Distinct Events Research Articles

Yangtze and Cathaysia blocks of South China: Their separate positions in Gondwana until early Paleozoic juxtaposition

The position of South China in Gondwana remains controversial. In all previous models, the Yangtze and Cathaysia blocks, the two major components of South China, were amalgamated by the Tonian, and South China was considered to be a single coherent block in Gondwana. Based on a summary and critical reevaluation of available paleomagnetic, paleontological, stratigraphic, and detrital zircon data, we propose that the Yangtze and Cathaysia blocks were not juxtaposed until the early Paleozoic and were located at two separate parts of the northern margin of Gondwana before that time. The Yangtze block was located to the northwest of India in the Ediacaran and early Cambrian. Cathaysia was close to or a part of northern Australia in the Ediacaran, when Australia and India were separated by the Kuunga Ocean, and amalgamated with the eastern margin of India in the late Ediacaran to early Cambrian when the ocean closed. Our model implies that the early Paleozoic orogenesis in South China could have been related to two distinct events, the late Ediacaran to early Cambrian collision of Cathaysia/Australia with India (the Kuunga orogeny) and the Late Ordovician amalgamation of Cathaysia with Yangtze. It also implies that the Yangtze and Cathaysia blocks likely occupied two separate positions in Rodinia.

Oxygen-Glucose Deprivation in Organotypic Hippocampal Cultures Leads to Cytoskeleton Rearrangement and Immune Activation: Link to the Potential Pathomechanism of Ischaemic Stroke.

Ischaemic stroke is characterized by a sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. As a result of this process, neurons in the ischaemic core are deprived of oxygen and trophic substances and are consequently destroyed. Tissue damage in brain ischaemia results from a complex pathophysiological cascade comprising various distinct pathological events. Ischaemia leads to brain damage by stimulating many processes, such as excitotoxicity, oxidative stress, inflammation, acidotoxicity, and apoptosis. Nevertheless, less attention has been given to biophysical factors, including the organization of the cytoskeleton and the mechanical properties of cells. Therefore, in the present study, we sought to evaluate whether the oxygen-glucose deprivation (OGD) procedure, which is a commonly accepted experimental model of ischaemia, could affect cytoskeleton organization and the paracrine immune response. The abovementioned aspects were examined ex vivo in organotypic hippocampal cultures (OHCs) subjected to the OGD procedure. We measured cell death/viability, nitric oxide (NO) release, and hypoxia-inducible factor 1α (HIF-1α) levels. Next, the impact of the OGD procedure on cytoskeletal organization was evaluated using combined confocal fluorescence microscopy (CFM) and atomic force microscopy (AFM). Concurrently, to find whether there is a correlation between biophysical properties and the immune response, we examined the impact of OGD on the levels of crucial ischaemia cytokines (IL-1β, IL-6, IL-18, TNF-α, IL-10, IL-4) and chemokines (CCL3, CCL5, CXCL10) in OHCs and calculated Pearsons' and Spearman's rank correlation coefficients. The results of the current study demonstrated that the OGD procedure intensified cell death and nitric oxide release and led to the potentiation of HIF-1α release in OHCs. Moreover, we presented significant disturbances in the organization of the cytoskeleton (actin fibers, microtubular network) and cytoskeleton-associated protein 2 (MAP-2), which is a neuronal marker. Simultaneously, our study provided new evidence that the OGD procedure leads to the stiffening of OHCs and a malfunction in immune homeostasis. A negative linear correlation between tissue stiffness and branched IBA1 positive cells after the OGD procedure suggests the pro-inflammatory polarization of microglia. Moreover, the negative correlation of pro- and positive anti-inflammatory factors with actin fibers density indicates an opposing effect of the immune mediators on the rearrangement of cytoskeleton induced by OGD procedure in OHCs. Our study constitutes a basis for further research and provides a rationale for integrating biomechanical and biochemical methods in studying the pathomechanism of stroke-related brain damage. Furthermore, presented data pointed out the interesting direction of proof-of-concept studies, in which follow-up may establish new targets for brain ischemia therapy.

From Rodinian passive margin to peri-Siberian continental arc: Evidence from the multiphase Neoproterozoic–early Paleozoic magmatic record of the Zavkhan Block in the Mongolian Collage

Geochronological and geochemical study of the Neoproterozoic–early Paleozoic magmatic record was carried out in two sections of the Zavkhan Block, one of the largest continental fragments within the Mongolian Collage of the Central Asian Orogenic Belt. Our results show that two distinct magmatic events occurred in both studied domains, the Late Tonian (c. 840–800 Ma) and the Cambro–Ordovician (c. 510–470 Ma). Based on the variable geochemical signatures and two-stage Nd model ages (TNd.2stgDM=1.4–3.0 Ga), the late Tonian magmatism included both mantle-derived magmas that suffered a crustal contamination as well as partial melts of a heterogeneous continental crust that ranged from Paleo- to Mesoproterozoic (felsic metaigneous rocks or immature metagreywackes) to Neoarchean–Paleoproterozoic (metabasalts or metatonalites). The Cambro–Ordovician basic–acidic magmatism (TNd.2stgDM=1.3–2.2 Ga) reflected interplay between two components, mafic juvenile (depleted-mantle-derived) and felsic, generated by anatexis of Tonian, mainly metabasic crust. The late Tonian (c. 840–800 Ma) magmatic activity is interpreted as result of intracontinental rifting, whereas the Cambro–Ordovician (c. 510–470 Ma) magmatism is linked to a continental magmatic-arc system.The comparison of the data from the Zavkhan Block with other microcontinents of the Mongolian Collage shows that most of them experienced an identical two-stage magmatic evolution. The first stage is interpreted as a result of the Rodinia break-up, whereas the second one was associated with inception of the Paleo-Pacific Plate subduction. Based on similarities in the magmatic record, we conclude that the Mongolian Collage microcontinents were located at the Rodinia periphery, as a part of either the Siberian or Tarim cratons. They were separated in the late Tonian, established a passive margin and drifted towards southern Siberia, where they recorded arc magmatism related to the Cambro–Ordovician subduction of the Paleo-Pacific Plate.

Automated Diet Capture Using Voice Alerts and Speech Recognition on Smartphones: Pilot Usability and Acceptability Study.

Effective monitoring of dietary habits is critical for promoting healthy lifestyles and preventing or delaying the onset and progression of diet-related diseases, such as type 2 diabetes. Recent advances in speech recognition technologies and natural language processing present new possibilities for automated diet capture; however, further exploration is necessary to assess the usability and acceptability of such technologies for diet logging. This study explores the usability and acceptability of speech recognition technologies and natural language processing for automated diet logging. We designed and developed base2Diet-an iOS smartphone application that prompts users to log their food intake using voice or text. To compare the effectiveness of the 2 diet logging modes, we conducted a 28-day pilot study with 2 arms and 2 phases. A total of 18 participants were included in the study, with 9 participants in each arm (text: n=9, voice: n=9). During phase I of the study, all 18 participants received reminders for breakfast, lunch, and dinner at preselected times. At the beginning of phase II, all participants were given the option to choose 3 times during the day to receive 3 times daily reminders to log their food intake for the remainder of the phase, with the ability to modify the selected times at any point before the end of the study. The total number of distinct diet logging events per participant was 1.7 times higher in the voice arm than in the text arm (P=.03, unpaired t test). Similarly, the total number of active days per participant was 1.5 times higher in the voice arm than in the text arm (P=.04, unpaired t test). Furthermore, the text arm had a higher attrition rate than the voice arm, with only 1 participant dropping out of the study in the voice arm, while 5 participants dropped out in the text arm. The results of this pilot study demonstrate the potential of voice technologies in automated diet capturing using smartphones. Our findings suggest that voice-based diet logging is more effective and better received by users compared to traditional text-based methods, underscoring the need for further research in this area. These insights carry significant implications for the development of more effective and accessible tools for monitoring dietary habits and promoting healthy lifestyle choices.

Assessing Sustainable Development of Deep Aquifers

AbstractDeep groundwater aquifers are exploited for a variety of purposes. In general, impermeable rock layers protect these aquifers from anthropogenic influences. As such, they are a last resort for groundwater in a pre-industrial state, and a crucial resource in cases of emergency, such as floods contaminating shallow groundwater. The EU Water Framework Directive (WFD) provides the regulatory framework to protect its quality and quantity. Recent monitoring of the hydrochemical state of Upper Jurassic wells in Bavaria and Austria has shown fluctuations that were connected to new exploitation activities and might indicate an unsustainable development of the aquifer. We propose a new workflow in accordance with the WFD which uses clustering algorithms to assess these fluctuations. Our data consists of 5 to 42 hydrochemical analyses per well with yearly sampling intervals spanning up to 30 years. From the cluster analysis we derived thresholds for two corridors: Natural Range Corridor (NC) and Action Corridor (AC). While the NC represents a well-specific natural variation range, the AC hints towards unsustainable development and should trigger a detailed (re)assessment. To show the potential of the new method, the workflow was applied to two wells with different geological characteristics. Distinct fluctuation events were clearly recognized and can be used in the context of an early warning system, such that malign hydrochemical variations can be detected before they become legally problematic to well operators. Our workflow thus provides a novel, robust, and reproducible method to assess the grade of sustainability at which a well is exploited and ensures a good status of a unique and important resource.

Trauma history predicts depression and posttraumatic stress symptoms better than a psychiatric diagnosis: Comparing wartime, routine time, and early COVID-19 in Israel.

Individuals with a psychiatric diagnosis and those with a history of trauma are at high risk for depression and posttraumatic stress symptoms (PTSS) following exposure to new traumatic events. Nevertheless, research is scarce on how having both a psychiatric diagnosis and a trauma history affect reactions to new traumatic events, and how different trauma types may affect individuals with a psychiatric diagnosis. We thus examined whether different stressful contexts (War and COVID-19) affected individuals with and without a psychiatric diagnosis differentially and whether results might be explained by prior trauma exposure. In the same cohort, we assessed depression and PTSS during wartime (2014), routine time (2016), and during the COVID-19 pandemic (2020) in a sample with (n=89) and without (n=104) a self-reported psychiatric diagnosis. This cohort was recruited during the 2014 Israel-Gaza War using social media, snowballing and outreach to mental health rehabilitation centres. We used a linear mixed modelling approach on data from the entire sample, as well as on the two study groups separately. We found that trauma history predicted PTSS and depression whereas a history of psychiatric diagnosis did not. Regarding trauma types, we found that individuals in the psychiatric diagnosis group relative to themselves had more symptoms during COVID-19 compared to war and routine time, while those without diagnosis had more PTSS and depression symptoms during wartime compared to routine time and COVID-19. In conclusion, a traumatic past may have an important influence on reactions to different types of traumatic events. Distinct traumatic events may affect individuals with or without a psychiatric diagnosis differentially.

Chronology of detrital carbonate events in Baffin Bay reveals different timing but similar average recurrence time of North American-Arctic and Laurentide ice sheet collapse events during MIS 3

Baffin Bay Detrital Carbonate (BBDC) layers represent periods of elevated discharge of terrigenous sediments, icebergs and freshwater originating from the North American Arctic-ice sheet complex. Distinct from Heinrich event layers in their dolomitic composition, these sedimentary deposits are found throughout Baffin Bay. They are considered a signature of large-scale instability of the ice sheets discharging into the Baffin Bay, akin to the Heinrich events of the North Atlantic. However, the precise timing of and potential forcing mechanisms for the North American Arctic-ice sheet instabilities remains elusive. Previous work suggests that BBDC events were not in phase with Heinrich events originating from the Hudson Strait, but this hypothesis could not be tested without rigorous chronological constraints. By combining radiocarbon ages and relative paleointensity (RPI) dating in a central western Baffin Bay marine sedimentary sequence, we were able to derive a new chronology for BBDC events covering a large part of MIS3. Sedimentological and elemental data indicate the occurrence of seven distinct BBDC events over the last 52 ka. These events occur during both glacials (stadials) and interglacials (interstadials) and have no consistent phase relationship with Heinrich events. However, the mean duration and mean recurrence time of BBDC events appears similar to Heinrich events. We conclude that BBDC events reflect repeated ice sheet instability periods, with similar statistical properties but different timing compared to the Heinrich events. This implies that episodic instability was an intrinsic property of the North American Arctic-ice sheet complex as well, but over the studied period of MIS3, instabilities of the Arctic and the Laurentide Ice sheets did not appear to have been linked.

ARPC5 isoforms and their regulation by calcium-calmodulin-N-WASP drive distinct Arp2/3-dependent actin remodeling events in CD4 T cells.

CD4 T cell activation induces nuclear and cytoplasmic actin polymerization via the Arp2/3 complex to activate cytokine expression and strengthen T cell receptor (TCR) signaling. Actin polymerization dynamics and filament morphology differ between nucleus and cytoplasm. However, it is unclear how the Arp2/3 complex mediates distinct nuclear and cytoplasmic actin polymerization in response to a common stimulus. In humans, the ARP3, ARPC1, and ARPC5 subunits of the Arp2/3 complex exist as two different isoforms, resulting in complexes with different properties. Here, we show that the Arp2/3 subunit isoforms ARPC5 and ARPC5L play a central role in coordinating distinct actin polymerization events in CD4 T cells. While ARPC5L is heterogeneously expressed in individual CD4 T cells, it specifically drives nuclear actin polymerization upon T cell activation. In contrast, ARPC5 is evenly expressed in CD4 T cell populations and is required for cytoplasmic actin dynamics. Interestingly, nuclear actin polymerization triggered by a different stimulus, DNA replication stress, specifically requires ARPC5 but not ARPC5L. TCR signaling but not DNA replication stress induces nuclear actin polymerization via nuclear calcium-calmodulin signaling and N-WASP. Diversity in the molecular properties and individual expression patterns of ARPC5 subunit isoforms thus tailors Arp2/3-mediated actin polymerization to different physiological stimuli.

Intermediate Outcomes of the Novel 63-μm Gelatin Microstent versus the Conventional 45-μm Gelatin Microstent

To determine intermediate intraocular pressure (IOP)-lowering and adverse event profile of the 63-μm gelatin microstent (Xen63) with mitomycin C (MMC) compared with the 45-μm gelatin microstent (Xen45) with MMC. Single center, consecutive, retrospective cohort study. Eighty-four glaucomatous eyes (42 63-μm gelatin microstent and 42 45-μm gelatin microstent) with or without previous subconjunctival glaucoma surgery. Consecutive eyes that underwent 63-μm gelatin microstent implantation with MMC from February 2020 to June 2021 were compared with eyes that underwent 45-μm gelatin microstent implantation with MMC. Standalone and combined cases with phacoemulsification were included. Primary outcome was the hazard ratio of failure of 45-μm gelatin microstent vs. 63-μm gelatin microstent eyes at 12 months, with failure defined as 2 consecutive IOPs, (1) >17 mmHg, (2) <6 mmHg with 2 lines of vision loss, or (3) <20% reduction from baseline IOP, without (complete) or with (qualified) glaucoma medications. Secondary outcomes included IOP thresholds of 14 mmHg and 21 mmHg, postoperative IOP, medications, adverse events, interventions, and reoperations. The complete success rate was higher in the 63-μm gelatin microstent group (59.5% vs. 28.6%, P=0.009) at the primary IOP threshold of 6 to 17 mmHg but did not differ significantly for qualified success (66.7% vs. 45.2%, P= 0.08). The crude hazard ratio of failure of 45-μm gelatin microstent relative to 63-μm gelatin microstent was 2.28 (95% confidence interval [CI], 1.21-4.32), and the adjusted hazard ratio was 7.90 (95% CI, 2.12-29.43). 63-μm gelatin microstent eyes had significantly lower mean IOP (12.7 ± 4.8 vs. 15.5 ± 5.1 mmHg, P= 0.001) and fewer medication classes (0.6 ± 1.1 vs. 1.7 ± 1.6 medications, P= 0.0005), with the degree of reduction in IOP and medication count being significantly greater in 63-μm gelatin microstent eyes. There were 28 and 21 distinct interventions in 63-μm gelatin microstent and 45-μm gelatin microstent eyes respectively, with 11.9% of eyes undergoing needling in each group. There were 34 and 19 distinct adverse events, in 63-μm gelatin microstent and 45-μm gelatin microstent eyes, respectively, most of which were early and transient. Nine Xen63 eyes (21.4%) and 6 45-μm gelatin microstent eyes (14.3%) underwent reoperation. 63-μm gelatin microstent resulted in higher surgical success rates and fewer medications compared with 45-μm gelatin microstent. This was tempered by more postoperative interventions and adverse events, although most were transient. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Making sense of transmission resonances and Smith lifetimes in one-dimensional scattering: The extended phase space quantum trajectory picture

Resonances are ubiquitous in a wide range of physical and chemical phenomena. Their impact on quantum scattering processes renders their study as important as it can be puzzling. In this paper, we illustrate the accuracy of a fully quantum, purely trajectory based reformulation of quantum mechanics proposed by one of the authors (Poirier) to acquire insights on shape resonances through direct and accurate computation of the diagonal elements of Smith’s lifetime matrix. This study also generalizes the relationship between the quantum trajectory propagation time and the Eisenbud–Wigner time delay – introduced in our previous publication (Dupuy et al., 2022) for symmetric potentials – to the general case of asymmetric potential profiles. In addition, we show how the complex amplitudes of the scattering matrix can be extracted from left- and right-incident quantum trajectories. Finally, we demonstrate that extended phase space quantum trajectories not only recover S-matrix and quantum time quantities, but they also provide their own picture of resonant phenomena, as dynamically distinct events characterized by an integer number of closed orbits in the quantum phase space.

Safety of continuous intraoperative vagus nerve neuromonitoring during thyroid surgery.

Continuous intraoperative neuromonitoring has successfully demonstrated to predict impending damage to the recurrent laryngeal nerve, by detecting changes in electromyographic recordings. Despite the apparent benefits associated with continuous intraoperative neuromonitoring, its safety is still a debate. The aim of this study was to investigate the electrophysiological impact of continuous intraoperative neuromonitoring on the vagus nerve. In this prospective study, the amplitude of the electromyographic wave of the vagus nerve-recurrent laryngeal nerve axis was measured both proximally and distally to the stimulation electrode placed upon the vagus nerve. Electromyographic signal amplitudes were collected at three distinct events during the operation: during the dissection of the vagus nerve, before application of the continuous stimulation electrode onto the vagus nerve and after its removal. In total, 169 vagus nerves were analysed, among 108 included patients undergoing continuous intraoperative neuromonitoring-enhanced endocrine neck surgeries. Electrode application resulted in a significant overall decrease in measured proximo-distal amplitudes of -10.94 µV (95 per cent c.i. -17.06 to -4.82 µV) (P < 0.005), corresponding to a mean(s.d.) decrease of -1.4(5.4) per cent. Before the removal of the electrode, the measured proximo-distal difference in amplitudes was -18.58 µV (95 per cent c.i. -28.31 to -8.86 µV) (P < 0.005), corresponding to a mean(s.d.) decrease of -2.50(9.59) per cent. Seven nerves suffered a loss of amplitude greater than 20 per cent of the baseline measurement. In addition to supporting claims that continuous intraoperative neuromonitoring exposes the vagus nerve to injury, this study shows a mild electrophysiological impact of continuous intraoperative neuromonitoring electrode placement on the vagus nerve-recurrent laryngeal nerve axis. However, the small observed differences are negligible and were not associated with a clinically relevant outcome, making continuous intraoperative neuromonitoring a safe adjunct in selected thyroid surgeries.

Mapping Pluvial Flood-Induced Damages with Multi-Sensor Optical Remote Sensing: A Transferable Approach

Pluvial floods caused by extreme overland flow inland account for half of all flood damage claims each year along with fluvial floods. In order to increase confidence in pluvial flood susceptibility mapping, overland flow models need to be intensively evaluated using observations from past events. However, most remote-sensing-based flood detection techniques only focus on the identification of degradations and/or water pixels in the close vicinity of overflowing streams after heavy rainfall. Many occurrences of pluvial-flood-induced damages such as soil erosion, gullies, landslides and mudflows located further away from the stream are thus often unrevealed. To fill this gap, a transferable remote sensing fusion method called FuSVIPR, for Fusion of Sentinel-2 &amp; Very high resolution Imagery for Pluvial Runoff, is developed to produce damage-detection maps. Based on very high spatial resolution optical imagery (from Pléiades satellites or airborne sensors) combined with 10 m change images from Sentinel-2 satellites, the Random Forest and U-net machine/deep learning techniques are separately trained and compared to locate pluvial flood footprints on the ground at 0.5 m spatial resolution following heavy weather events. In this work, three flash flood events in the Aude and Alpes-Maritimes departments in the South of France are investigated, covering over more than 160 km2 of rural and periurban areas between 2018 and 2020. Pluvial-flood-detection accuracies hover around 75% (with a minimum area detection ratio for annotated ground truths of 25%), and false-positive rates mostly below 2% are achieved on all three distinct events using a cross-site validation framework. FuSVIPR is then further evaluated on the latest devastating flash floods of April 2022 in the Durban area (South Africa), without additional training. Very good agreement with the impact maps produced in the context of the International Charter “Space and Major Disasters” are reached with similar performance figures. These results emphasize the high generalization capability of this method to locate pluvial floods at any time of the year and over diverse regions worldwide using a very high spatial resolution visible product and two Sentinel-2 images. The resulting impact maps have high potential for helping thorough evaluation and improvement of surface water inundation models and boosting extreme precipitation downscaling at a very high spatial resolution.

Atypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated with the Development of Post-Traumatic Epilepsy.

Traumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under investigation. The dentate gyrus-a structure that is highly susceptible to injury-has been implicated in the evolution of seizure development. Utilizing the murine unilateral focal control cortical impact (CCI) injury, we evaluated seizure onset using 24/7 EEG video analysis at 2-4 months post-injury. Cellular changes in the dentate gyrus and hilus of the hippocampus were quantified by unbiased stereology and Imaris image analysis to evaluate Prox1-positive cell migration, astrocyte branching, and morphology, as well as neuronal loss at four months post-injury. Isolation of region-specific astrocytes and RNA-Seq were performed to determine differential gene expression in animals that developed post-traumatic epilepsy (PTE+) vs. those animals that did not (PTE-), which may be associated with epileptogenesis. CCI injury resulted in 37% PTE incidence, which increased with injury severity and hippocampal damage. Histological assessments uncovered a significant loss of hilar interneurons that coincided with aberrant migration of Prox1-positive granule cells and reduced astroglial branching in PTE+ compared to PTE- mice. We uniquely identified Cst3 as a PTE+-specific gene signature in astrocytes across all brain regions, which showed increased astroglial expression in the PTE+ hilus. These findings suggest that epileptogenesis may emerge following TBI due to distinct aberrant cellular remodeling events and key molecular changes in the dentate gyrus of the hippocampus.

Antibody toolkit to investigate eEF1A methylation dynamics in mRNA translation elongation

Protein synthesis is a fundamental step in gene expression, with modulation of mRNA translation at the elongation step emerging as an important regulatory node in shaping cellular proteomes. In this context, five distinct lysine methylation events on eukaryotic elongation factor 1A (eEF1A), a fundamental nonribosomal elongation factor, are proposed to influence mRNA translation elongation dynamics. However, a lack of affinity tools has hindered progress in fully understanding how eEF1A lysine methylation impacts protein synthesis. Here we develop and characterize a suite of selective antibodies to investigate eEF1A methylation and provide evidence that methylation levels decline in aged tissue. Determination of the methyl state and stoichiometry on eEF1A in various cell lines by mass spectrometry shows modest cell-to-cell variability. We also find by Western blot analysis that knockdown of individual eEF1A-specific lysine methyltransferases leads to depletion of the cognate lysine methylation event and indicates active crosstalk between different sites. Further, we find that the antibodies are specific in immunohistochemistry applications. Finally, application of the antibody toolkit suggests that several eEF1A methylation events decrease in aged muscle tissue. Together, our study provides a roadmap for leveraging methyl state and sequence-selective antibody reagents to accelerate discovery of eEF1A methylation-related functions and suggests a role for eEF1A methylation, via protein synthesis regulation, in aging biology.

When Words Fail: “Miscarriage,” Referential Ambiguity, and Psychological Harm

Despite significant efforts to support those bereaved by intrauterine death, they remain susceptible to avoidable psychological harm such as disenfranchised grief, misplaced guilt, and emotional shock. This is in part because the words available to describe intrauterine death-"miscarriage," "spontaneous abortion," and "pregnancy loss"-are referentially ambiguous. Despite appearing to refer to one event, they can refer to two distinct events: the baby's death and his preterm delivery. Disenfranchised grief increases when people understand "miscarriage" as the physical process of preterm delivery alone, for this obscures the baby's death and excludes non-gestational parents, such as the father. Additionally, focusing on the delivery reinforces the mistaken idea that a gestational mother bears responsibility for her baby's death, increasing misplaced guilt. When these terms instead shift the focus to the baby's intrauterine death rather than the preterm delivery, they can obscure the physically difficult and often traumatic experience women have when they deliver their dead children, leaving women shocked by preterm delivery's physical reality. Given their outsized role in framing the bereaved's experiences, and their duty to avoid harming their patients, healthcare practitioners in particular should take special care to discuss intrauterine death and preterm delivery appropriately with patients and their families. Changing language to describe intrauterine death and preterm delivery clearly and precisely helps mitigate disenfranchised grief, misplaced guilt, and shock, while also helping to reframe the social response to intrauterine death, making it more obvious why certain steps, such as allowing bereavement leave following an intrauterine death, promote healing.

Coordination between the Ndc80 complex and dynein is essential for microtubule plus-end capture by kinetochores during early mitosis

Mitotic kinetochores are initially captured by dynamic microtubules via a "search-and-capture" mechanism. The microtubule motor, dynein, is critical for kinetochore capture as it has been shown to transport microtubule-attached chromosomes toward the spindle pole during prometaphase. The microtubule-binding nuclear division cycle 80 (Ndc80) complex that is recruited to kinetochores in prophase is known to play a central role in forming kinetochore-microtubule (kMT) attachments in metaphase. It is not yet clear, however, how Ndc80 contributes to initial kMT capture during prometaphase. Here, by combining CRISPR/Cas9-mediated knockout and RNAi technology with assays specific to study kMT capture, we show that mitotic cells lacking Ndc80 exhibit substantial defects in this function during prometaphase. Rescue experiments show that Ndc80 mutants deficient in microtubule-binding are unable to execute proper kMT capture. While cells inhibited of dynein alone are predominantly able to make initial kMT attachments, cells co-depleted of Ndc80 and dynein show severe defects in kMT capture. Further, we use an in vitro total internal reflection fluorescence microscopy assay to reconstitute microtubule capture events, which suggest that Ndc80 and dynein coordinate with each other for microtubule plus-end capture and that the phosphorylation status of Ndc80 is critical for productive kMT capture. A novel interaction between Ndc80 and dynein that we identify in prometaphase extracts might be critical for efficient plus-end capture. Thus, our studies, for the first time, identify a distinct event in the formation of initial kMT attachments, which is directly mediated by Ndc80 and in coordination with dynein is required for efficient kMT capture and chromosome alignment.

Cretaceous southern high latitude benthic foraminiferal assemblages during OAE 2 at IODP Site U1516, Mentelle Basin, Indian Ocean

At Site U1516 (Mentelle Basin, southeast Indian Ocean, offshore western Australia), the International Ocean Discovery Program (IODP) Expedition 369 recovered an almost complete pelagic record of the Upper Cretaceous, including the Oceanic Anoxic Event 2 (OAE 2). To better understand paleoenvironmental changes across OAE 2, 32 samples were analysed for benthic foraminiferal abundance data that represent one of the few benthic foraminiferal datasets spanning the OAE 2 in the southern high latitudes.The OAE 2 interval at Site U1516 is characterized by an interval of low CaCO3 content that contains a prominent positive Carbon Isotope Excursion (CIE). The record of the OAE 2 can be subdivided in pre OAE 2, pre max-CIE, low CaCO3, and post low CaCO3 intervals. Through the Cenomanian–Turonian boundary, we document an extreme decline in benthic foraminifera during OAE 2, that is followed by a profound repopulation event in the post low CaCO3 interval.Benthic foraminiferal assemblages indicate an outer neritic to upper bathyal depositional environment. During the pre OAE 2 and pre max-CIE intervals, calcareous deep-water gavelinellids, lingulogavelinellids and gyroidinids are dominant. In the low-carbonate interval, the microfossil record documents a substantial increase in radiolaria and foraminifera are almost absent as only three out of nine samples contain benthic foraminifera. Changes in benthic foraminiferal assemblage composition are documented in the initial low CaCO3 interval, underlying the maximum CIE and associated interferences. Comparison of the pre- and post-CIE benthic foraminiferal assemblages highlights a distinct repopulation event during the post max- CIE interval mainly represented by the conspicuous increase in abundance of agglutinated taxa and Conorboides. Compared to other southern high latitude records, the dataset collected at Site U1516 represents one of the most complete benthic foraminiferal records across the OAE 2 that registers the Late Cretaceous environmental changes in the Southern Hemisphere.

Surface impacts and associated mechanisms of a moisture intrusion into the Arctic observed in mid-April 2020 during MOSAiC

Distinct events of warm and moist air intrusions (WAIs) from mid-latitudes have pronounced impacts on the Arctic climate system. We present a detailed analysis of a record-breaking WAI observed during the MOSAiC expedition in mid-April 2020. By combining Eulerian with Lagrangian frameworks and using simulations across different scales, we investigate aspects of air mass transformations via cloud processes and quantify related surface impacts. The WAI is characterized by two distinct pathways, Siberian and Atlantic. A moist static energy transport across the Arctic Circle above the climatological 90th percentile is found. Observations at research vessel Polarstern show a transition from radiatively clear to cloudy state with significant precipitation and a positive surface energy balance (SEB), i.e., surface warming. WAI air parcels reach Polarstern first near the tropopause, and only 1–2 days later at lower altitudes. In the 5 days prior to the event, latent heat release during cloud formation triggers maximum diabatic heating rates in excess of 20 K d-1. For some poleward drifting air parcels, this facilitates strong ascent by up to 9 km. Based on model experiments, we explore the role of two key cloud-determining factors. First, we test the role moisture availability by reducing lateral moisture inflow during the WAI by 30%. This does not significantly affect the liquid water path, and therefore the SEB, in the central Arctic. The cause are counteracting mechanisms of cloud formation and precipitation along the trajectory. Second, we test the impact of increasing Cloud Condensation Nuclei concentrations from 10 to 1,000 cm-3 (pristine Arctic to highly polluted), which enhances cloud water content. Resulting stronger longwave cooling at cloud top makes entrainment more efficient and deepens the atmospheric boundary layer. Finally, we show the strongly positive effect of the WAI on the SEB. This is mainly driven by turbulent heat fluxes over the ocean, but radiation over sea ice. The WAI also contributes a large fraction to precipitation in the Arctic, reaching 30% of total precipitation in a 9-day period at the MOSAiC site. However, measured precipitation varies substantially between different platforms. Therefore, estimates of total precipitation are subject to considerable observational uncertainty.

Vesicle-associated membrane protein 2 is a cargo-selective v-SNARE for a subset of GPCRs.

Vesicle fusion at the plasma membrane is critical for releasing hormones and neurotransmitters and for delivering the cognate G protein-coupled receptors (GPCRs) to the cell surface. The SNARE fusion machinery that releases neurotransmitters has been well characterized. In contrast, the fusion machinery that delivers GPCRs is still unknown. Here, using high-speed multichannel imaging to simultaneously visualize receptors and v-SNAREs in real time in individual fusion events, we identify VAMP2 as a selective v-SNARE for GPCR delivery. VAMP2 was preferentially enriched in vesicles that mediate the surface delivery of μ opioid receptor (MOR), but not other cargos, and was required selectively for MOR recycling. Interestingly, VAMP2 did not show preferential localization on MOR-containing endosomes, suggesting that v-SNAREs are copackaged with specific cargo into separate vesicles from the same endosomes. Together, our results identify VAMP2 as a cargo-selective v-SNARE and suggest that surface delivery of specific GPCRs is mediated by distinct fusion events driven by distinct SNARE complexes.

Abstract 94: Advanced preclinical modeling reveals unique monosomy 3 associated biology in late-stage uveal melanoma

Abstract Uveal melanoma (UM) is a rare and lethal malignancy with very limited therapeutic options characterized by mutually exclusive activating mutations in GNAQ and GNA11, resulting in overactive proliferative signaling of Gαq/11 heterotrimeric G proteins. Additionally, tumors typically present with mutually exclusive mutations in one of three proteins with little functional overlap: BAP1, SF3B1, or EIF1AX. Metastatic progression of late-stage uveal melanoma is highly associated with chromosome 3 copy-loss, a unique chromosomal event (monosomy 3 or M3). However, the underlying biology of this distinct copy-loss event, and whether this event directly contributes towards the metastatic phenotype observed in late-stage disease, has largely been unexplored partially due to a lack of available models in the field. Here, using CRISPR-based centromere targeting we artificially created multiple isogenic clones exhibiting monosomy 3 (M3) from a well characterized disomy 3 (D3) UM cell model. Remarkably, the selective loss of one copy of chromosome 3 was sufficient to recapitulate clinical hallmarks of metastatic UM, including pigmentation loss, alterations in cell morphology and expression of late-stage disease markers. In addition, we also show how chromosome 3 copy-loss increases invasive potential and site-specific liver metastasis upon orthotopic implantation. Furthermore, successful development of this isogenic system has allowed for a comprehensive understanding of the molecular signaling, transcriptomic changes and chromatin-level modifications directly regulated by chromosome 3 copy-loss. Specifically, the monosomy 3 event emerged as the major contributor towards the molecular variance across D3 vs. M3 UM contexts and the primary driving force underpinning the large-scale epigenomic rewiring observed in M3 isogenic clones via transposase-accessible chromatin with sequencing (ATACseq). These observations together supported a scenario where the epigenomic rewiring associated to a selective genomic alteration, in this case the loss of one copy of chromosome 3, directs the acquisition of a new and aggressive phenotype. Current studies are focused on defining how these epigenomic alterations contribute towards the metastatic phenotype and identifying context-specific vulnerabilities associated with chromosome 3 copy-loss to develop novel therapeutics strategies to treat late-stage metastatic disease. Citation Format: Johnathon L. Rose, Sanjana Srinivasan, Meng He, Rosalba Minelli, Chiu-Yi Liu, Jason Gay, Joseph R. Daniele, Michael Peoples, Melinda Soeung, Vandhana Ramamoorthy, Anastasia Lopez, Charles Deckard, Brooke Meyers, Edoardo Del Poggetto, Daniel Zamler, Justin Huang, Luigi Perelli, Khalida Wani, Christopher Bristow, Ningping Feng, Christopher P. Vellano, Joe Marszalek, Alexander J. Lazar, Andrew Futreal, Giulio F. Draetta, Scott E. Woodman, Timothy Heffernan, Giannicola Genovese, Alessandro Carugo, Virginia Giuliani. Advanced preclinical modeling reveals unique monosomy 3 associated biology in late-stage uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 94.