Unveiling Spatial and Temporal Dynamics of Plasmon-Enhanced Localized Fields in Metallic Nanoframes through Ultrafast Electron Microscopy.

Plasmonic nanomaterials, particularly noble metal nanoframes (NFs), are important for applications such as catalysis, biosensing, and energy harvesting due to their ability to enhance localized electric fields and atomic efficiency via localized surface plasmon resonance (LSPR). Yet the fundamental structure-function relationships and plasmonic dynamics of the NFS are difficult to study experimentally and thus far rely predominately on computational methodologies, limiting their utilization. This study leverages the capabilities of ultrafast electron microscopy (UEM), specifically photon-induced near-field electron microscopy (PINEM), to probe the light-matter interactions within plasmonic NF structures. The effects of shape, size, and plasmonic coupling of Pt@Au core-shell NFs on spatial and temporal characteristics of plasmon-enhanced localized electric fields are explored. Importantly, time-resolved PINEM analysis reveals that the plasmonic fields around hexagonal NF prisms exhibit a spatially dependent excitation and decay rate, indicating a nuanced interplay between the spatial geometry of the NF and the temporal evolution of the localized electric field. These results and observations uncover nanophotonic energy transfer dynamics in NFs and highlight their potential for applications in biosensing and photocatalysis.

Multiscale topological analysis of kinetoplast DNA via high-resolution AFM.

Kinetoplast DNA is a complex nanoscale network, naturally assembled from thousands of interconnected DNA circles within the mitochondrion of certain parasites. Despite the relevance of this molecule to parasitology and the recent discovery of tuneable mechanics, its topology remains highly contested. Here we present a multiscale analysis into the structure of kDNA using a combination of high-resolution atomic force microscopy and custom-designed image analysis protocols. By capturing a notably large set of high-resolution images, we are able to look beyond individual kDNA variations and quantify population properties throughout several length scales. Within the sample, geometric fluctuations of area and mean curvature are observed, corresponding with previous in vitro measurements. These translate to localised variations in density, with a sample-wide decrease in DNA density from the outer rim of the molecule to the centre and an increase in pore size. Nodes were investigated in a single molecule study, and their estimated connectivity significantly exceeded mean valence, with a high dependence on their position in the network. While node separation was approximately half the minicircle circumference, it followed a strong bimodal distribution, suggesting more complex underlying behaviour. Finally, upon selective digestion of the network, breakdown of the fibril-cap heterogeneity was observed, with molecules expanding less upon immobilisation on the mica surface. Additionally, preferential digestion was seen in localised areas of the network, increasing pore size disproportionately. Overall, the combination of high-resolution AFM and single molecule image analysis provides a promising method to the continued investigation of complex nanoscale structures. These findings support the ongoing characterisation of kDNA topology to aid understanding of its biological and mechanical phenomena.

Zombie diatoms: acoustically powered diatom frustule bio-templated microswimmers.

Frustules, or the silica based cell walls of diatomaceous algae Aulacoseira granulata, provide large numbers of reliably cylindrical microstructures with an inner cavity and surface chemistry suitable for constructing bubble-based, acoustically-powered micro-swimmers. In this way, microswimmers can be made in a scalable, accessible and low-cost manner, enabling studies of their individual and collective behavior as active colloids.

Simultaneous viscoelasticity and sprayability in antimicrobial acetic acid-alginate fluid gels.

Acetic acid is a promising alternative to antibiotics for topical applications, particularly burn wounds, however its site specificity and retention are impaired by poor material properties. In this study, acetic acid was investigated as both the gelling agent and antimicrobial active in alginate fluid gels. The formed microstructure was found to be directly dependent on acetic acid concentration, leading to highly tuneable material properties. At clinically relevant concentrations of 2.5-5 % acetic acid, the fluid gels were elastically dominated at rest, with viscosities up to 7 orders of magnitude greater than acetic acid alone. These material properties imparted long term surface retention and microparticle barrier function, not seen with either acetic acid or alginate solutions. Most notably, sprayability was enhanced simultaneously with the increased viscosity and elasticity due to the introduction of a discretised microstructure, leading to a remarkable tenfold increase in spray coverage. Formulation was found not to inhibit antimicrobial activity, despite the less acidic pH, with common burn wound pathogens Staphylococcus aureus and Pseudomonas aeruginosa being equally susceptible to the fluid gels as to acetic acid solutions.

NNI Nanoinformatics Conference 2023: Movement Toward a Common Infrastructure for Federal nanoEHS Data Computational Toxicology: Short Communication.

The National Nanotechnology Initiative organized a Nanoinformatics Conference in the 2023 Biden-Harris Administration's Year of Open Science, which included interested U.S. and EU stakeholders, and preceded the U.S.-EU COR meeting on November 15th, 2023 in Washington, D.C. Progress in the development of a common nanoinformatics infrastructure in the European Union and United States were discussed. Development of contributing, individual database projects, and their strengths and weaknesses, were highlighted. Recommendations and next steps for a U.S. nanoEHS common infrastructure were discussed in light of the pending update of the National Nanotechnology Initiative (NNI)'s Environmental, Health and Safety Research Strategy, and U.S. efforts to curate and house nano Environmental Health and Safety (nanoEHS) data from U.S. federal stakeholder groups. Improved data standards, for reporting and storage have been identified as areas where concerted efforts could most benefit initially. Areas that were not addressed at the conference, but that are critical to progress of the U.S. federal consortium effort are the evaluation of data formats according to use and sustainability measures; modeler and end user, including risk-assessor and regulator perspectives; a need for a community forum or shared data location that is not hosted by any individual U.S. federal agency, and is accessible to the public; as well as emerging needs for integration with new data types such as micro and nano plastics, and interoperability with other data and meta-data, such as adverse outcome pathway information. Future progress will depend on continued interaction of the U.S. and EU CORs, stakeholders and partners in the continued development goals for shared or interoperable infrastructure for nanoEHS.

Progressive heterogeneity of enlarged and irregularly shaped apicoplasts in Plasmodium falciparum persister blood stages after drug treatment.

Morphological modifications and shifts in organelle relationships are hallmarks of dormancy in eukaryotic cells. Communications between altered mitochondria and nuclei are associated with metabolic quiescence of cancer cells that can survive chemotherapy. In plants, changes in the pathways between nuclei, mitochondria, and chloroplasts are associated with cold stress and bud dormancy. Plasmodium falciparum parasites, the deadliest agent of malaria in humans, contain a chloroplast-like organelle (apicoplast) derived from an ancient photosynthetic symbiont. Antimalarial treatments can fail because a fraction of the blood-stage parasites enter dormancy and recrudesce after drug exposure. Altered mitochondrial-nuclear interactions in these persisters have been described for P. falciparum, but interactions of the apicoplast remained to be characterized. In the present study, we examined the apicoplasts of persisters obtained after exposure to dihydroartemisinin (a first-line antimalarial drug) followed by sorbitol treatment, or after exposure to sorbitol treatment alone. As previously observed, the mitochondrion of persisters was consistently enlarged and in close association with the nucleus. In contrast, the apicoplast varied from compact and oblate, like those of active ring-stage parasites, to enlarged and irregularly shaped. Enlarged apicoplasts became more prevalent later in dormancy, but regular size apicoplasts subsequently predominated in actively replicating recrudescent parasites. All three organelles, nucleus, mitochondrion, and apicoplast, became closer during dormancy. Understanding their relationships in erythrocytic-stage persisters may lead to new strategies to prevent recrudescences and protect the future of malaria chemotherapy.

DEK regulates B-cell proliferative capacity and is associated with aggressive disease in low-grade B-cell lymphomas.

This study sheds light on the pivotal role of the oncoprotein DEK in B-cell lymphoma. We reveal DEK expression correlates with increased tumor proliferation and inferior overall survival in cases diagnosed with low-grade B-cell lymphoma (LGBCL). We also found significant correlation between DEK expression and copy number alterations in LGBCL tumors, highlighting a novel mechanism of LGBCL pathogenesis that warrants additional exploration. To interrogate the mechanistic role of DEK in B-cell lymphoma, we generated a DEK knockout cell line model, which demonstrated DEK depletion caused reduced proliferation and altered expression of key cell cycle and apoptosis-related proteins, including Bcl-2, Bcl-xL, and p53. Notably, DEK depleted cells showed increased sensitivity to apoptosis-inducing agents, including venetoclax and staurosporine, which underscores the therapeutic potential of targeting DEK in B-cell lymphomas. Overall, our study contributes to a better understanding of DEK's role as an oncoprotein in B-cell lymphomas, highlighting its potential as both a promising therapeutic target and a novel biomarker for aggressive LGBCL. Further research elucidating the molecular mechanisms underlying DEK-mediated tumorigenesis could pave the way for improved treatment strategies and better clinical outcomes for patients with B-cell lymphoma.

High-dose IV ascorbic acid therapy in CCUS patients with TET2 mutations.

This was a phase II trial, evaluating the safety/efficacy of high-dose IV-ascorbic acid in patients with TET2 mutant CCUS. Eight of 10 patients enrolled were eligible for response assessment. At week 20, there were no responses by IWG MDS criteria. NCT03418038.

CODOX-M/IVAC-R versus DA-EPOCH-R in double hit/triple hit lymphoma patients aged 60 years or under.

Intensified chemoimmunotherapy regimens are often used in young patients with double hit and triple hit lymphoma (DHL/THL) despite no survival benefit compared to R-CHOP. Favorable retrospective reports on the application of CODOX-M/IVAC-R are subject to selection bias as only young fit patients can tolerate this treatment. We conducted a retrospective analysis to investigate outcome differences between CODOX-M/IVAC-R and DA-EPOCH-R in DHL/THL patients aged 60 years or younger. 113 patients were identified; CODOX-M/IVAC-R (N=49) and DA-EPOCH-R (N=64). 80% (39/49) achieved complete (CR) after completing CODOX-M/IVAC-R compared to 58% (37/64) with DA-EPOCH-R. The median follow-up was 5.3 years and 3.3 years for the CODOX-M/IVAC-R and DA-EPOCH-R group respectively. CODOX-M/IVAC-R demonstrated superior EFS on univariate (HR=0.54, 95%CI=0.31-0.97) and multivariable analysis adjusted for age, BCL translocation (BCL2 vs BCL6 vs both), IPI score and receipt of ASCT (aHR=0.52, 95%CI=0.29-0.93); however there was no significant influence on OS (aHR=0.92, 95%CI=0.46-1.84). The 1, 2 and 5 years EFS in the CODOX-M/IVAC-R group was 68.3%, 64.1% and 61.5% respectively compared to 52.4%, 48.9% and 39.5% respectively in the DA-EPOCH-R group. Primary refractory disease or relapse occurred in 33% (16/49) of CODOX-M/IVAC-R and 54% (35/64) of DA-EPOCH-R recipients, and produced median OS of 10.3 months and 33.7 months, respectively, indicating poor outcomes in the CODOX-M/IVAC-R subgroup with R/R disease. More patients were able to receive subsequent salvage therapies in the DA-EPOCH-R group. No patients died of regimen toxicity and the rates of CNS relapse and therapy related hematologic neoplasms were similar in both groups.

Sign language delays in deaf 3- to 5-year-olds with hearing parents.

Deaf children of hearing parents (DOH) are at risk for early language delays (ELD) due to environmental and etiological factors, compounding the previously reported higher incidence of ELD in deaf children of deaf parents (DOD) compared to the general population. Archival data from the online database of the Visual Communication and Sign Language Checklist yielded 147 ratings of DOH 3- to 5-year-old children whose parents reported American sign language (ASL) being used in the home at least equally to spoken language. Research goals included (1) examining the incidence of ELD in this cohort, (2) investigating differences in outcomes based on the scaling method used, (3) exploring patterns among the ratings of DOH children identified with ELD, (4) comparing the DOH outcomes to published DOD data, and (5) investigating differences between ratings and individual children. The DOH outcomes suggested an incidence of ELD twice that of the previous DOD sample, with a higher percentage of more severe delays. Even DOH children not identified with ELD demonstrated less well-developed ASL skills than their DOD peers. This emphasizes the need for ongoing monitoring of early ASL skills to allow for early identification of needs and adjustment of interventions to address ASL development.

Comparative Effectiveness of Baricitinib Versus Tocilizumab in Hospitalized Patients With COVID-19: A Retrospective Cohort Study of the National Covid Collaborative.

OBJECTIVES: COVID-19 treatment guidelines recommend baricitinib or tocilizumab for the management of hospitalized patients with COVID-19. We compared the effectiveness of baricitinib vs. tocilizumab on mortality and clinical outcomes among hospitalized patients with COVID-19. DESIGN: Multicenter, retrospective, propensity-weighted cohort study using a target trial emulation approach. SETTING: The National COVID Cohort Collaborative (N3C), which is the largest electronic health records data on COVID-19 in the United States. The setting included 75 hospitals. PATIENTS: Adults who were hospitalized for COVID-19. INTERVENTIONS: Newly initiated on baricitinib or tocilizumab. MEASUREMENTS AND MAIN RESULTS: Our primary outcome was 28-day mortality. We used propensity scores with inverse probability of treatment weights (IPTWs) to control bias and confounding while comparing treatments. Among 10,661 individuals included in the study, 6,229 (58.4%) received baricitinib and 4,432 (41.6%) tocilizumab. Overall, the mean age of the cohort was 60.0 ± 15.1 years, 6429 (60.3%) were male, and 19.2% received invasive mechanical ventilation. After IPTW adjustment, baricitinib use was associated with lower 28-day mortality (odds ratio [OR], 0.91; 95% CI, 0.85-0.98) and hospital (OR, 0.88; 95% CI, 0.82-0.94) mortality compared with tocilizumab. Baricitinib was also associated with shorter hospital length of stay (incident rate ratio, 0.92; 95% CI, 0.90-0.94) and lower rates of hospital-acquired infections (OR, 0.86; 95% CI, 0.75-0.99), although no difference in ICU length of stay was noted between the two groups. CONCLUSIONS: In this large, diverse cohort of U.S. hospitalized adults with COVID-19, baricitinib was associated with significantly lower 28-day mortality, hospital mortality, shorter hospital length of stay, and less hospital-acquired infections compared with tocilizumab.

The power of citizen science to advance fungal conservation.

Fungal conservation is gaining momentum globally, but many challenges remain. To advance further, more data are needed on fungal diversity across space and time. Fundamental information regarding population sizes, trends, and geographic ranges is also critical to accurately assess the extinction risk of individual species. However, obtaining these data is particularly difficult for fungi due to their immense diversity, complex and problematic taxonomy, and cryptic nature. This paper explores how citizen science (CS) projects can be lever-aged to advance fungal conservation efforts. We present several examples of past and ongoing CS-based projects to record and monitor fungal diversity. These include projects that are part of broad collecting schemes, those that provide participants with targeted sampling methods, and those whereby participants collect environmental samples from which fungi can be obtained. We also examine challenges and solutions for how such projects can capture fungal diversity, estimate species absences, broaden participation, improve data curation, and translate resulting data into actionable conservation measures. Finally, we close the paper with a call for professional mycologists to engage with amateurs and local communities, presenting a framework to determine whether a given project would likely benefit from participation by citizen scientists.

The global loss of avian functional and phylogenetic diversity from anthropogenic extinctions.

Humans have been driving a global erosion of species richness for millennia, but the consequences of past extinctions for other dimensions of biodiversity-functional and phylogenetic diversity-are poorly understood. In this work, we show that, since the Late Pleistocene, the extinction of 610 bird species has caused a disproportionate loss of the global avian functional space along with ~3 billion years of unique evolutionary history. For island endemics, proportional losses have been even greater. Projected future extinctions of more than 1000 species over the next two centuries will incur further substantial reductions in functional and phylogenetic diversity. These results highlight the severe consequences of the ongoing biodiversity crisis and the urgent need to identify the ecological functions being lost through extinction.

Heterogeneous genetic architectures of prostate cancer susceptibility in sub-Saharan Africa.

Men of African descent have the highest prostate cancer incidence and mortality rates, yet the genetic basis of prostate cancer in African men has been understudied. We used genomic data from 3,963 cases and 3,509 controls from Ghana, Nigeria, Senegal, South Africa and Uganda to infer ancestry-specific genetic architectures and fine-map disease associations. Fifteen independent associations at 8q24.21, 6q22.1 and 11q13.3 reached genome-wide significance, including four new associations. Intriguingly, multiple lead associations are private alleles, a pattern arising from recent mutations and the out-of-Africa bottleneck. These African-specific alleles contribute to haplotypes with odds ratios above 2.4. We found that the genetic architecture of prostate cancer differs across Africa, with effect size differences contributing more to this heterogeneity than allele frequency differences. Population genetic analyses reveal that African prostate cancer associations are largely governed by neutral evolution. Collectively, our findings emphasize the utility of conducting genetic studies that use diverse populations.

Specific retinal neurons regulate context-dependent defensive responses to visual threat.

While encountering a visual threat, an animal assesses multiple factors to choose an appropriate defensive strategy. For example, when a rodent detects a looming aerial predator, its behavioral response can be influenced by a specific environmental context, such as the availability of a shelter. Indeed, rodents typically escape from a looming stimulus when a shelter is present; otherwise, they typically freeze. Here we report that context-dependent behavioral responses can be initiated at the earliest stage of the visual system by distinct types of retinal ganglion cells (RGCs), the retina's output neurons. Using genetically defined cell ablation in mature mice, we discovered that some RGC types were necessary for either escaping (alpha RGCs) or freezing (intrinsically photosensitive RGCs) in response to a looming stimulus but not for both behaviors; whereas other RGC types were not required for either behavior (direction-selective RGCs preferring vertical motion). Altogether, our results suggest that specific RGC types regulate distinct behavioral responses elicited by the same threatening stimulus depending on contextual signals in the environment. These findings emphasize the unique contribution of early visual pathways to evolutionally conserved behavioral reactions.

Association between frailty and subsequent disability trajectories among older adults: a growth curve longitudinal analysis from the Survey of Health, Ageing and Retirement in Europe (2004-19).

Frailty is associated with adverse health outcomes in ageing populations, yet its long-term effect on the development of disability is not well defined. The study examines to what extent frailty affects disability trajectories over 15 years in older adults aged 50+. Using seven waves of data from the Survey of Health, Ageing and Retirement in Europe (SHARE), the study estimates the effect of baseline frailty on subsequent disability trajectories by multilevel growth curve models. The sample included 94 360 individuals from 28 European countries. Baseline frailty was assessed at baseline, using the sex-specific SHARE-Frailty-Instrument (SHARE-FI), including weight loss, exhaustion, muscle weakness, slowness, and low physical activity. Disability outcomes were the sum score of limitations in activities of daily living (ADL) and Instrumental ADL (IADL). Analyses were stratified by sex. Over 15 years, baseline frailty score was positively associated with disability trajectories in men [ßADL = 0.074, 95% confidence interval (CI) = 0.064; P = .083; ßIADL = 0.094, 95% CI = 0.080; P = 0.107] and women (ßADL = 0.097, 95% CI = 0.089; P = .105; ßIADL = 0.108, 95% CI = 0.097; P = .118). Frail participants showed higher ADL and IADL disability levels, independent of baseline disability, compared with prefrail and robust participants across all age groups. Overall, participants displayed higher levels of IADL disability than ADL disability. Study findings indicate the importance of early frailty assessment using the SHARE-FI in individuals 50 and older as it provides valuable insight into future disability outcomes.

Improvement in the sensitivity of LA-ICP-MS bioimaging by addition of nitrogen to the argon carrier gas.

Elemental bioimaging of low abundant elements via laser ablation-inductively coupled plasma mass spectrometry (LA-ICP-MS) is hampered by a lack of sensitivity. Novel solutions for specific applications have been developed, however there is a need for more universal approaches. Here we investigated the addition of N2 to the ICP carrier gas to increase sensitivity, defined as signal-to-background, for the majority of biologically relevant elements. A gelatine standard that contained 38 elements across the mass range was ablated with increasing amounts of N2 added to the carrier gas post-ablation. The results show that while all elements examined had an increase in signal intensity, some elements did not have a resultant increase in signal-to-background. Sc, V, Mn, Fe, and Se all exhibited a reduction in signal-to-background ratios across all N2 flow rates examined, with the remaining elements experiencing signal-to-background increases from 1.2-7.8x, depending on the N2 flow rate and element. A compromised optimum N2 flow rate was determined for the analysis all elements and used to image endogenous elements in a mouse brain, and antibody-conjugated elements in a quadriceps muscle section. These images confirmed that the addition of N2 to the carrier gas increased the signal-to-background of the analysis, improving image resolution for endogenous elements and low abundant analytes used for immuno-mass spectrometry imaging of biomarkers. These findings offer a promising avenue for advancing the capabilities of LA-ICP-MS in bio-imaging applications.

The Impact of Gardening on Dietary Inflammation: Mixed-Effect Models and Propensity Score Analyses.

Introduction: Gardening has been found to increase vegetable intake and reduce BMI; this suggests that it may improve diets by lowering inflammatory content. The goal of this study goal was to evaluate the effect of gardening on Dietary Inflammatory Index scores. Methods: Longitudinal data were collected annually between 2015 and 2018 from adults in low-income, urban neighborhoods of Cleveland and Columbus, Ohio. The authors measured the association between gardening and Dietary Inflammatory Index in the full data set using multivariable mixed-effect models with a random intercept for participant (Model 1; n=409). To further explore potential causation, the author used propensity score analyses in a subset of the data by building a 1-to-1 matched model (Model 2; n=339). Results: Of 409 adults, 30.3% were gardeners with Dietary Inflammatory Index scores ranging from -6.228 to +6.225. Participating in gardening was associated with lower Dietary Inflammatory Index scores in the mixed-effects model (-0.45; 95% CI= -0.85, -0.04; Model 1) and the 1-to-1 matched model (-0.77; 95% CI= -1.40, -0.14; Model 2). Conclusions: The analyses indicate that gardeners had lower Dietary Inflammatory Index scores than nongardeners, implying lower diet-driven inflammation. These findings highlight the potential for a causal relationship between gardening and Dietary Inflammatory Index, which should be confirmed in future studies. If this relationship is validated, strategies to increase gardening may be worth testing as primary prevention tools for diet-driven chronic disease.

Rational structure-guided design of a blood stage malaria vaccine immunogen presenting a single epitope from PfRH5.

There is an urgent need for improved malaria vaccine immunogens. Invasion of erythrocytes by Plasmodium falciparum is essential for its life cycle, preceding symptoms of disease and parasite transmission. Antibodies which target PfRH5 are highly effective at preventing erythrocyte invasion and the most potent growth-inhibitory antibodies bind a single epitope. Here we use structure-guided approaches to design a small synthetic immunogen, RH5-34EM which recapitulates this epitope. Structural biology and biophysics demonstrate that RH5-34EM is correctly folded and binds neutralising monoclonal antibodies with nanomolar affinity. In immunised rats, RH5-34EM induces PfRH5-targeting antibodies that inhibit parasite growth. While PfRH5-specific antibodies were induced at a lower concentration by RH5-34EM than by PfRH5, RH5-34EM induced antibodies that were a thousand-fold more growth-inhibitory as a factor of PfRH5-specific antibody concentration. Finally, we show that priming with RH5-34EM and boosting with PfRH5 achieves the best balance between antibody quality and quantity and induces the most effective growth-inhibitory response. This rationally designed vaccine immunogen is now available for use as part of future malaria vaccines, alone or in combination with other immunogens.

@TOME 3.0: Interfacing Protein Structure Modeling and Ligand Docking.

Knowledge of protein-ligand complexes is essential for efficient drug design. Virtual docking can bring important information on putative complexes but it is still far from being simultaneously fast and accurate. Receptors are flexible and adapt to the incoming small molecules while docking is highly sensitive to small conformational deviations. Conformation ensemble is providing a mean to simulate protein flexibility. However, modeling multiple protein structures for many targets is seldom connected to ligand screening in an efficient and straightforward manner. @TOME-3 is an updated version of our former pipeline @TOME-2, in which protein structure modeling is now directly interfaced with flexible ligand docking. Sequence-sequence profile comparisons identify suitable PDB templates for structure modeling and ligands from these templates are used to deduce binding sites to be screened. In addition, bound ligand can be used as pharmacophoric restraint during the virtual docking. The latter is performed by PLANTS while the docking poses are analysed through multiple chemoinformatics functions. This unique combination of tools allows rapid and efficient ligand docking on multiple receptor conformations in parallel. @TOME-3 is freely available on the web at https://atome.cbs.cnrs.fr.