV) from manually delineated images. After digitizing mammogram films, the percent mammographic breast density (%MBD) was measured using computer-assisted software. Partial correlation coefficients (r partial) were used to evaluate associations between breast density measures and BTC from these three different measurement approaches, adjusting for age and body mass index. %BDI from OS was associated with %FGV from DXA in adolescent girls (r partial = 0.46, p-value = 0.003), but not in mothers (r partial = 0.17, p-value = 0.32). In mothers, %FGV from DXA was associated with %MBD from mammograms (r partial = 0.60, p-value

Giant icy volcanos (cryovolcanos) on Pluto are unique in the imaged solar system and provide evidence for unexpected, active geology late in Pluto’s history.

Abstract Maar-diatreme volcanoes are the second-most common type on land, occurring in volcanic fields within all major tectonic environments. Their deposits typically contain an abundance of lithic fragments quarried from the substrate, and many contain large, deep-sourced lithic fragments that were erupted to the surface. Primary volcaniclastic deposits fill the diatreme structure formed during eruption. There is negligible inelastic deformation of diatreme-adjacent country rock, indicating that country rock is removed to create the diatreme structures, either by being shifting downward below observable levels, ejected upward to contribute to surficial deposits, or dissolved and hidden in magma erupted or intruded at depth. No previous study has systematically reviewed and analysed the reported lithic fragments of maar-diatreme systems. We present a comprehensive compilation from published work of lithic characteristics in maar ejecta rings and in diatreme deposits of both common and kimberlite maar-diatremes. For maar-diatremes and their tephra ring deposits, we find no correlations among lithic clast sizes, shapes, depositional sites, and excavation depths. This is difficult to reconcile with models involving systematic diatreme deepening coupled with tephra-ring growth, but consistent with those involving chaotic explosions and mixing. Larger amounts of data are needed to further examine how these types of volcanoes operate.

Abstract Reading requires the correct identification of letters and letter positions within words. Selective attention is, therefore, required to select chunks of the text for sequential processing. Despite the extensive literature on visual attention, the well-known effects of spatial cues in simple perceptual tasks cannot inform us about the role of attention in a task as complex as reading. Here, we systematically manipulate spatial attention in a multi-letter processing task to understand the effects of spatial cues on letter encoding in typical adults. Overall, endogenous (voluntary) cue benefits were larger than exogenous (reflexive). We show that cue benefits are greater in the left than in the right visual field and larger for the most crowded letter positions. Endogenous valid cues reduced errors due to confusing letter positions more than misidentifications, specifically for the most crowded letter positions. Therefore, shifting endogenous attention along a line of text is likely an important mechanism to alleviate the effects of crowding on encoding letters within words. Our results help set the premise for constructing theories about how specific mechanisms of attention support reading development in children. Understanding the link between reading development and attention mechanisms has far-reaching implications for effectively addressing the needs of children with reading disabilities.

The success of CAR-T cells for treating acute myeloid leukaemia (AML) is hampered by toxicity to normal cells and low CAR-T cell persistence. Here, the authors show that the demethylating compound 5′-Azacitdine increases anti-CD123 CAR-T cell cytotoxicity against AML.

Abstract Ruxolitinib (rux) Phase II clinical trials are underway for the treatment of high-risk JAK2-rearranged (JAK2r) B-cell acute lymphoblastic leukemia (B-ALL). Treatment resistance to targeted inhibitors in other settings is common; elucidating potential mechanisms of rux resistance in JAK2r B-ALL will enable development of therapeutic strategies to overcome or avert resistance. We generated a murine pro-B cell model of ATF7IP-JAK2 with acquired resistance to multiple type-I JAK inhibitors. Resistance was associated with mutations within the JAK2 ATP/rux binding site, including a JAK2 p.G993A mutation. Using in vitro models of JAK2r B-ALL, JAK2 p.G993A conferred resistance to six type-I JAK inhibitors and the type-II JAK inhibitor, CHZ-868. Using computational modeling, we postulate that JAK2 p.G993A enabled JAK2 activation in the presence of drug binding through a unique resistance mechanism that modulates the mobility of the conserved JAK2 activation loop. This study highlights the importance of monitoring mutation emergence and may inform future drug design and the development of therapeutic strategies for this high-risk patient cohort.

Using phasor-FLIM (Fluorescence Lifetime Imaging Microscopy), Wang et al. reveal differential usages of oxidative phosphorylation and glycolysis in living islet cells following glucose stimulation. This study suggests the applicability of FLIM as a drug discovery tool as it reports perturbations in glucose metabolism in living islet cells.

Abstract In this study we used the Illumina Infinium Methylation array to investigate in a cohort of matched archival human tissue samples (n = 32) from 14 individuals with soft tissue sarcomas if genome-wide methylation changes occur during metastatic and recurrent (Met/Rec) disease. A range of sarcoma types were selected for this study: leiomyosarcoma (LMS), myxofibrosarcoma (MFS), rhabdomyosarcoma (RMS) and synovial sarcoma (SS). We identified differential methylation in all Met/Rec matched samples, demonstrating that epigenomic differences develop during the clonal evolution of sarcomas. Differentially methylated regions and genes were detected, not been previously implicated in sarcoma progression, including at PTPRN2 and DAXX in LMS, WT1-AS and TNXB in SS, VENTX and NTRK3 in pleomorphic RMS and MEST and the C14MC / miR-379/miR-656 in MFS. Our overall findings indicate the presence of objective epigenetic differences across primary and Met/Rec human tissue samples not previously reported.

As quantum computing devices become more complex, they enter the realm of correlated noise, which is difficult to characterise and mitigate. Here, the authors demonstrate, over a range of superconducting devices, a method for non-Markovian dynamics characterisation based on the process tensor framework.

Abstract Quantitative shape analysis of juvenile pyroclasts is applied in volcanology to reconstruct the dynamics and styles of eruptions, and to explore the details of tephra transport, dispersal, and emplacement. Morphometric analyses often include comparison of multiple data sets with a set of dimensionless shape parameters. Here we present “DendroScan”, an open source Matlab program that provides the user with all the multivariate statistical methods needed to produce such morphometric comparisons. Serving as a statistical “toolbox”, DendroScan conducts Levene-, t-, and equivalence tests, presenting the results in ad hoc interpretable graphs. Furthermore, it is designed to conduct dendrogrammatic analyses of particle morphometry, a recently developed approach for the inter-comparison of multiple morphometric data sets. DendroScan produces tree diagrams, in which the analysed samples are sorted according to their morphometric dissimilarity, allowing the user to identify, e.g., samples that are statistically equivalent. To demonstrate DendroScan’s potential, ten experimental samples are compared with volcanic ash samples generated by the Havre 2012 deep-sea eruption in the Kermadec arc (New Zealand). We show how, using DendroScan-based results, information on the eruptive mechanism can be inferred, and how the cooling history of the experimental melt is reflected in the dissimilarity of thermally granulated fragments.

Pluto is covered by numerous deposits of methane. Here, the authors show that the formation of methane frost on mountain tops and crater rims in Pluto’s equatorial regions completely differ from those forming snow-capped mountains on Earth.

The activity of several protein kinases is increased upon cellular production of reactive oxygen species, which can cause cysteine oxidation. Here the authors show that sulfenylation of specific cysteine residues within Src induce local structural changes that directly impact its activation.

Shallow magmatic feeder systems in monogenetic volcanic fields may determine how a volcano erupts. Here, the authors use numerical modeling to show that explosive excavation and infilling of eruptive craters affects local stress states, with feedbacks controlling sites and depths of crater-forming explosions.

Copper selenide is super-ionic only at high temperatures. Here, the authors discover room temperature super-ionic behaviour in ultrasmall clusters of Cu2Se—but not in its larger or bulk forms—owing to an unusual liquid-like cationic sub-lattice, in which octahedral sites are stabilized by size-dependent compressive strain.