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The Plight of “Dual Noneligible” People in the United States

The NE/AAT/CBG axis regulates adipose tissue glucocorticoid exposure

AbstractCorticosteroid binding globulin (CBG; SERPINA6) binds >85% of circulating glucocorticoids but its influence on their metabolic actions is unproven. Targeted proteolytic cleavage of CBG by neutrophil elastase (NE; ELANE) significantly reduces CBG binding affinity, potentially increasing ‘free’ glucocorticoid levels at sites of inflammation. NE is inhibited by alpha-1-antitrypsin (AAT; SERPINA1). Using complementary approaches in mice and humans to manipulate NE or AAT, we show high-fat diet (HFD) increases the NE:AAT ratio specifically in murine visceral adipose tissue, an effect only observed in males. Notably, HFD-fed male mice lacking NE have reduced glucocorticoid levels and action specifically in visceral adipose tissue, with improved glucose tolerance and insulin sensitivity, independent of systemic changes in free glucocorticoids. The protective effect of NE deficiency is lost when the adrenals are removed. Moreover, human asymptomatic heterozygous carriers of deleterious mutations in SERPINA1 resulting in lower AAT levels have increased adipose tissue glucocorticoid levels and action. However, in contrast to mice, humans present with systemic increases in free circulating glucocorticoid levels, an effect independent of HPA axis activation. These findings show that NE and AAT regulate local tissue glucocorticoid bioavailability in vivo, providing crucial evidence of a mechanism linking inflammation and metabolism.

High genetic variation, low differentiation, and Pleistocene expansions of the migratory and endangered long-nosed tequila bat, Leptonycteris nivalis, inferred using both maternal and paternal genetic markers

Tequila bats (genus Leptonycteris) have gained attention for their critical role in pollinating different plant species, especially Agave spp. and columnar cacti. Leptonycteris nivalis is the largest nectar-feeding bat in the Americas, and the females exhibit migratory behavior during the breeding season. Due to its relatively small and seemingly declining population sizes, this species is protected by government agencies in the United States and Mexico. We conducted population genetics and phylogeographic analyses to elucidate the genetic structure and demographic history of the species using two mitochondrial markers and a Y chromosome-associated gene, to describe both maternal and paternal lineages. We estimated high haplotypic diversity measures for the different markers (Dloop—Hd = 0.775; Cyt-b—Hd = 0.937; DBY -Hd = 0.946). We found that geographic genetic differentiation is very low, and there is high connectivity among localities. The estimated divergence time between L. nivalis and L. yerbabuenae, the other species in the genus found in Mexico, aligns with previous estimates for the genus (6.91–9.43 mya). A demographic expansion was detected approximately at 600 ka—700 ka (thousands of years ago). The historical demographic changes observed in L. nivalis appear to be associated with environmental shifts during the Pleistocene, which likely impacted the distribution range of the plants that these bats feed on, such as Agave species.

Neoadjuvant or concurrent atezolizumab with chemoradiation for locally advanced cervical cancer: a randomized phase I trial

AbstractCombined immune checkpoint blockade (ICB) and chemoradiation (CRT) is approved in patients with locally advanced cervical cancer (LACC) but optimal sequencing of CRT and ICB is unknown. NRG-GY017 (NCT03738228) was a randomized phase I trial of atezolizumab (anti-PD-L1) neoadjuvant and concurrent with CRT (Arm A) vs. concurrent with CRT (Arm B) in patients with high-risk node-positive LACC. The primary endpoint was the fraction of expanded tumor-associated T-cell receptor (TCR) clones in blood at day 21 as a surrogate measure of anti-tumor immune response. Secondary objectives were safety and feasibility, 2-year disease-free survival (DFS), and predictive value of PD-L1 expression. Forty patients were randomized, 36 received treatment, and 25 were evaluable for the primary endpoint. After cycle 1, there was peripheral expansion of higher proportion of tumor-associated TCR clones in Arm A than in Arm B (p = 0.0025) that remained higher at day 21, meeting the pre-specified endpoint on two-sample T-test (p = 0.052), but not on sensitivity analysis by Wilcoxon test (p = 0.13). At the median follow up of 25.8 months, 2-year DFS was 76% in Arm A and 56% in Arm B (p = 0.28). There were no new safety signals. In conclusion, neoadjuvant ICB prior to CRT was safe and was associated with immunologically and clinically favorable outcomes, warranting larger confirmatory studies.

Correction: Not one Brexit: How local context and social processes influence policy analysis

Klebsiella oxytoca facilitates microbiome recovery via antibiotic degradation and restores colonization resistance in a diet-dependent manner

AbstractCompetition among bacteria for carbohydrates is pivotal for colonization resistance (CR). However, the impact of Western-style diets on CR remains unclear. Here we show how the competition between Klebsiella oxytoca and Klebsiella pneumoniae is modulated by consuming one of three Western-style diets characterized by high-starch, high-sucrose, or high-fat/high-sucrose content. In vivo competition experiments in ampicillin-treated mice reveal that K. oxytoca promotes K. pneumoniae decolonization on all dietary backgrounds. However, mice on the high-fat/high-sucrose diet show reduced pathogen clearance. Microbiome analysis reveals that the combination of Western-style diets and ampicillin treatment synergize in microbiome impairment, particularly noticeable in the presence of high dietary fat content. The diet-independent degradation of ampicillin in the gut lumen by K. oxytoca beta-lactamases facilitates rapid commensal outgrowth, which is required for subsequent pathogen clearance. Our findings provide insights into how diet modulates functional microbiome recovery and K. oxytoca-mediated pathogen elimination from the gut.

Biophysical and biochemical evidence for the role of acetate kinases (AckAs) in an acetogenic pathway in pathogenic spirochetes

Unraveling the metabolism of Treponema pallidum is a key component to understanding the pathogenesis of the human disease that it causes, syphilis. For decades, it was assumed that glucose was the sole carbon/energy source for this parasitic spirochete. But the lack of citric-acid-cycle enzymes suggested that alternative sources could be utilized, especially in microaerophilic host environments where glycolysis should not be robust. Recent bioinformatic, biophysical, and biochemical evidence supports the existence of an acetogenic energy-conservation pathway in T . pallidum and related treponemal species. In this hypothetical pathway, exogenous D-lactate can be utilized by the bacterium as an alternative energy source. Herein, we examined the final enzyme in this pathway, acetate kinase (named TP0476), which ostensibly catalyzes the generation of ATP from ADP and acetyl-phosphate. We found that TP0476 was able to carry out this reaction, but the protein was not suitable for biophysical and structural characterization. We thus performed additional studies on the homologous enzyme (75% amino-acid sequence identity) from the oral pathogen Treponema vincentii , TV0924. This protein also exhibited acetate kinase activity, and it was amenable to structural and biophysical studies. We established that the enzyme exists as a dimer in solution, and then determined its crystal structure at a resolution of 1.36 Å, showing that the protein has a similar fold to other known acetate kinases. Mutation of residues in the putative active site drastically altered its enzymatic activity. A second crystal structure of TV0924 in the presence of AMP (at 1.3 Å resolution) provided insight into the binding of one of the enzyme’s substrates. On balance, this evidence strongly supported the roles of TP0476 and TV0924 as acetate kinases, reinforcing the hypothesis of an acetogenic pathway in pathogenic treponemes.

Oscillatory mechanoluminescence of Mn2+-doped SrZnOS in dynamic response to rapid compression

Secure privacy-preserving record linkage system from re-identification attack

Privacy-preserving record linkage (PPRL) technology, crucial for linking records across datasets while maintaining privacy, is susceptible to graph-based re-identification attacks. These attacks compromise privacy and pose significant risks, such as identity theft and financial fraud. This study proposes a zero-relationship encoding scheme that minimizes the linkage between source and encoded records to enhance PPRL systems’ resistance to re-identification attacks. Our method’s efficacy was validated through simulations on the Titanic and North Carolina Voter Records (NCVR) datasets, demonstrating a substantial reduction in re-identification rates. Security analysis confirms that our zero-relationship encoding effectively preserves privacy against graph-based re-identification threats, improving PPRL technology’s security.

Influenza A Virus H7 nanobody recognizes a conserved immunodominant epitope on hemagglutinin head and confers heterosubtypic protection

Abstract Influenza remains a persistent global health challenge, largely due to the virus’ continuous antigenic drift and occasional shift, which impede the development of a universal vaccine. To address this, the identification of broadly neutralizing antibodies and their epitopes is crucial. Nanobodies, with their unique characteristics and binding capacity, offer a promising avenue to identify such epitopes. Here, we isolate and purify a hemagglutinin (HA)-specific nanobody that recognizes an H7 subtype of influenza A virus. The nanobody, named E10, exhibits broad-spectrum binding, cross-group neutralization and in vivo protection across various influenza A subtypes. Through phage display and in vitro characterization, we demonstrate that E10 specifically targets an epitope on HA head which is part of the conserved lateral patch and is highly immunodominant upon H7 infection. Importantly, immunization with a peptide including the E10 epitope elicits cross-reactive antibodies and mediates partial protection from lethal viral challenge. Our data highlights the potential of E10 and its associated epitope as a candidate for future influenza prevention strategies.

Characterization and evaluation of the cytotoxic, antioxidant, and anti-human lung cancer properties of copper nanoparticles green-synthesized by fennel extract following the PI3K/AKT/Mtor signaling pathway

This work established the cytotoxic, antioxidant and anticancer effects of copper nanoparticles (CuNPs) manufactured with fennel extract, especially on non-small cell lung cancer (NSCLC) as well. CuNPs caused cytotoxicity in a dose-dependent manner for two NSCLC cell lines, A549 and H1650. At 100 μg/ml, CuNPs reduced cell viability to 70% in A549 cells and 65% in H1650 cells. which showed a cytotoxic effect (p<0. 05). Lactate dehydrogenase (LDH) was correspondingly present in a high proportion in the cells, demonstrated upon testing. Together with their cytotoxic properties, CuNPs demonstrated high antioxidative activity. When the concentration of the nano particles was high (100 μg/ml), the ratio of reactive oxygen species (ROS) was reduced as much as 50%, which in turn suggested antioxidant activity. There was plenty of evidence that CuNPs had anti-cancer potential; this has been shown by the effect of the molecules on the PI3K/AKT/mTOR pathway, which was one of the pathways crucial for cancer survival. Western blot analysis and qRT-PCR results indicated a widespread degradation of the proteins in this pathway upon CuNP exposure. Interestingly, there was a declined phosphorylation up to 75% of PI3K, AKT, and mTOR at 100 μg/ml (p<0. 001). In summary, these findings illustrated the mechanisms behind the therapeutic effect of CuNPs, thus making them good targets for the NSCLC treatment. CuNPs have cytotoxic and antioxidant capacity, as well as significant alterations in lung cancers pathway, and therefore they can be considered as anti-cancer candidates.

Photocatalytic asymmetric C-C coupling for CO2 reduction on dynamically reconstructed Ruδ+-O/Ru0-O sites

Baseline assessment of knowledge, attitude, practice, and adherence toward antimicrobials among women living in two urban municipalities in Lalitpur district, Nepal

Introduction Antimicrobial resistance (AMR) is a significant problem in developing, low- and middle-income countries like Nepal. Community engagement can be an important means to address the problem. Knowledge, attitude, practice, and adherence of women regarding antibiotics and AMR was studied. Methods This baseline study was conducted in two urban municipalities of Lalitpur district as preparation for a larger intervention study (Mahalaxmi municipality will be the intervention and Godawari the comparison/control area). The study population was women belonging to the mother’s groups of 45 female community health volunteers (FCHVs) from each municipality. The study was done from September 2023 to January 2024. A total of 1207 individuals (580 in Mahalaxmi and 627 in Godawari) were involved. Data on demographics, knowledge, attitude, practice, and adherence was collected using a pre-validated structured questionnaire. Results The average age, educational status, monthly income, occupation, presence of respiratory disease, chronic diseases and communicable diseases were found to be not different among the two municipalities. Work experience, presence of respiratory disease and of health worker in the household was different in the baseline survey among the two locations. Knowledge was higher in Mahalaxmi municipality, but adherence was higher in Godawari municipality (p <0.0001). No significant difference was seen in attitude and practice scales. Knowledge, attitude, practice and adherence scores among different subgroups of respondents in the two municipalities were found to be significantly different for occupation (p <0.0001), and education (p <0.0001). The attitude scores were also significantly different according to presence/absence of respiratory disease in the household (p = 0.027). Conclusion At baseline the two study sites were broadly comparable in terms of participants’ demographic characteristics. There was higher knowledge and lower adherence in Mahalaxmi municipality. An educational intervention to improve KAP and adherence is required and will be conducted.

Hyperedge overlap drives explosive transitions in systems with higher-order interactions

Correction: Aphid infestations reduce monarch butterfly colonization, herbivory, and growth on ornamental milkweed

STOP & GO: discontinuing TPO-RA in chronic ITP

Author Correction: Native RNA nanopore sequencing reveals antibiotic-induced loss of rRNA modifications in the A- and P-sites

Assessing indirect biodiversity conservation benefits of fisheries closures in the Gulf of St. Lawrence, Canada

Marine biodiversity loss is a pressing global issue, intensified by human activities and climate change. Complementary to marine protected areas (MPAs), Other Effective Area-Based Conservation Measures (OECMs) have emerged as a key tool to mitigate this loss by providing long-term biodiversity protection. However, while OECMs primarily target specific taxa, they can also offer indirect biodiversity conservation benefits (BCBs) to a wider range of taxa. In this study, we assess the indirect BCBs of eleven OECMs in the Gulf of St. Lawrence, focusing on their role in supporting the life-history processes of commercially important species such as Atlantic halibut, Greenland halibut, and redfish. We apply an integrated assessment that combines knowledge and data previously unconnected to provide information to support OECM management. Our analysis reveals that eight of the eleven OECMs overlap with potential spawning habitats for these species, suggesting important life-history benefits. However, projected climate-driven changes in bottom temperature, oxygen concentration, and pH levels pose a threat to these habitats, potentially undermining the long-term effectiveness of OECMs. These findings underscore the need for adaptive management strategies that incorporate climate-informed ecosystem indicators and broaden the conservation focus beyond economically important species. Such approaches are crucial to ensuring that OECMs continue to provide both direct and indirect BCBs in the face of accelerating climate change, thereby contributing to global marine biodiversity conservation efforts.

GSI: myeloma—cold case closed?

Distinct patterns of volcano deformation for hot and cold magmatic systems

AbstractVolcano deformation can be detected over timescales from seconds to decades, offering valuable insights for magma dynamics. However, these signals are shaped by the long-term evolution of magmatic systems, a coupling that remains poorly understood. Here we integrate thermal models of crustal-scale magmatism with thermo-mechanical simulations of ground deformation. This allows us to determine the influence of magmatic flux over 105–106 years on viscoelastic deformation spanning a 10-year observation period. Our results reveal a coupling between surface deformation and the thermal evolution of magma systems, modulated by magma flux and system lifespan. Relatively cold magma systems exhibit cycles of uplift and subsidence, while comparatively hot plumbing systems experience solely uplift. These findings align with geophysical observations from caldera systems, emphasizing the potential of surface deformation measurements as tool for deciphering the state and architecture of magmatic systems. Considering long-term magmatic system evolution is imperative for accurate interpretation of volcanic unrest.