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Abstract Recently classified as a unique species by the IUCN, African forest elephants (Loxodonta cyclotis) are critically endangered due to severe poaching. With limited knowledge about their ecological role due to the dense tropical forests they inhabit in central Africa, it is unclear how the Afrotropics are influenced by elephants. Although their role as seed dispersers is well known, they may also drive large‐scale processes that determine forest structure through the creation of elephant trails and browsing the understory, allowing larger, carbon‐dense trees to succeed. Multiple scales of lidar were collected by NASA in Lopé National Park, Gabon from 2015 to 2022. Utilizing two airborne lidar datasets in an African forest elephant stronghold, detailed canopy structural information was used in conjunction with elephant trail data to determine how forest structure varies on and off trails. Forest along elephant trails displayed different structural characteristics than forested areas off trails, with lower canopy height, canopy cover, and different vertical distribution of plant density. Less plant area density was found on trails at 1 m in height, while more vegetation was found at 12 m, compared to off trail locations. Trails in forest areas with previous logging history had lower plant area in the top of the canopy. Forest elephants can be considered as “logging light” ecosystem engineers, affecting canopy structure through browsing and movement. Both airborne lidar scales were able to capture elephant impact along trails, with the high‐resolution discrete return lidar performing higher than waveform lidar.

Ocean observational gridded products are vital for climate monitoring, ocean and climate research, model evaluation, and supporting climate mitigation and adaptation measures. This paper describes the 4th version of the Institute of Atmospheric Physics (IAPv4) ocean temperature and ocean heat content (OHC) objective analysis product. It accounts for recent developments in quality control (QC) procedures, climatology, bias correction, vertical and horizontal interpolation, and mapping and is available for the upper 6000 m (119 levels) since 1940 (more reliable after ∼ 1957) for monthly and 1°×1° temporal and spatial resolutions. IAPv4 is compared with the previous version, IAPv3, and with the other data products, sea surface temperatures (SSTs), and satellite observations. It has a slightly stronger long-term upper 2000 m OHC increase than IAPv3 for 1955–2023, mainly because of newly developed bias corrections. The IAPv4 0–2000 m OHC trend is also higher during 2005–2023 than IAPv3, mainly because of the QC process update. The uppermost level of IAPv4 is consistent with independent SST datasets. The month-to-month OHC variability for IAPv4 is desirably less than IAPv3 and the other OHC products investigated in this study, the trend of ocean warming rate (i.e., warming acceleration) is more consistent with the net energy imbalance at the top of the atmosphere than IAPv3, and the sea level budget can be closed within uncertainty. The gridded product is freely accessible at https://doi.org/10.12157/IOCAS.20240117.002 for temperature data (Cheng et al., 2024a) and at https://doi.org/10.12157/IOCAS.20240117.001 for ocean heat content data (Cheng et al., 2024b).

Abstract Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.

Abstract Introduction Rare myocarditis and pericarditis cases have occurred in coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccine recipients. Troponin levels, a potential marker of myocardial injury, were assessed in healthy participants before and after BNT162b2 vaccination. Methods Vaccine-experienced 12- to 30-year-olds in phase 3 crossover C4591031 Substudy B (NCT04955626) who had two or three prior BNT162b2 30-μg doses were randomized to receive BNT162b2 30 μg followed by placebo, or placebo followed by BNT162b2 30 µg, 1 month apart. A participant subset, previously unvaccinated against COVID-19, in the phase 3 C4591007 study (NCT04816643) received up to three vaccinations (BNT162b2 10 μg or placebo [5- to 11-year-olds]) or open-label BNT162b2 30 μg (12- to 15-year-olds). Blood samples collected pre-vaccination, 4 days post-vaccination, and 1-month post-vaccination (C4591031 Substudy B only) were analyzed. Frequencies of elevated troponin I levels (male, > 35 ng/l; female, > 17 ng/l) were assessed. Results Percentages of 12- to 30-year-olds (n = 1485) in C4591031 Substudy B with elevated troponin levels following BNT162b2 or placebo receipt were 0.5% and 0.8% before vaccination, 0.7% and 1.0% at day 4, and 0.7% and 0.5% at 1 month, respectively. In Study C4591007 (n = 1265), elevated troponin I levels were observed in 0.2, 0.4, and 0.2% of 5- to 11-year-old BNT162b2 recipients at baseline and 4 days post-dose 2 and 3, respectively; corresponding values in 12- to 15-year-olds were 0.4, 0.4, and 0.7%. No 5- to 11-year-old placebo recipients had elevated troponin levels. No myocarditis or pericarditis cases or deaths were reported. Conclusions Among 5- to

With an ever-increasing amount of (meta)genomic data being deposited in sequence databases, (meta)genome mining for natural product biosynthetic pathways occupies a critical role in the discovery of novel pharmaceutical drugs, crop protection agents and biomaterials. The genes that encode these pathways are often organised into biosynthetic gene clusters (BGCs). In 2015, we defined the Minimum Information about a Biosynthetic Gene cluster (MIBiG): a standardised data format that describes the minimally required information to uniquely characterise a BGC. We simultaneously constructed an accompanying online database of BGCs, which has since been widely used by the community as a reference dataset for BGCs and was expanded to 2021 entries in 2019 (MIBiG 2.0). Here, we describe MIBiG 3.0, a database update comprising large-scale validation and re-annotation of existing entries and 661 new entries. Particular attention was paid to the annotation of compound structures and biological activities, as well as protein domain selectivities. Together, these new features keep the database up-to-date, and will provide new opportunities for the scientific community to use its freely available data, e.g. for the training of new machine learning models to predict sequence-structure-function relationships for diverse natural products. MIBiG 3.0 is accessible online at https://mibig.secondarymetabolites.org/.

Introduction: Concurrent prescribing of opioids and benzodiazepines is associated with increased risk of emergency department visits and overdose. Postpartum women commonly receive opioids for pain after delivery and are at risk for postpartum depression/anxiety. Although prior research finds increases in opioid prescribing and symptoms of depression/anxiety during COVID-19, concurrent prescribing among postpartum women has not been examined in the context of COVID-19. Methods: Using data from a large sample of privately insured postpartum women (N=514,120), the authors compared concurrent prescription fills of opioids and benzodiazepines before March 1, 2020, and after March 1, 2020. Primary outcome variables measured whether a patient ever filled concurrent opioid and benzodiazepine prescriptions and the number of concurrent prescription fills per patient in the 6 months after delivery. Results: Roughly 46.4% of postpartum women filled an opioid prescription, 2.4% filled a benzodiazepine prescription, and 1.2% of women filled a concurrent prescription. Among postpartum women filling a benzodiazepine prescription, 50.7% filled a concurrent opioid prescription. The number of concurrent fills among postpartum women significantly increased during the early period of COVID-19. On average, postpartum women filled 0.009 more concurrent prescriptions than expected on the basis of the preexisting trend, representing a 22.0% increase in the number of concurrent prescriptions relative to the sample mean. Conclusions: Concurrent prescribing of opioids and benzodiazepines places postpartum women at higher risk of emergency department visits and overdose. To reduce the harms associated with concurrent prescribing, clinicians should carefully consider whether opioids and/or benzodiazepines are clinically necessary for treatment and consult their state prescription drug monitoring program prior to prescribing these medications.

Abstract Background The tumour microenvironment (TME) consists of tumour-supportive immune cells, endothelial cells, and fibroblasts. PhenoCycler, a high-plex single cell spatial biology imaging platform, is used to characterize the complexity of the TME. Researchers worldwide harvest and bank tissues from mouse models which are employed to model a plethora of human disease. With the explosion of interest in spatial biology, these panoplies of archival tissues provide a valuable resource to answer new questions. Here, we describe our protocols for developing tunable PhenoCycler multiplexed imaging panels and describe our open-source data analysis pipeline. Using these protocols, we used PhenoCycler to spatially resolve the TME of 8 routinely employed pre-clinical models of lymphoma, breast cancer, and melanoma preserved as FFPE. Results Our data reveal distinct TMEs in the different cancer models that were imaged and show that cell-cell contacts differ depending on the tumour type examined. For instance, we found that the immune infiltration in a murine model of melanoma is altered in cellular organization in melanomas that become resistant to αPD-1 therapy, with depletions in a number of cell-cell interactions. Conclusions This work presents a valuable resource study seamlessly adaptable to any field of research involving murine models. The methodology described allows researchers to address newly formed hypotheses using archival materials, bypassing the new to perform new mouse studies.

Understanding the ability of particles to maneuver through disordered environments is a central problem in innumerable settings, from active matter and biology to electronics. Macroscopic particles ultimately exhibit diffusive motion when their energy exceeds the characteristic potential barrier of the random landscape. In stark contrast, wave-particle duality causes electrons in disordered media to come to rest even when the potential is weak—a remarkable phenomenon known as Anderson localization. Here, we present a hydrodynamic active system with wave-particle features, a millimetric droplet self-guided by its own wave field over a submerged random topography, whose dynamics exhibits localized statistics analogous to those of electronic systems. Consideration of an ensemble of particle trajectories reveals a suppression of diffusion when the guiding wave field extends over the disordered topography. We rationalize mechanistically the emergent statistics by virtue of the wave-mediated resonant coupling between the droplet and topography, which produces an attractive wave potential about the localization region. This hydrodynamic analog, which demonstrates how a classical particle may localize like a wave, suggests new directions for future research in various areas, including active matter, wave localization, many-body localization, and topological matter.

Abstract Anthropogenic eutrophication of ecosystems is an important driver of biodiversity loss. Even protected areas (PAs) may be impacted by anthropogenic nutrients, for example, from atmospheric deposition or the provision of supplementary feeding. However, the resultant nutrient patterns, and the role of local wildlife in shaping them, remain poorly understood. We investigated anthropogenic influences on the role that red deer (Cervus elaphus) play in the nutrient balance of a PA in Denmark. We used habitat selection modeling and theoretical scenarios where we varied the proportion of energy the deer obtained from supplementary versus natural forage and compared it with the nutrients removed due to hunting. We show that the movement and distribution of the red deer population within the PA are very heterogeneous and likely influenced by the need for shelter. Moreover, depending on their reliance on supplementary feeding, deer can potentially import large amounts of nutrients to the PA, and concentrate them in localized hotspots. However, we also explore the potential for nutrient loss due to hunting activities. Such indirect anthropogenic impacts on nutrient landscapes may counteract restoration and conservation efforts. We therefore recommend incorporating anthropogenic influences on zoogeochemistry and the animal‐mediated connectivity between PAs and anthropogenically dominated landscapes into future management plans.

Background: This study compares the effectiveness of laser-assisted periodontal therapy (LAPT) to conventional scaling and root planing (SRP) in the treatment of periodontal disease. Materials and Methods: Patients with periodontal disease were divided into two groups. One group received LAPT, while the other group underwent conventional SRP. The periodontal parameters, including pocket depth (PD) and clinical attachment level (CAL), were measured before and after the treatments. The data were statistically analyzed using appropriate methods. Results: After the treatments, the LAPT group showed a mean reduction in PD of 2.5 mm, while the conventional SRP group had a mean reduction of 2.0 mm. Additionally, the laser group demonstrated a mean improvement in CAL of 1.8 mm, whereas the conventional group showed an improvement of 1.3 mm. These differences were statistically significant (P < 0.05). Conclusion: The findings of this study suggest that LAPT may be more effective in reducing PD and improving CAL compared with conventional SRP in the treatment of periodontal disease.

Due to their nutritional and sensorial characteristics, tropical fruits like guava, mamey sapote, and passion fruit are regularly incorporated into daily diets. Their by-products, especially peels, are approximately 10 to 35% of their weight and possess an important content of bioactive compounds, such as dietary fiber and phenolics. The nutritional, technological, physio-functional properties and phenolic compound compositions of guava, mamey sapote, and passion fruit peels were studied. Peels had promising techno- and physio-functional characteristics, good dietary fiber contents (45.18-61.42 g/100 g), and phenolic profiles with ferulic acid, gallic acid, p -coumaric, and catechin as the main compounds. Peel powders also showed excellent DPPH radical scavenging activity (125.3–252.4 µmol TE/100 g) and Trolox equivalent antioxidant capacity, TEAC (369.2–656.8 µmol TE/100 g). The α-amylase and lipase inhibitory activity varied from 28.15 to 51.4% and 30.89 to 57.15%, respectively. Higher values of α-glucosidase inhibition capacity were found, ranging from 51.64 to 70.32%. The chemical composition and properties reported in the present work suggest that peel powders of these guava, mamey sapote, and passion fruit could be used as constituents in different foods, such as bakery and meat goods, with beneficial health effects like control of hyperglycemia, improved intestinal function, and control of overweight; however, more studies are necessary for animal models and humans to confirm these bioactivities conclusively.

Abstract Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.

The importance of bioactive compounds in agro-industrial by-products of plant origin lies in their direct impacts on human health. These compounds have been shown to possess antioxidant, anti-inflammatory, and antimicrobial properties, contributing to disease prevention and strengthening the immune system. In particular, the antimicrobial action of these compounds emerges as an important tool in food preservation, providing natural alternatives to synthetic preservatives and contributing to combating antimicrobial resistance. Using agro-industrial by-products of plant origin not only addresses the need to reduce waste and promote sustainability but also inaugurates a new era in the formulation of functional foods. From fruit peels to pulps and seeds, these by-products are emerging as essential ingredients in the creation of products that can promote health. Continued research in this area will unveil new applications and properties of these by-products and open doors to a food paradigm in which health and sustainability converge, paving the way to a healthier and more equitable future. The present review presents an overview of our knowledge of agro-industrial by-products and some of their more relevant health-promoting bioactivities.

Understanding the role of biased taste T1R2/T1R3 G protein-coupled receptors (GPCR) agonists on glycosylated receptor signaling may provide insights into the opposing effects mediated by artificial and natural sweeteners, particularly in cancer and metastasis. Sweetener-taste GPCRs can be activated by several active states involving either biased agonism, functional selectivity, or ligand-directed signaling. However, there are increasing arrays of sweetener ligands with different degrees of allosteric biased modulation that can vary dramatically in binding- and signaling-specific manners. Here, emerging evidence proposes the involvement of taste GPCRs in a biased GPCR signaling crosstalk involving matrix metalloproteinase-9 (MMP-9) and neuraminidase-1 (Neu-1) activating glycosylated receptors by modifying sialic acids. The findings revealed that most natural and artificial sweeteners significantly activate Neu-1 sialidase in a dose-dependent fashion in RAW-Blue and PANC-1 cells. To confirm this biased GPCR signaling crosstalk, BIM-23127 (neuromedin B receptor inhibitor, MMP-9i (specific MMP-9 inhibitor), and oseltamivir phosphate (specific Neu-1 inhibitor) significantly block sweetener agonist-induced Neu-1 sialidase activity. To assess the effect of artificial and natural sweeteners on the key survival pathways critical for pancreatic cancer progression, we analyzed the expression of epithelial-mesenchymal markers, CD24, ADLH-1, E-cadherin, and N-cadherin in PANC-1 cells, and assess the cellular migration invasiveness in a scratch wound closure assay, and the tunneling nanotubes (TNTs) in staging the migratory intercellular communication. The artificial and natural sweeteners induced metastatic phenotype of PANC-1 pancreatic cancer cells to promote migratory intercellular communication and invasion. The sweeteners also induced the downstream NFκB activation using the secretory alkaline phosphatase (SEAP) assay. These findings elucidate a novel taste T1R2/T1R3 GPCR functional selectivity of a signaling platform in which sweeteners activate downstream signaling, contributing to tumorigenesis and metastasis via a proposed NFκB-induced epigenetic reprogramming modeling.

In many commercial steel processing routes, steel microstructures are reverted to an austenitic condition prior to the final processing steps. Understanding the microstructure development during austenitization is crucial for improving the performance and reliability of the microstructure that forms from austenite. In this work, austenite formation in a high-C steel (0.85 wt%) from a microstructure containing martensite/austenite and bainite bands is investigated. It is shown that austenite formation from bainite results in a refined austenite grain structure, and the martensite matrix thus obtained on quenching has a homogeneous distribution of carbides with a relatively low fraction of retained austenite (24%). On the other hand, a coarser austenite microstructure is obtained when austenite forms from a mixture of martensite and retained austenite. The reason for the coarse austenite grains is argued to be a memory effect, which is substantiated by in situ X-ray diffraction analysis. After quenching, an inhomogeneous carbide distribution and a higher retained austenite fraction (30%) are observed in the regions that were initially martensite/austenite. The global microstructure, hence, has a bimodal size distribution of prior austenite grains and carbide-dense bands. The causes for these heterogeneities are discussed with the help of interrupted quench experiments, equilibrium phase calculations, and DICTRA simulations.

Autologous fat transfers show promise in treating fibrotic skin diseases, reversing scarring and stiffness, and improving quality of life. Adipose-derived stem cells (ADSCs) within these grafts are believed to be crucial for this effect, particularly their secreted factors, though the specific mechanisms remain unclear. This study investigates transcriptomic changes in ADSCs after in vitro fibrotic, inflammatory, and hypoxic conditioning. High-throughput gene expression assays were conducted on ADSCs exposed to IL1-β, TGF-β1, and hypoxia and in media with fetal bovine serum (FBS). Flow cytometry characterized the ADSCs. RNA-Seq analysis revealed distinct gene expression patterns between the conditions. FBS upregulated pathways were related to the cell cycle, replication, wound healing, and ossification. IL1-β induced immunomodulatory pathways, including granulocyte chemotaxis and cytokine production. TGF-β1 treatment upregulated wound healing and muscle tissue development pathways. Hypoxia led to the downregulation of mitochondria and cellular activity.

Avocado paste (AP) is an industrial byproduct and a potential source of bioactive compounds, so there is great interest in its valorization. The objective of the present study was to evaluate the effects of adding AP to corn chips regarding their nutritional profile and sensory acceptability. Three AP-supplemented corn chip samples were prepared (C-2%, C-6%, and C-10%), along with a control chip (C), whose total phenolics, flavonoids, antioxidant capacity, proximate composition, minerals, fatty acids, and sensory acceptability were evaluated. Regarding the content of phenolic compounds and flavonoids, significant increases were found between all samples (p < 0.05), particularly between C and C-10% (from 0.93 to 3.56 mg GAE/g dw and 1.17 to 6.61 mg QE/g dw, respectively). Their antioxidant capacity also increased significantly (p < 0.05) with all methods used (FRAP, DPPH, ORAC, and TEAC). Regarding the sensory analysis, no significant differences were found (p > 0.05) between C and C-2% in the parameters of smell, color, flavor, and overall acceptability; however, the texture of C-2% was better evaluated. The C-2% sample also had the highest acceptability; 82% of the participants mentioned that they would buy the C-2%, higher than the rest of the samples. These results suggest the feasibility of adding 2% AP as a strategy to improve the nutritional properties of corn chips without compromising their sensory acceptability; therefore, AP may be used as a food ingredient.

IntroductionZika virus (ZIKV) infection during pregnancy results in a spectrum of birth defects and neurodevelopmental deficits in prenatally exposed infants, with no clear understanding of why some pregnancies are more severely affected. Differential control of maternal ZIKV infection may explain the spectrum of adverse outcomes.MethodsHere, we investigated whether the magnitude and breadth of the maternal ZIKV-specific antibody response is associated with better virologic control using a rhesus macaque model of prenatal ZIKV infection. We inoculated 18 dams with an Asian-lineage ZIKV isolate (PRVABC59) at 30-45 gestational days. Plasma vRNA and infectious virus kinetics were determined over the course of pregnancy, as well as vRNA burden in the maternal-fetal interface (MFI) at delivery. Binding and neutralizing antibody assays were performed to determine the magnitude of the ZIKV-specific IgM and IgG antibody responses throughout pregnancy, along with peptide microarray assays to define the breadth of linear ZIKV epitopes recognized.ResultsDams with better virologic control (n= 9) cleared detectable infectious virus and vRNA from the plasma by 7 days post-infection (DPI) and had a lower vRNA burden in the MFI at delivery. In comparison, dams with worse virologic control (n= 9) still cleared detectable infectious virus from the plasma by 7 DPI but had vRNA that persisted longer, and had higher vRNA burden in the MFI at delivery. The magnitudes of the ZIKV-specific antibody responses were significantly lower in the dams with better virologic control, suggesting that higher antibody titers are not associated with better control of ZIKV infection. Additionally, the breadth of the ZIKV linear epitopes recognized did not differ between the dams with better and worse control of ZIKV infection.DiscussionThus, the magnitude and breadth of the maternal antibody responses do not seem to impact maternal virologic control. This may be because control of maternal infection is determined in the first 7 DPI, when detectable infectious virus is present and before robust antibody responses are generated. However, the presence of higher ZIKV-specific antibody titers in dams with worse virologic control suggests that these could be used as a biomarker of poor maternal control of infection and should be explored further.

Background: Fully porous acetabular shells are an appealing choice for patients with extensive acetabular defects undergoing revision total hip arthroplasty (rTHA). This study reports on the early outcomes of a novel 3-D printed fully porous titanium acetabular shell in revision acetabular reconstruction. Methods: A multicenter retrospective study of patients who received a fully porous titanium acetabular shell for rTHA with a minimum of 2 years of follow-up was conducted. The primary outcome was rate of acetabular revision. Results: The final study cohort comprised 68 patients with a mean age of 67.6 years (standard deviation 10.4) and body mass index of 29.5 kg/m2 (standard deviation 5.9). Ninety-four percent had a preoperative Paprosky defect grade of 2A or higher. The average follow-up duration was 3.0 years (range 2.0-5.1). Revision-free survivorship at 2 years was 81% for all causes, 88% for acetabular revisions, and 90% for acetabular revision for aseptic acetabular shell failure. Eight shells were explanted within 2 years (12%): 3 for failure of osseointegration/aseptic loosening (4%) after 15, 17, and 20 months; 3 for infection (4%) after 1, 3, and 6 months; and 2 for instability (3%). At the latest postoperative follow-up, all unrevised shells showed radiographic signs of osseointegration, and none had migrated. Conclusions: This novel 3-D printed fully porous titanium shell in rTHA demonstrated good survivorship and osseointegration when used in complex acetabular reconstruction at a minimum of 2 years. Level of evidence: IV, case series.

A gridded ocean subsurface salinity dataset with global coverage is useful for research on climate change and its variability. Here, we explore the feed-forward neural network (FFNN) approach to reconstruct a high-resolution (0.25∘ × 0.25∘) ocean subsurface (1–2000 m) salinity dataset for the period 1993–2018 by merging in situ salinity profile observations with high-resolution (0.25∘ × 0.25∘) satellite remote-sensing altimetry absolute dynamic topography (ADT), sea surface temperature (SST), sea surface wind (SSW) field data, and a coarse-resolution (1∘ × 1∘) gridded salinity product. We show that the FFNN can effectively transfer small-scale spatial variations in ADT, SST, and SSW fields into the 0.25∘ × 0.25∘ salinity field. The root-mean-square error (RMSE) can be reduced by ∼11 % on a global-average basis compared with the 1∘ × 1∘ salinity gridded field. The reduction in RMSE is much larger in the upper ocean than the deep ocean because of stronger mesoscale variations in the upper layers. In addition, the new 0.25∘ × 0.25∘ reconstruction shows more realistic spatial signals in the regions with strong mesoscale variations, e.g., the Gulf Stream, Kuroshio, and Antarctic Circumpolar Current regions, than the 1∘ × 1∘ resolution product, indicating the efficiency of the machine learning approach in bringing satellite observations together with in situ observations. The large-scale salinity patterns from 0.25∘ × 0.25∘ data are consistent with the 1∘ × 1∘ gridded salinity field, suggesting the persistence of the large-scale signals in the high-resolution reconstruction. The successful application of machine learning in this study provides an alternative approach for ocean and climate data reconstruction that can complement the existing data assimilation and objective analysis methods. The reconstructed IAP0.25∘ dataset is freely available at https://doi.org/10.57760/sciencedb.o00122.00001 (Tian et al., 2022).

Guava and mamey are phenolic- and carotenoid-rich fruits with potential health benefits, but are minimally used as ingredients in functional beverages. The objectives of the present work are to optimize the content of guava and mamey pulps and a stevia solution in the formulation of a functional beverage with high content of bioactive compounds and sensory acceptability using a mixture design analysis, and to analyze its composition after in vitro digestion. The optimized formulation (17.77 and 19.23 g of guava and mamey pulps, respectively; 1% stevia solution) yielded a beverage with 418.21 mg gallic acid equivalents (GAE)/100 mL and 0.20 mg β-carotene/100 mL, and an antioxidant capacity of 213.58, 78.90 and 234.03 mg Trolox equivalents (TE)/100 mL using three methodologies. The mathematical model developed was significant (p < 0.05), according to R2 values between 0.70 and 0.75. α- and β-carotene were quantified during the oral phase of in vitro digestion. Gallic, p-coumaric, ferulic and chlorogenic acids were also identified. The beverage had a general acceptability of 6.72. We conclude that the mathematical model developed was a good predictor of the experimental data and that the optimized beverage contained high bioactive concentrations (phenolics and carotenoids) and was well-accepted by potential consumers.

Childhood neuroblastomas exhibit plasticity between an undifferentiated neural crest–like mesenchymal cell state and a more differentiated sympathetic adrenergic cell state. These cell states are governed by autoregulatory transcriptional loops called core regulatory circuitries (CRCs), which drive the early development of sympathetic neuronal progenitors from migratory neural crest cells during embryogenesis. The adrenergic cell identity of neuroblastoma requires LMO1 as a transcriptional cofactor. Both LMO1 expression levels and the risk of developing neuroblastoma in children are associated with a single nucleotide polymorphism, G/T, that affects a GATA motif in the first intron of LMO1. Here, we showed that WT zebrafish with the GATA genotype developed adrenergic neuroblastoma, while knock-in of the protective TATA allele at this locus reduced the penetrance of MYCN-driven tumors, which were restricted to the mesenchymal cell state. Whole genome sequencing of childhood neuroblastomas demonstrated that TATA/TATA tumors also exhibited a mesenchymal cell state and were low risk at diagnosis. Thus, conversion of the regulatory GATA to a TATA allele in the first intron of LMO1 reduced the neuroblastoma-initiation rate by preventing formation of the adrenergic cell state. This mechanism was conserved over 400 million years of evolution, separating zebrafish and humans.

Summary: Genes that are key to cell identity are generally regulated by cell-type-specific enhancer elements bound by transcription factors, some of which facilitate looping to distant gene promoters. In contrast, genes that encode housekeeping functions, whose regulation is essential for normal cell metabolism and growth, generally lack interactions with distal enhancers. We find that Ronin (Thap11) assembles multiple promoters of housekeeping and metabolic genes to regulate gene expression. This behavior is analogous to how enhancers are brought together with promoters to regulate cell identity genes. Thus, Ronin-dependent promoter assemblies provide a mechanism to explain why housekeeping genes can forgo distal enhancer elements and why Ronin is important for cellular metabolism and growth control. We propose that clustering of regulatory elements is a mechanism common to cell identity and housekeeping genes but is accomplished by different factors binding distinct control elements to establish enhancer-promoter or promoter-promoter interactions, respectively.

We propose digital nets conformational sampling (DNCS) - an enhanced sampling technique to explore the conformational ensembles of peptides, especially intrinsically disordered peptides (IDPs). The DNCS algorithm relies on generating history-dependent samples of dihedral variables using bitwise XOR operations and binary angle measurements (BAM). The algorithm was initially studied using metenkephalin, a highly elusive neuropeptide. The DNCS method predicted near-native structures and the energy landscape of met-enkephalin was observed to be in direct correlation with earlier studies on the neuropeptide. Clustering analysis revealed that there are only 24 low-lying conformations of the molecule. The DNCS method has then been tested for predicting optimal conformations of 42 oligopeptides of length varying from 3 to 8 residues. The closest-to-native structures of 86% of cases are near-native and 24% of them have a root mean square deviation of less than 1.00 Å with respect to their crystal structures. The results obtained reveal that the DNCS method performs well, that too in less computational time. [ABSTRACT FROM AUTHOR]

Consuming foods of vegetable origin has been shown to exert multiple health-related effects, many of them attributed to their phenolic compounds. These molecules are known for being bioactive across multiple cells and organs, with documented changes in gene expression being commonly reported. Nuclear receptors are signal transducers capable of regulating gene expression in response to endogenous and/or exogenous ligands. Liver X receptor (LXR) and retinoid X receptor (RXR) are two important nuclear receptors that can be acted on by phenolic compounds, thereby modifying gene expression and potentially exerting numerous subsequent bioactivities. The present work summarizes recent evidence of the effects of the phenolic compounds that are exerted by targeting LXR and/or RXR. The data show that, when LXR is being targeted, changes in lipid metabolism are commonly observed, due to its ability to regulate genes relevant to this process. The effects vary widely when RXR is the target since it is involved in processes like cell proliferation, vitamin D metabolism, and multiple others by forming heterodimers with other transcription factors that regulate said processes. The evidence therefore shows that phenolic compounds can exert multiple bioactivities, with a mechanism of action based, at least in part, on their ability to modulate the cell at the molecular level by acting on nuclear receptors. The data point to a promising and novel area of study that links diet and health, although various unknowns justify further experimentation to reveal the precise way in which a given phenolic can interact with a nuclear receptor.

This work covers a three-week program designed to provide undergraduate students with a background in structural chemistry and materials science. Sessions are based on the programming of regular polyhedra and their geometrical relationships by using an object-oriented language (i.e., POV-Ray). Three lectures introduce the basics of programming (syntax), Platonic solids, and the geometrical study of metal clusters and carbon structures. Students work with geometrical aspects of two-dimensional (2D) polygons and generate computer-based algorithms. Next, students study dual three-dimensional (3D) polyhedral shapes, where they adapt the written code to generate Cartesian coordinates of the Platonic solids. Materials to guide the students include an explanation of pseudocodes, tutoring to accompany the programming sessions, reviews of generated codes, and session exercises and challenges. All activities during each hands-on session aim to engage and maintain the initial expectations of the students. Students gain capabilities and knowledge allowing them to code final tests: the C[subscript 60] molecule; an icosahedral metal cluster; and a cuboctahedron.

Abstract Background Genome-wide protein-DNA binding is popularly assessed using specific antibody pulldown in Chromatin Immunoprecipitation Sequencing (ChIP-Seq) or Cleavage Under Targets and Release Using Nuclease (CUT&RUN) sequencing experiments. These technologies generate high-throughput sequencing data that necessitate the use of multiple sophisticated, computationally intensive genomic tools to make discoveries, but these genomic tools often have a high barrier to use because of computational resource constraints. Results We present a comprehensive, infrastructure-independent, computational pipeline called SEAseq, which leverages field-standard, open-source tools for processing and analyzing ChIP-Seq/CUT&RUN data. SEAseq performs extensive analyses from the raw output of the experiment, including alignment, peak calling, motif analysis, promoters and metagene coverage profiling, peak annotation distribution, clustered/stitched peaks (e.g. super-enhancer) identification, and multiple relevant quality assessment metrics, as well as automatic interfacing with data in GEO/SRA. SEAseq enables rapid and cost-effective resource for analysis of both new and publicly available datasets as demonstrated in our comparative case studies. Conclusions The easy-to-use and versatile design of SEAseq makes it a reliable and efficient resource for ensuring high quality analysis. Its cloud implementation enables a broad suite of analyses in environments with constrained computational resources. SEAseq is platform-independent and is aimed to be usable by everyone with or without programming skills. It is available on the cloud at https://platform.stjude.cloud/workflows/seaseq and can be locally installed from the repository at https://github.com/stjude/seaseq .

Context and Aim: Diabetes mellitus (DM) can affect one's quality of life (QoL). Literature on the association of QoL among type II diabetics with drug compliance and diet quality among rural communities is poor. This study aimed to determine the QoL among those with type II DM attending an outpatient clinic at a secondary hospital in Tamil Nadu. Settings and Design: A cross-sectional, interview-based study was carried out among those with type II DM. A questionnaire comprising the WHO-BREF tool, Diabetes Healthy Eating Index, Hill-Bone Medication Adherence Scale was administered to participants selected via systematic random sampling. Results: The prevalence of good QoL was estimated to be 51.7% (n = 45, 95% CI: 41.20–62.20). There was no association between good QoL and medication compliance. None of the patients had a good diet quality. Bivariate analysis revealed significant association (p < 0.05) between good QoL and higher education (OR-2.70), those not on medication for complications (OR-2.81) and decreased frequency of general random blood sugar (GRBS) monitoring (OR-2.44). Multivariable analysis adjusting for gender, education, treatment/medication for complications, hospitalisation for DM and GRBS frequency demonstrated significant association between good QoL, lack of medication for complications/co-morbidities and decreased GRBS monitoring frequency with likelihood ratios of 3.25 and 3.44, respectively. Conclusions: The drop in QoL observed could be due to the aftermath of the COVID pandemic. Keeping in mind the impact of healthcare interventions on the QoL of type II DM patients, primary physicians must consider dietary and treatment plans suited to their socio-economic status.

Background: Hypertension is one of the most common medical disorders complicating pregnancy. In India, high blood pressure contributes to 7.1% of maternal deaths. This study was carried out to describe the characteristics and pregnancy outcomes of patients presenting with eclampsia or pre-eclampsia to a secondary care hospital in rural India. Methods: Patients diagnosed with pre-eclampsia or eclampsia between January 2018 and April 2021 were identified and included in the study. Medical records were searched and general patient characteristics, obstetrical history, information about the antenatal period, mode of delivery and outcomes were documented and analysed. Results: Among the 3651 women who delivered in this hospital during this time period, 2.3% (n = 83) presented with eclampsia and 1.9% (n = 71) with pre-eclampsia. More than 50% of the women delivered by lower segment caesarean section among both the eclamptics and pre-eclamptics. The stillbirth rate among those with either pre-eclampsia or eclampsia was 1 per 1000. The number of low birth weight babies born to those presenting with eclampsia (66.7%) was significantly more than those presenting with pre-eclampsia (48.6%). Eclampsia/pre-eclampsia accounted for 21% of all maternal deaths with a case fatality rate of 2.6%. Conclusions: This study identified that in this setting the patients presenting with eclampsia were much higher than those presenting with pre-eclampsia which is in stark contrast to the status even in developing countries. This could be an important finding indicating poorer health-seeking behaviour among the population and will need more studies on various interventions to change this status.

A battery of in vivo evaluations is done on bioscaffolds to ascertain its biocompatibility and host responses. Fibroblast proliferation in a controlled manner is integral part in scaffold assisted wound healing and tissue regeneration. Therefore, AgNOR staining was employed in this study for quantification of fibroblast proliferation and therefore evaluating the host bioscaffold response. Here full thickness skin wound healing studies were done in adult male New Zealand White rabbits using decellularized porcine cholecyst derived scaffolds (dPCS), scaffold supplemented with autologous bone marrow cells (dPCSM) and open wound control group (OW). The scaffolds were explanted seven and forteen days post implantation and were subjected to AgNOR staining. Statistical analysis showed significant variations between scaffold assisted and open wound healing. The study concluded that AgNOR could be used as a good quantitative marker involving fibroblast proliferation and could be used in primary screening of bioscaffold assisted healing and regeneration studies.

Systemic sclerosis (SSc) is a complex, immune-mediated rheumatic disease characterised by excessive extracellular matrix deposition in the skin and internal organs. B cell infiltration into lesional sites such as the alveolar interstitium and small blood vessels, alongside the production of defined clinically relevant autoantibodies indicates that B cells play a fundamental role in the pathogenesis and development of SSc. This is supported by B cell and fibroblast coculture experiments revealing that B cells directly enhance collagen and extracellular matrix synthesis in fibroblasts. In addition, B cells from SSc patients produce large amounts of profibrotic cytokines such as IL-6 and TGF-β, which interact with other immune and endothelial cells, promoting the profibrotic loop. Furthermore, total B cell counts are increased in SSc patients compared with healthy donors and specific differences can be found in the content of naïve, memory, transitional and regulatory B cell compartments. B cells from SSc patients also show differential expression of activation markers such as CD19 which may shape interactions with other immune mediators such as T follicular helper cells and dendritic cells. The key role of B cells in SSc is further supported by the therapeutic benefit of B cell depletion with rituximab in some patients. It is notable also that B cell signaling is impaired in SSc patients, and this could underpin the failure to induce tolerance in B cells as has been shown in murine models of scleroderma.

Objectives: For patients with geriatric frailty, reducing inappropriate medication is an important goal to improve patient safety in primary care. GP-side barriers include knowledge gaps, legal concerns, and lack of communication between the actors involved. The aim was to develop a multi-faceted intervention to facilitate deprescribing and shared prioritisation among frail elderlies with polypharmacy living at home. Methods: Mixed methods study including: 1) scoping review on family conferences, expert panels; 2) group discussions with GPs, mapping of needs and challenges in Primary Care; 3) workshops and expert interviews with GPs, patient advocates, researchers as a basis for a theoretical intervention model; 4) piloting. Results: A major challenge for GPs is to conduct a productive discussion with patients and family cares on deprescribing and drug safety. A guideline for a structured family conference with a medication check and geriatric assessment was developed and proved to be feasible in the pilot study. Conclusion: The intervention developed to facilitate deprescribing and shared prioritisation of drug therapy based on family conferences seems suitable to be tested in a subsequent cRCT. Innovation: Adapting family conferences to primary care for frail patients with polypharmacy.

Summary: Modulating R-loop triplex nucleic acid structures reveals their roles across the genome. However, common approaches cannot ascribe functions to R-loops in a locus-associated manner. This protocol presents the use of a locus-associated R-loop-modulating system (dubbed LasR), which employs an inducible RNaseH1-EGFP-dCas9 chimaera. We detail the in silico design of sgRNAs and their transfection with the chimaera, and outline steps confirming RNaseH1-EGFP-dCas9 expression, localization, locus-targeted association, and R-loop modulation in cis or trans using immunoblotting, microscopy, and chromatin and DNA-RNA immunoprecipitation.For complete details on the use and execution of this protocol, please refer to Abraham et al. (2020). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.