Search

Remarkable performance improvements occur at the end of the third postnatal week in rodents tested in various tasks that require navigation according to spatial context. While alterations in hippocampal function at least partially subserve this cognitive advancement, physiological explanations remain incomplete. Previously, we discovered that developmental modifications to hippocampal glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in juvenile rats was related to more mature spontaneous alternation behavior in a symmetrical Y-maze. Moreover, a positive allosteric modulator of AMPA receptors enabled immature rats to alternate at rates seen in older animals, suggesting an excitatory synaptic limitation to hippocampal maturation. We then validated the Barnes maze for juvenile rats in order to test the effects of positive AMPA receptor modulation on a goal-directed spatial memory task. Here we report the effects of the AMPA receptor modulator, CX614, on spatial learning and memory in the Barnes maze. Similar to our prior report, animals just over 3 weeks of age display substantial improvements in learning and memory performance parameters compared to animals just under 3 weeks of age. A moderate dose of CX614 enabled immature animals to move more directly to the goal location, but only after 1 day of training. This performance improvement was observed on the second day of training with drug delivery or during a memory probe trial performed without drug delivery after the second day of training. Higher doses created more search errors, especially in more mature animals. Overall, CX614 provided modest performance benefits for immature rats in a goal-directed spatial memory task.

This work discusses a systematic approach for design and analysis of a steering upright based on suspension hardpoint analysis. The steps followed would ensure anticipated performance of a vehicle in terms of ride comfort and handling. The suspension hardpoints were determined using LOTUS™ Shark suspension analysis software based on kinematic simulations. The geometric model of the upright was then created in accordance with the hardpoints obtained. Static structural analysis was performed on the preliminary upright design and design modifications were done to reduce the weight. Further, a suitable material was selected for the upright based on a comparison of values of stress, deformation, safety factor and mass for different upright materials. In addition, fatigue analysis was performed to compute the life of the upright. The manufactured uprights were assembled with other suspension assembly components and were tested under different on road conditions to observe for any failure.

Lunar exploration missions require detailed and accurate planning to ensure their safety. Remote sensing data, such as optical satellite imagery acquired by lunar orbiters, are key for the identification of future landing and mission sites. Here robot- and astronaut-scale obstacles are the most relevant to resolve; however, the spatial resolution of the available image data is often insufficient, particularly in the poorly illuminated polar regions of the moon, leading to uncertainty. This work shows how a novel single-image superresolution (SISR) application, the Adversarial Network for Uncertainty-Based Image SR (ANUBIS), can enhance lunar surface imagery by improving the resolution by a factor of two, outperforming other approaches and benchmarks. The enhanced images improve the reliability and detail of lunar traverse planning and topographic reconstruction, while providing an estimate of the uncertainty associated with the enhancement process, vital to ensure mission planning integrity. This work demonstrates how machine-learning-driven processing can enhance existing data products to maximize their value for science and the exploration of the moon and other celestial bodies.

The first is with the components themselves. The speakers in your smartphone and the system that gives your finger feedback when you touch a virtual button may be relatively small, but they are still big enough to limit how thin our mobile devices can get. These little components are also delicate, as you may have learned if you have dropped your phone. And they require openings in the enclosure that can admit moisture or debris.

Correlations between radiation dose/volume measures and small bowel (SB) toxicity are inconsistent in the medical literature. We assessed the impact of inter‐provider variation in bowel bag contouring technique on estimates of radiation dose received by the SB during pelvic radiotherapy. Ten radiation oncologists contoured rectum, bladder and bowel bags on treatment planning computed tomography (CT) scans of two patients receiving adjuvant radiation for endometrial cancer. A radiation plan was generated for each patient and used to determine the radiation dose/volume for each organ. Kappa statistics were applied to assess the inter‐provider contouring agreement, and Levene test evaluated the homogeneity of variance for radiation dose/volume metrics, including the V45Gy(cm3). The bowel bag showed greater variation in radiation dose/volume estimates compared to the bladder and rectum. The V45Gyranged from 163 to 384 cm3for data set A and 109 to 409 cm3for dataset B. Kappa values were 0.82/0.83, 0.92/0.92 and 0.94/0.86 for the bowel bag, rectum, and bladder on data sets A/B, demonstrating lower inter‐provider agreement for bowel bag compared with bladder and rectum. Inter‐provider contouring variability is more significant for the bowel bag than the rectum and bladder, with an associated greater variability in dose and volume estimates during radiation planning. We assessed the impact of inter‐provider variation in bowel bag contouring technique on estimates of radiation dose received by the small bowel during pelvic radiotherapy. Ten radiation oncologists contoured rectum, bladder and bowel bags on treatment planning CT scans of two patients receiving adjuvant radiation for endometrial cancer; radiation plans were generated for each patient and used to determine radiation dose/volume for each organ. Among assessed organs at risk, the bowel bag showed the greatest inter‐provider contouring variability and associated variation in estimated radiation dose.

AbstractHigh altitude pulmonary edema (HAPE) is a life threatening non-cardiogenic pulmonary edema that occurs in an otherwise healthy individuals travelling to altitude above 2500 m. Earlier studies have reported association of mutations in nuclear (nDNA) and mitochondrial DNA (mtDNA) with HAPE susceptibility. However, the molecular mechanisms involved in the pathobiology of HAPE have not been fully understood. The present study investigates the genetic predisposition to HAPE by analyzing the mtDNA mutations in HAPE susceptibles (n = 23) and acclimatized controls (n = 23) using next generation sequencing. Structural analysis of mutations was done using SWISS Model server and stability was determined using ΔΔGvalues. Meta-analysis of GSE52209 dataset was done to identify differentially expressed genes (DEGs) in HAPE susceptibles and acclimatized controls. Fourteen non-synonymous, conserved and pathogenic mutations were predicted using SIFT and PolyPhen scoring in protein coding genes, whereas six mutations in mt-tRNA genes showed association with HAPE (p ≤ 0.05). The structural analysis of these mutations revealed conformational changes in critical regions in Complexes I–V which are involved in subunit assembly and proton pumping activity. The protein–protein interaction network analysis of DEGs showed that HIF1α, EGLN2, EGLN3, PDK1, TFAM, PPARGC1α and NRF1 genes form highly interconnected cluster. Further, pathway enrichment analysis using DAVID revealed that “HIF-1 signaling”, “oxidative phosphorylation” and “Metabolic pathways” had strong association with HAPE. Based on the findings it appears that the identified mtDNA mutations may be a potential risk factor in development of HAPE with the associated pathways providing mechanistic insight into the understanding of pathobiology of HAPE and sites for development of therapeutic targets.Communicated by Ramaswamy H. Sarma

The data on incidence of recovered Left Ventricular Ejection Fraction (LVEF) and outcome in patients with non ischemic systolic heart failure is limited. We report the incidence, determinants and mortality in patients with recovered LVEF. Methods: The 369 patients with HFrEF with LVEF of less than 40% of non ischemic etiology with available follow up echocardiography study at one year were enrolled. The baseline data of clinical characteristics and treatment was recorded prospectively and were followed up annually for mean of 3.6 years (range 2 to 5 years) to record all cause death and LVEF measured echocardiographically. The recovered, partially recovered and no recovery of LVEF was defined based on increase in LVEF to 50% and more, 41% to 49% and to persistently depressed LVEF to 40% or lower respectively.

An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine.

This paper focuses on the kinematic simulation, design and analysis of a double wishbone suspension system that will be used in an adventure class vehicle designed and manufactured according to Electric Solar Vehicle Championship specifications. Initially, the suspension hardpoints were determined using LOTUSTMShark suspension analysis software based on kinematic simulations to ensure better vehicle handling. The resulting hardpoints were used to create the geometric model of the wishbone. The operating loads on the wishbone were estimated and static structural analysis was carried out using ANSYSTM Workbench software to propose a suitable light weight wishbone design and material for the same. In addition, to compute the life of the wishbone, fatigue analysis was performed. After interference checks, the wishbones were fabricated and put together with other suspension assembly parts. The vehicle was driven on the campus road under various road conditions in order to ensure whether the wishbones work as intended.

Hydrogen mitigation using Passive Autocatalytic Recombiners (PARs) has been widely accepted methodology inside reactor containment of accident struck Nuclear Power Plants. They reduce hydrogen concentration inside reactor containment by recombining it with oxygen from containment air on catalyst surfaces at ambient temperatures. Exothermic heat of reaction drives the product steam upwards, establishing natural convection around PAR, thus invoking homogenisation inside containment. CFD models resolving individual catalyst plate channels of PAR provide good insight about temperature and hydrogen recombination. But very thin catalyst plates compared to large dimensions of the enclosures involved result in intensive calculations. Hence, empirical correlations specific to PARs being modelled are often used in integral containment studies. In this work, an experimentally validated CFD model of PAR has been employed for developing an empirical correlation for Indian PAR. For this purpose, detailed parametric study involving different gas mixture variables at PAR inlet has been performed. For each case, respective values of gas mixture variables at recombiner outlet have been tabulated. The obtained data matrix has then been processed using regression analysis to obtain a set of correlations between inlet and outlet variables. The empirical correlation thus developed, can be easily plugged into commercially available CFD software.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by loss of function TP53and RB1mutations in addition to mutations in other oncogenes including MYC. Overexpression of MYC together with Trp53and Rb1loss in pulmonary neuroendocrine cells of the mouse lung drives an aggressive neuroendocrine low variant subtype of SCLC. However, the transforming potential of MYC amplification alone on airway epithelium is unclear. Therefore, we selectively and conditionally overexpressed MYC stochastically throughout the airway or specifically in neuroendocrine, club, or alveolar type II cells in the adult mouse lung. We observed that MYC overexpression induced carcinoma in situ which did not progress to invasive disease. The formation of adenoma or SCLC carcinoma in situ was dependent on the cell of origin. In contrast, MYC overexpression combined with conditional deletion of both Trp53and Rb1exclusively gave rise to SCLC, irrespective of the cell lineage of origin. However, cell of origin influenced disease latency, metastatic potential, and the transcriptional profile of the SCLC phenotype. Together this reveals that MYC overexpression alone provides a proliferative advantage but when combined with deletion of Trp53and Rb1it facilitates the formation of aggressive SCLC from multiple cell lineages.

The first evidence that cannabinoids may have in vitro and in vivo antineoplastic activity against tumor cell lines and animal tumor models was published in the Journal of the National Cancer Institutenearly 50 years ago. Cannabinoids appear to induce apoptosis in rodent brain tumors by way of direct interaction with the cannabinoid receptor. They may inhibit angiogenesis and tumor cell invasiveness. Despite preclinical findings, attempts to translate the benefits from bench to bedside have been limited. This session provides a review of the basic science supporting the use of cannabinoids in gliomas, paired with the first randomized clinical trial of a cannabis-based therapy for glioblastoma multiforme. Another preclinical presentation reports the effects of cannabinoids on triple-negative breast cancer cell lines and how cannabidiol may affect tumors. The session’s second human trial raises concerns about the use of botanical cannabis in patients with advanced cancer receiving immunotherapy suggesting inferior outcomes.

Human microbial alterations are associated with environmental stress, nutrition, genetic, and triggering de-novo variations. Nevertheless, the human gut microbiome at extreme altitude (> 5800 m) remains unexplored. We aimed to demonstrate the microbial predominance in individuals with the same ethnicity and dietary pattern at extreme altitude with unique challenges like cold, hypoxia, radiation, etc. Different analysis pipelines were used for fecal whole genome sequencing at 210 m, 3500 m, 4420 m and 5805 m, and 16S rRNA V3-V4 regions amplification sequencing of 19 individuals belonging to the same ethnicity and dietary pattern for the presence of taxonomy and functional potential and confirming the prediction up to the strain level within the same cohort. Principal component analysis revealed distinct microbiome changes at different altitudes, with varied and higher Bacteroidesand Prevotellaratio. There was a predominance of genus Prevotellaat altitudes 4420 m and 5805 m than at 210 m and 3500 m. The appearance of species Prevotella copristrain 61,740 increased significantly at extreme altitude, whereas co-occurrence of other bacterial strains had a different pattern than Prevotella. The extensive strain-level analysis indicated alteration in the metabolic pathways. This study under the stressful and hypoxic environment of extreme altitudes, associated microbial variation with altered metabolic pathways, reveals the influence of extreme environment on human gut microbiota with the predominance of Prevotella.

Context:Symptomatic post-traumatic syringomyelia can affect the quality of life in patients whose neurologic function has already been impacted by a spinal cord injury.Objective:To investigate the radiographic and clinical outcomes following surgery for syringomyelia, we present a literature review along with a case series from a single surgeon’s experience.Methods:A retrospective review was conducted on patients with post-traumatic syringomyelia who were treated by a single surgeon. Thirty-four patients who underwent surgical treatment consisting of syrinx fenestration, lysis of adhesions, and duraplasty were identified. In addition, a narrative literature review was conducted with a primary focus on diagnosis and management of post-traumatic syringomyelia.Results:Literature review suggests that regardless of age, sex, vertebral location, or severity of trauma, patients who experience a spinal cord injury should be closely monitored for post-traumatic syringomyelia. Retrospective review of our 34 patients revealed 24 patients for whom pre- and post- operative MRI was available. The predominant location of the injury was cervical (15). The average syrinx length, measured in spinal segments, was similar when comparing pre- and post-operative MRIs; average syrinx length was 5.5 and 5.4 spinal segments, respectively. In contrast, syrinx axial dimension was decreased in 16 of the patients post-operatively and stable or increased in the other eight. The change in syrinx size did not correlate with clinical outcomes.Conclusion:Current surgical treatment of post-traumatic syringomyelia involves restoration of normal CSF flow dynamics; further prospective work is needed to correlate the clinical state, radiographic measures, and efficacy of surgical intervention.

Background: Chikungunya virus (CHIKV) is an arthropod-borne RNA virus which induces host Endoplasmic Reticulum (ER) stress by accumulating unfolded or misfolded proteins. ER stress activates the unfolded protein response (UPR) pathway to enable proper protein folding and maintain cellular homeostasis. There is no approved drug or vaccine available for CHIKV treatment, therefore, a pharmacological countermeasure is warranted for preventing CHIKV infection. Objective: With a view to find a treatment modality for chikungunya infection, “andrographolide”, a plant-derived diterpenoid with reported antiviral, anti-inflammatory and immunomodulatory effects, was used to investigate its role in chikungunya induced unfolded protein stress and apoptosis. Methods: Cells and supernatant collected on andrographolide and VER-155008, a GRP78 inhibitor, treatment in CHIKV infected and mock-infected THP-1 cells were tested for differential expression of UPR pathway proteins including GRP78, PERK, EIF-2α, IRE-1α, XBP-1 and ATF6. Furthermore, the inflammasome and apoptosis pathway proteins, i.e., caspase-1, caspase-3 and PARP, were tested by immunoblotting, and cytokines, i.e., IL-1β, IL-6 and IFN-γ were tested by ELISA. Results: Andrographolide treatment in CHIKV infected THP-1 cells significantly reduced IRE1α and downstream spliced XBP1 protein expression. Furthermore, CHIKV induced apoptosis and viral protein expression were also reduced on andrographolide treatment. A comparative analysis of andrographolide versus VER-155008, confirmed that andrographolide surpasses the effects of VER-155008 in suppressing the CHIKV induced ER stress. Conclusion: The study, therefore, confirms that andrographolide is a potential remedy for chikungunya infection and suppresses CHIKV induced ER stress and apoptosis.

On behalf of the journal, AGU, and the scientific community, the editors of Geophysical Research Letters would like to sincerely thank those who reviewed manuscripts for us in 2023. The hours reading and commenting on manuscripts not only improve the manuscripts, but also increase the scientific rigor of future research in the field. With the advent of AGU's data policy, many reviewers have also helped immensely to evaluate the accessibility and availability of data, and many have provided insightful comments that helped to improve the data presentation and quality. We greatly appreciate the assistance of the reviewers in advancing open science, which is a key objective of AGU's data policy. We particularly appreciate the timely reviews in light of the demands imposed by the rapid review process at Geophysical Research Letters. We received 4,512 submissions in 2023 and 5,112 reviewers contributed to their evaluation by providing 8,587 reviews in total. We deeply appreciate their contributions. Individuals in italics provided three or more reviews for GRL in 2023. The editors thank the 2023 peer‐reviewers The editors thank the 2023 peer‐reviewers

TP53mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53mutation status in ovarian mucinous tumors and to evaluate the association of TP53mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5–14.3, p= 0.0087). Within MOC, 61.1% (259/424) harbored a TP53mutation, but this was not associated with survival (overall survival, p= 0.77). TP53 IHC is an accurate proxy for TP53mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

We report the gender-based differences in the prevalence, severity, pattern of valvular involvement, and complications in patients with Rheumatic Fever/Rheumatic heart disease (RF/RHD).

Although checklists and guidelines for reporting and interpretation of clinical trial results are of immense value there is still room for a biased presentation in journal publications. Two important sources of bias that remain are as follows: (1) The absence of a principle guiding the display of point estimates in abstracts. For example, bias arises, even for a primary endpoint, when the reported point estimate is preferentially selected and does not correspond to the prespecified method of analysis. The benefit of treatment on an endpoint is often communicated through point estimates, and as abstracts contain the main takeaways, establishing ground rules for what to include and what not to include is crucial. (2) A commingling in the body of the publication of results from α-controlled endpoints, non–α-controlled endpoints, and post hoc analyses. The total number of non–α-controlled and post hoc analyses are unknown. Blending a favored selection of these with α-controlled results provides opportunities to overstate or understate findings as desired. Publicly available results provide the grist for the changes proposed to improve reporting standards. Additional changes are recommended as well, including a threshold of significance more stringent than 0.05 for non–α-controlled analyses. For safety, the proposal is to display the data via the mean cumulative function graph for prespecified adverse events of interest. The bottom line is that more objective reporting can be achieved if journals establish standards for reporting of point estimates in abstracts and require a hierarchical display of results in the main body.

Extreme environments are inherently stressful and are characterized by a variety of physical and psychosocial stressors, including, but not limited to, isolation, confinement, social tensions, minimal possibility of medical evacuation, boredom, monotony, and danger. Previous research studies recommend adaptation to the environment to maintain optimal function and remain healthy. Different interventions have been tried in the past for effective management of stress. Yoga practices have been shown to be beneficial for coping with stress and enhance quality of life, sleep and immune status.

Although checklists and guidelines for reporting and interpretation of clinical trial results are of immense value there is still room for a biased presentation in journal publications. Two important sources of bias that remain are as follows: (1) The absence of a principle guiding the display of point estimates in abstracts. For example, bias arises, even for a primary endpoint, when the reported point estimate is preferentially selected and does not correspond to the prespecified method of analysis. The benefit of treatment on an endpoint is often communicated through point estimates, and as abstracts contain the main takeaways, establishing ground rules for what to include and what not to include is crucial. (2) A commingling in the body of the publication of results from α-controlled endpoints, non–α-controlled endpoints, and post hoc analyses. The total number of non–α-controlled and post hoc analyses are unknown. Blending a favored selection of these with α-controlled results provides opportunities to overstate or understate findings as desired. Publicly available results provide the grist for the changes proposed to improve reporting standards. Additional changes are recommended as well, including a threshold of significance more stringent than 0.05 for non–α-controlled analyses. For safety, the proposal is to display the data via the mean cumulative function graph for prespecified adverse events of interest. The bottom line is that more objective reporting can be achieved if journals establish standards for reporting of point estimates in abstracts and require a hierarchical display of results in the main body.

We report the impact of capacity building and teleconsultation on change in the thrombolysis rates and one-year mortality in patients with STEMI using a hub and the spoke model of STEMI care.

Sea level rise is leading to the rapid migration of marshes into coastal forests and other terrestrial ecosystems. Although complex biophysical interactions likely govern these ecosystem transitions, projections of sea level driven land conversion commonly rely on a simplified “threshold elevation” that represents the elevation of the marsh‐upland boundary based on tidal datums alone. To determine the influence of biophysical drivers on threshold elevations, and their implication for land conversion, we examined almost 100,000 high‐resolution marsh‐forest boundary elevation points, determined independently from tidal datums, alongside hydrologic, ecologic, and geomorphic data in the Chesapeake Bay, the largest estuary in the U.S. located along the mid‐Atlantic coast. We find five‐fold variations in threshold elevation across the entire estuary, driven not only by tidal range, but also salinity and slope. However, more than half of the variability is unexplained by these variables, which we attribute largely to uncaptured local factors including groundwater discharge, microtopography, and anthropogenic impacts. In the Chesapeake Bay, observed threshold elevations deviate from predicted elevations used to determine sea level driven land conversion by as much as the amount of projected regional sea level rise by 2050. These results suggest that local drivers strongly mediate coastal ecosystem transitions, and that predictions based on elevation and tidal datums alone may misrepresent future land conversion. As sea level rise (SLR) drives saltwater further inland, terrestrial ecosystems change to tidally controlled ecosystems. A common ecosystem transition is coastal forest conversion to marsh, which forms ghost forests, characterized as dead trees surrounded by marsh. Most projections of SLR assume that the boundary between forest and marsh can be defined simply by the furthest landward extent of the tide. However, forest to marsh conversion can be influenced by other physical processes and vegetation interactions. Here we analyze the location of the marsh‐forest boundary across the entire Chesapeake Bay, defined using 100,000 elevation points, alongside environmental variable data sets to determine drivers of coastal forest retreat. As the largest estuary in the U.S., the Chesapeake Bay provides a study area where the elevation of transition from forest to marsh varies substantially. We find this variation in elevation to be driven by not only tidal range, but also soil salinity and slope of the land, yet these variables explain <50% of the variability in elevation. This suggests that local factors unaccounted for in this study also strongly influence the retreat of coastal forests, even at regional scales. Therefore, projections of SLR that rely solely on tidal extents may misrepresent future land conversion. Treeline elevations increase with tidal range, salinity and slope, but are not correlated with climate or marsh characteristicsMacro‐scale drivers account for <50% treeline elevation variability indicating that local factors mediate estuary‐scale sea level responsesOffsets between treeline elevation and tidal datums suggest that standard sea level rise projection methods may misrepresent land conversion Treeline elevations increase with tidal range, salinity and slope, but are not correlated with climate or marsh characteristics Macro‐scale drivers account for <50% treeline elevation variability indicating that local factors mediate estuary‐scale sea level responses Offsets between treeline elevation and tidal datums suggest that standard sea level rise projection methods may misrepresent land conversion

The growth (or decay) of salt marshes depends on suspended‐sediment flux into and out of the marsh. Suspended‐sediment concentration (SSC) is a key element of the flux, and SSC‐based metrics reflect the long‐term sediment‐flux trajectories of a variety of salt marshes. One metric, the flood‐ebb SSC differential, correlates with area‐normalized sediment flux and can indicate salt‐marsh resilience over months to years. We hypothesize that these metrics may be relevant over shorter time periods. With data from 13 salt‐marsh channels, we show that sediment flux direction and magnitude can be inferred from SSC differential over a wide range of timescales. Furthermore, in settings characterized by a standing tidal wave, the water‐level gradient can be used instead of velocity to compute the SSC differential, enabling less‐intensive measurements that capture fundamental sediment‐flux parameters. Distilling the sediment‐flux trajectory into simple metrics improves sediment‐budget assessment, drives geomorphic model development, and clarifies field observations. The difference between suspended‐sediment concentration on flood and ebb in salt‐marsh channels can predict the net sediment fluxThis relationship holds over a range of timescales, from tidal to seasonalDistilling sediment‐flux characteristics into simple metrics helps drive model development and observational campaigns

We investigated the hydrodynamic and morphologic response of Barnegat Bay‐Little Egg Harbor, New Jersey, USA, to Hurricane Sandy. We implemented a three‐dimensional, coupled ocean‐wave‐sediment transport model of the estuary and explored the role of offshore water levels, offshore waves, local winds, and waves by systematically removing forcings from a series of simulations. Offshore water levels had the largest impact on water levels in the bay, while waves and local wind forcing created substantial spatial variation along the longitudinal axis of the bay. The shape of the bay and its orientation relative to the storm track influenced the response to winds and restricted the maximum water levels in the northern bay and reduced the maximum volume of surge. Basin‐average hydrodynamic residence time was reduced by 40%, though its typical spatial distribution remained during the storm. Wave‐ and current‐induced bed shear stress resuspended fine sediment resulting in net erosion from the shoals with ensuing net deposition over fringing low‐lying land. The net sediment exchange between the bay and the ocean was several times smaller than the exchange at the peak of the storm resulting in negligible net change in the bay volume. Overall, our results suggest that water level responses are highly sensitive to the specific orientation of storm winds relative to the estuary, thereby limiting the utility of simple inundation models. The sediment transport patterns indicate that storms are an important mechanism for redistributing sediment from shoals to fringing wetlands, while net change to sediment budget can be negligible. In this study we have used computer simulations and measurements to study the changes to a coastal system, Barnegat Bay‐Little Egg Harbor, New Jersey, because of Hurricane Sandy. These simulations, which were verified with measurements, provided animations of the real‐life conditions of water levels, current speeds, and change in the sea bottom everywhere in the bay during the hurricane. They also enabled studying imaginary cases where we could isolate major factors like winds, waves, and storm surge and decide which of them had the leading role. Our findings indicated that during Hurricane Sandy, the bay was sheltered by the barrier islands from the direct impact of the hurricane‐induced local waves and currents, but storm surge from offshore reached the bay with much less resistance and caused extensive flooding. The orientation of the wind played a large role in the maximum water level within the bay. The hurricane caused large amounts of sand and water to be exchanged between the bay and the ocean during the storm, but the overall change in the depth of the bay was negligible. This work provides an understanding of how a coastal system responds to intense storms. Bay geometry, location, and orientation with respect to storm track is an important factor in the characteristic response of a bayChanges in water level were primarily driven by offshore surge, while the rest of the forcings had induced along‐estuary variabilityStorm supplied sediment to marshes, exported silt offshore, and imported sand, but the net change in sediment budget was close to neutral

Tidal wetland fluxes of particulate organic matter and carbon (POM, POC) are important terms in global budgets but remain poorly constrained. Given the link between sediment fluxes and wetland stability, POM and POC fluxes should also be related to stability. We measured POM and POC fluxes in eight microtidal salt marsh channels, with net POM fluxes ranging between −121 ± 33 (export) and 102 ± 28 (import) g OM·m−2·year−1and net POC fluxes ranging between −52 ± 14 and 43 ± 12 g C·m−2·year−1. A regression employing two measures of stability, the unvegetated‐vegetated marsh ratio (UVVR) and elevation, explained >95% of the variation in net fluxes. The regression indicates that marshes with lower elevation and UVVR import POM and POC while higher elevation marshes with high UVVR export POM and POC. We applied these relationships to marsh units within Barnegat Bay, New Jersey, USA, finding a net POM import of 2,355 ± 1,570 Mg OM/year (15 ± 10 g OM·m−2·year−1) and a net POC import of 1,263 ± 632 Mg C/year (8 ± 4 g C·m−2·year−1). The magnitude of this import was similar to an estimate of POM and POC export due to edge erosion (−2,535 Mg OM/year and − 1,291 Mg C/year), suggesting that this system may be neutral from a POM and POC perspective. In terms of a net budget, a disintegrating wetland should release organic material, while a stable wetland should trap material. This study quantifies that concept and demonstrates a linkage between POM/POC flux and geomorphic stability. The worldwide budgets of organic material, especially carbon, are important to understand future climate change, environmental health, and habitat change. Tidal wetlands and salt marshes are large “banks” of organic material and carbon that can store material over centuries or lose it quickly if they are eroded by waves or submerged by sea level rise. We measured the “deposits” and “withdrawals” from this organic material bank, at eight salt marshes across the United States. We found a wide range of deposits and withdrawals and determined that the budget is related to how stable the marsh is. Marshes with a lot of plants and more height were more likely to have deposits of organic materials, while marshes with less plants and less height had withdrawals. These results will help complete the accounting of organic material and carbon in worldwide budgets. Tidal wetland flux budgets of particulate organic matter and carbon are poorly constrainedParticulate organic matter and carbon fluxes are strongly linked with the unvegetated‐vegetated marsh ratio and elevationApplication of flux estimates to a large wetland complex indicates that export due to lateral erosion is balanced by import through tidal channels

Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.

Objective:Standardised rapid response team (RRT) calling criteria may not be applicable to all patients, and thus, modifications of these criteria may be reasonable to prevent unnecessary calls. Little data are available regarding the efficacy or safety of modifying RRT calling criteria; therefore, this study aimed to detail the prevalence and characteristics of modifications to RRT call triggers and explore their relationship with patient outcomes.

To report the prevalence, risk factors and consequences of atrial fibrillation (AF) in patients of rheumatic heart disease (RHD).

Karst subterranean estuaries (KSEs) extend into carbonate platforms along 12% of all coastlines. A recent study has shown that microbial methane (CH4) consumption is an important component of the carbon cycle and food web dynamics within flooded caves that permeate KSEs. In this study, we obtained high‐resolution (~2.5‐day) temporal records of dissolved methane concentrations and its stable isotopic content (δ13C) to evaluate how regional meteorology and hydrology control methane dynamics in KSEs. Our records show that less methane was present in the anoxic fresh water during the wet season (4,361 ± 89 nM) than during the dry season (5,949 ± 132 nM), suggesting that the wet season hydrologic regime enhances mixing of methane and other constituents into the underlying brackish water. The δ13C of the methane (−38.1 ± 1.7‰) in the brackish water was consistently more 13C‐enriched than fresh water methane (−65.4 ± 0.4‰), implying persistent methane oxidation in the cave. Using a hydrologically based mass balance model, we calculate that methane consumption in the KSE was 21–28 mg CH4·m−2·year−1during the 6‐month dry period, which equates to ~1.4 t of methane consumed within the 102‐ to 138‐km2catchment basin for the cave. Unless wet season methane consumption is much greater, the magnitude of methane oxidized within KSEs is not likely to affect the global methane budget. However, our estimates constrain the contribution of a critical resource for this widely distributed subterranean ecosystem. Subterranean estuaries occur worldwide where fresh and marine‐derived waters mix within coastal aquifers, creating a chemical reaction zone that alters the composition of materials transported to the sea. According to a recent study, methane—a potent greenhouse gas—and the bacteria that feed on it form the basis of a complex food web restricted to cave networks flooded by the subterranean estuary. Questions about the seasonality and magnitude of this methane sink remain unclear. Unprecedented chemical records collected during this study with simultaneous meteorological and hydrological data reveal that methane accumulation is significantly greater during the dry season than during the wet season when rainfall is more prevalent and greater mixing in the coastal aquifer facilitates methane consumption. We estimate that ~1.4 t of methane are consumed during a 6‐month‐long dry period within the ~100‐km2catchment region. This estimate constrains the contribution of a critical energy source for karst subterranean estuary ecosystems. Concurrent meteorological, hydrological, and chemical records are used to study sources and sinks of methane in a karst subterranean estuaryIncreased precipitation enhances methane oxidation by mixing anoxic methane‐rich waters with oxygenated watersA hydrologically based mass balance model provides a first‐order estimate for the magnitude of the methane sink within the catchment region

The study aimed to estimate the prevalence, risk determinants, and its clinical significance of iron deficiency and anemia in patients of nonischemic heart failure with reduced ejection fraction (HFrEF).

AbstractIntroduction:The protective effects of breastfeeding against developing breast cancer are well known; however, it is unknown whether women are aware of this breastfeeding benefit.Research Aim/Questions:The aim of this investigation was to determine whether mothers received information about breast cancer risk reduction during breastfeeding counseling and whether this knowledge affected their decision to initiate and sustain breastfeeding.Materials and Methods:The survey was conducted at The Ohio State University Comprehensive Cancer Center with women aged 18–50 who had at least one live birth. Participants were recruited through primary care practice and a national clinical research registry.Results:Six hundred sixty-seven (92%) of the 724 respondents breastfed. Over half of them (56%), that is, 407 women (60.4% Caucasian, 46.9% African American), were aware before their most recent childbirth that breastfeeding reduced the risk of breast cancer. Of the 407 women, 36.4% said this knowledge affected their decision to breastfeed. Of the 39 who did not breastfeed, 23 women (59.0%) responded that awareness of risk reduction would have influenced their decision to breastfeed. Only 120 of 724 respondents (16.6%) received this information from healthcare providers. Women with this knowledge breastfed longer than those without this knowledge (13.2 versus 9.3 months; p< 0.001). More Caucasian women (76.4%) breastfed any one child for more than 6 months compared with African American women (63.2%; p= 0.011; chi-squared test).Conclusion:While several factors affect the initiation and duration of breastfeeding, this study demonstrates that knowledge of association between breastfeeding and breast cancer risk reduction may influence breastfeeding practices. Our study illustrates the need for improved counseling for mothers by healthcare providers regarding this benefit.

Introduction: The RAS superfamily of small GTPases mediate hallmarks of cancer cell proliferation, viability, migration, invasion and metastasis. Several GTPases such as RAL, RHO and RAC are required for RAS to induce malignant transformation. RAS post-translational modification (PTM) by farnesyltransferase (FT) as well as RAL, RHO and RAC PTM by geranylgeranyltransferase 1 (GGT-1) are critical for the membrane localization and oncogenicity of these GTPases. Mutations in HRAS, NRAS, KRASand RHOAare prevalent in solid tumors as well as T-cell lymphomas (TCL) such as peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), PTCL-not otherwise specified and cutaneous T-cell lymphoma (CTCL). PTX-100 is a small molecule inhibitor of GGT-1 that disrupts the oncogenic activity by inhibiting RAL, RHO and RAC PTM.

The Powder Bed Fusion (PBF) additive manufacturing technique, although widely studied and implemented in the industry, still presents issues of porosity and lack of fusion even when optimal processing parameters are used. The benefits and drawbacks of PBF utilizing pulsed lasers are both consequences of the transient temperature field induced by laser-matter interaction. During laser processing with nanosecond pulse durations, intense heating and cooling rates are induced, setting the melt pool dimensions, which are directly related to the occurrence of lack of fusion, and ablation of the processed material, leading to recoil pressure that induces the keyhole effect, increasing the occurrence of porosity. Consequently, controlling the transient temperature field is a major challenge in incorporating pulsed wave laser technology into PBF to minimize porosity and lack of fusion defects. In this study, to reduce porosity and lack of fusion, a smooth heating rate able to sinter powder grains is designed to facilitate heat flow through the heat affected zone, followed by a sharper heating rate that generates a fully molten region while reducing ablation at the same time. This work represents the first attempt to control the transient temperature field, by shaping a nanosecond laser pulse in the time domain, thereby affecting the formation of defects. The effects of the pulse shape on build quality quantified by lack of fusion and high-energy spherical pores were investigated using X-ray microtomography, molecular dynamics (MD), X-ray diffraction (XRD), Electron Backscatter Diffraction (EBSD), and finite element simulations. The variation of porosity and lack of fusion within manufactured samples were revealed by the high-resolution 3D X-ray micro computed tomography. The differences in the transient temperature field, resulting residual stresses, and microstructure are attributed to the differences in the energy delivery rates within the time domain shaped laser pulses. Laser pulse shaping is an additional parameter that plays an important role in optimizing the PBF as-processed part's production opening a new research niche.

Hepatitis E infection (HEV) in pregnant females, especially in the third trimester is associated with poor foetomaternal outcomes. However, the mechanisms of severe liver injury remain obscure. In a recent HEV outbreak in North India, six pregnant females were detected to be positive for HEV infection with concomitant hepatitis A infection in three pregnant females. None of the pregnant females were positive for hepatitis B or hepatitis C infection. The mortality was 50% in pregnant females. In an outbreak, besides, testing for hepatitis markers and understanding the pathogenesis of HEV infection in pregnancy, improving basic hygienic standards is of utmost importance.

The current paradigm is that salt marshes and their important ecosystem services are threatened by global climate change; indeed, large marsh losses have been documented worldwide. Morphological changes associated with salt marsh erosion are expected to influence the hydrodynamics and sediment dynamics of coastal systems. Here the influence of salt marsh erosion on the tidal hydrodynamics and sediment storage capability of shallow bays is investigated. Hydrodynamics, sediment transport, and vegetation dynamics are simulated using the numerical framework Coupled Ocean‐Atmosphere‐Wave‐Sediment Transport in the Barnegat Bay‐Little Egg Harbor system, USA. We show that salt marsh erosion influences the propagation of tides into back‐barrier basins, reducing the periodic inundation and sediment delivery to marsh platforms. As salt marshes erode, the sediment trapping potential of marsh platforms decreases exponentially. In this test case, up to 50% of the sediment mass trapped by vegetation is lost once a quarter of the marsh area is eroded. Similarly, without salt marshes the sediment budget of the entire bay significantly declines. Therefore, a positive feedback might be triggered such that as the salt marsh retreats the sediment storage capacity of the system declines, which could in turn further exacerbate marsh degradation. Morphological changes induced by marsh lateral erosion affect tidal dynamics in estuarine systemsPositive feedback between marsh loss and reduction in sediment trapping capacity of estuarine systemsEffects of marsh loss on sediment budget destinations

The chemokine CXCL12 has been shown to regulate breast tumor growth, however, its mechanism in initiating distant metastasis is not well understood. Here, we generated a novel conditional allele of Cxcl12in mice and used a fibroblast-specific Cretransgene along with various mammary tumor models to evaluate CXCL12 function in the breast cancer metastasis. Ablation of CXCL12 in stromal fibroblasts of mice significantly delayed the time to tumor onset and inhibited distant metastasis in different mouse models. Elucidation of mechanisms using in vitro and in vivo model systems revealed that CXCL12 enhances tumor cell intravasation by increasing vascular permeability and expansion of a leaky tumor vasculature. Furthermore, our studies revealed CXCL12 enhances permeability by recruiting endothelial precursor cells and decreasing endothelial tight junction and adherence junction proteins. High expression of stromal CXCL12 in large cohort of breast cancer patients was directly correlated to blood vessel density and inversely correlated to recurrence and overall patient survival. In addition, our analysis revealed that stromal CXCL12 levels in combination with number of CD31+ blood vessels confers poorer patient survival compared to individual protein level. However, no correlation was observed between epithelial CXCL12 and patient survival or blood vessel density. Our findings describe the novel interactions between fibroblasts-derived CXCL12 and endothelial cells in facilitating tumor cell intrvasation, leading to distant metastasis. Overall, our studies indicate that cross-talk between fibroblast-derived CXCL12 and endothelial cells could be used as novel biomarker and strategy for developing tumor microenvironment based therapies against aggressive and metastatic breast cancer.

Picture fuzzy set (PFS) is a recently developed tool to deal with uncertainty which is a direct extension of intuitionistic fuzzy set (IFS) that can model uncertainty in such situations involving more answers of these types: yes, abstain, no. In this paper, (α,δ,β)-cut and strong (α,δ,β)-cut of PFS have been defined and decomposition theorems of PFS are proved. Later on extension principle for PFS has been defined and studied some of its properties. Finally, picture fuzzy arithmetic based on extension principle has been performed with examples.

Seagrasses are marine flowering plants that strongly impact their physical and biological surroundings and are therefore frequently referred to as ecological engineers. The effect of seagrasses on coastal bay resilience and sediment transport dynamics is understudied. Here we use six historical maps of seagrass distribution in Barnegat Bay, USA, to investigate the role of these vegetated surfaces on the sediment storage capacity of shallow bays. Analyses are carried out by means of the Coupled‐Ocean‐Atmosphere‐Wave‐Sediment Transport (COAWST) numerical modeling framework. Results show that a decline in the extent of seagrass meadows reduces the sediment mass potentially stored within bay systems. The presence of seagrass reduces shear stress values across the entire bay, including unvegetated areas, and promotes sediment deposition on tidal flats. On the other hand, the presence of seagrasses decreases suspended sediment concentrations, which in turn reduces the delivery of sediment to marsh platforms. Results highlight the relevance of seagrasses for the long‐term survival of coastal ecosystems, and the complex dynamics regulating the interaction between subtidal and intertidal landscapes. Seagrasses influence the resilience of coastal wetlands to external agents, such as sea level rise, by altering the velocity field and sediment transport dynamics of coastal environments. In many areas worldwide seagrass habitats are declining. This paper studies how seagrasses influence the sediment budget of shallow bays using a computer model, and Barnegat Bay, New Jersey, as test case. Specifically, we used computer models to simulate velocity and sediment transport dynamics in Barnegat Bay with historical seagrass maps for the period 1968–2009. These maps show that for Barnegat Bay seagrasses have decreased in time. We found that seagrasses are important for the retention of sediments within bay systems, and when seagrasses are present less sediments are lost in the ocean, which is relevant for the long‐term survival of coastal wetlands as an abundance of sediments generally corresponds to more resilient wetlands. The presence of seagrasses mainly increases the storage of sediments on tidal flats, while it decreases the delivery of sediments to the marsh platforms during high tide. Our results highlight the importance of seagrasses and are relevant for coastal communities and coastal managers worldwide as they could aid the design of coastal protection schemes. Seagrass loss increases bay‐wide sediment concentrationsInfluence of seagrass decline on sediment budget in shallow baysSeagrass impact on sediment exchange between tidal flats and salt marsh