The National Academies of Sciences, Engineering, and Medicine

Alzheimer's disease (AD) is a progressive neurological disorder that gradually impairs all cognitive functions. The diagnosis typically requires a combination of cognitive assessments, neuroimaging techniques, and biomarker analysis. In healthy neurons, Tau protein stabilizes microtubules, which are vital for maintaining the structure and proper functioning of nerve cells. However, elevated levels of Tau in cerebrospinal or other body fluids can be related to the progression of Alzheimer's disease. This study introduces an optical technique that employs a dual label‐free and fluorescence operation mode to detect Tau protein in both standard running buffer and cerebrospinal fluid. This innovative method enables label‐free analysis of the bio‐conjugation process on biochips used for resolved fluorescence‐based Tau detection. This work successfully demonstrates Tau protein detection in both matrixes, achieving an outstanding limit of detection of 2.4 pM in cerebrospinal fluid. Moreover, the analysis of the dose‐response curve allows to estimate the dissociation constant (KD = 18 nM) for Tau interactions, yielding values that are in excellent agreement with existing literature using other techniques. These aspects highlight the added value of this technique, providing a valuable tool for investigating Alzheimer's‐related biomarkers, as demonstrated in this study with Tau protein.

Mitochondrial dysfunction has been implicated in a broad range of age‐related pathologies and has been proposed as a causative factor in Alzheimer's disease (AD). Analysis of post‐mortem brains from AD patients showed increased levels of Voltage‐dependent anion‐selective channel 1 (VDAC1) in the dystrophic neurites surrounding amyloid‐β (Aβ) deposits, suggesting a direct association between VDAC1 and mitochondrial toxicity. VDAC1 is the most abundant pore‐forming protein of the outer mitochondrial membrane and, as a channel, it plays a pivotal role in regulating cellular bioenergetics, allowing the continuous exchange of ions and metabolites (ATP/ADP, Krebs cycle intermediates) between cytosol and mitochondria. In light of this evidence, we looked into the effects of Aβ oligomers on VDAC1 functions through electrophysiological and respirometric techniques. Our findings indicate that Aβ oligomers significantly modify the conductance, voltage dependency, and kinetic features of VDAC1, as well as its slight selectivity for anions, leading to a marked preference for cations. Given that VDAC1 is mainly involved in the trafficking of charged molecules in and out of mitochondria, a general reduction of cell viability and mitochondrial respiration was detected in neuroblastoma cells and primary cortical neurons exposed to Aβ oligomers. Interestingly, the toxic effect mediated by Aβ oligomers was counteracted by the use of NHK1, a small synthetic, cell‐penetrating peptide that binds and modulates VDAC1. On these results, VDAC1 emerges as a crucial molecule in mitochondrial dysfunction in AD and as a promising pharmacological target for the development of new therapeutic avenues for this devastating neurodegenerative disease still without a cure.

Achieving high-Q resonances in photonics is crucial for devices such as sensors, filters, and emitters of electromagnetic radiation. One effective strategy for achieving such resonances involves the bound state in the continuum effect (BIC). In this paper, we demonstrate a comprehensive study of the BIC in complementary planar Babinet metamaterials in a microwave regime. A symmetry-protected BIC has been induced in a planar metamaterial due to rotation of an incident wave for small angles from normal incidence, thus releasing the high Q-factor (9.245 · 10³ in theory and 1.606 · 10³ in experiment) trapped mode at 6.625 GHz with localized components of electric dipoles and electric octopoles radiating exclusively in the plane of the metamaterial, which can be promising for planar lasers.

The rapid snowmelt that typically occurs after snow accumulates at low temperatures and precipitation develops at higher temperatures is a defining characteristic of rain-on-snow (ROS). During ROS events, the swift release of melted snow water can result in flash floods and a substantial surge in runoff, which in turn can lead to the overflow or elevation of rivers and consequently severe inundation and flooding. This study reveals the climatology of ROS events and examines the connections between ROS events and surface runoff quantities, aiming to contribute to flood projections and snow research for Türkiye, specifically focusing on the regions in the north and east of the country that receive substantial snowfall and have previously encountered serious flooding. The findings indicate a decline in ROS events in the Eastern and Southeastern Anatolia regions, particularly throughout the past three decades, while there has been an increase in the Central and Western Black Sea regions. The decline in the quantity of ROS (rainfall over snow) in the Southeastern Anatolia region, which serves as the primary water source for Türkiye, is a favorable outcome as it leads to a decrease in the risk of floods, a longer duration of snow cover, and the feeding of water resources. Given the rise in ROS events in the Central and Western Black Sea regions, it is imperative to formulate novel urbanization strategies to mitigate potential flood risks and minimize associated damages that consider the region’s topography, urbanization, and precipitation patterns. In addition, the results reveal a startling new trend: ROS events are shifting both spatially and temporally.

Blast-induced traumatic ocular injury (bTOI) is a major cause of vision loss in military personnel involved in recent combat operations. However, its underlying mechanisms remain poorly understood, hindering the development of effective treatments. This study investigated the temporal expression patterns of key inflammatory markers in the retina after blast exposure using a ferret model. Ferrets (n = 40) were subjected to two tightly coupled blasts (20 psi) using an advanced blast simulator. Retinal tissues were collected at 4 h, 24 h, or 28 days post-blast. Differential mRNA expression of Toll-like receptors (TLRs: 1–9), cytokines (IL: 1β, 6, and 10), and cyclooxygenase enzymes (COX: 1 and 2) was assessed using quantitative real-time polymerase chain reaction after blast exposure and compared with sham controls. Our results revealed a rapid and sustained upregulation of multiple TLRs (1, 2, 4, 5, 7, and 8) in the retina following blast exposure, indicating a robust inflammatory response. This was accompanied by a significant increase in pro- and anti-inflammatory cytokines (IL-1β, IL-6 IL-10, and COX2) at 4 h post-blast, suggesting their involvement in the acute pathogenesis of bTOI. Our findings emphasize the critical role of early innate immune responses and the potential for chronic inflammation in bTOI, highlighting the importance of timely therapeutic interventions. Targeting these inflammatory pathways may offer therapeutic avenues for mitigating retinal damage and improving ocular function.

This study investigates the benthic invertebrate community in the Venice Lagoon using environmental DNA (eDNA) metabarcoding based on superficial water samples. Our objective is to understand if, in a shallow lagoon system, sampling at the surface can provide information on benthic biodiversity, allowing us to establish a baseline for future assessments and to monitor the community's seasonal and spatial variation. eDNA was collected from surface water samples at two sites during nine sampling campaigns from November 2018 to October 2019, and metabarcoding was performed using an available primer pair targeting 16S mitochondrial rDNA of echinoderms, never tested empirically before. Analyses revealed 80 taxonomic units, five not assigned at the species level, belonging not only to the phylum Echinodermata but predominantly assigned to Mollusca, with the majority of the identified species (60 out of 75) representing benthic invertebrates. Several species known to be invasive were detected, some previously recorded in the Venice Lagoon environment and others detected for the first time. Significant spatial differences in species composition were observed between the northern and the southern site of the lagoon. Temporal variation of the benthic community was also observed, mainly due to the distinctiveness of autumn samples, highlighting the dynamic nature of the Venice Lagoon ecosystem. Our results confirm the utility of eDNA for ongoing biodiversity monitoring and management and show that eDNA isolated from superficial water can provide information on the benthic invertebrate community, which might be particularly useful for biodiversity assessment in lagoons, ports, and areas characterized by limited or interdicted access.

Background Cachexia is a severe form of muscle wasting disorder particularly observed in patients with advanced cancer. The absence of effective strategies to ameliorate cachexia indicates our poor understanding of the mechanisms of cachexia. By employing system‐wide approaches, we investigated molecular mechanisms underlying cancer secreted pro‐inflammatory cytokine‐induced cachexia (CIC). Methods As cellular model systems, we employed mouse satellite stem cell‐derived primary muscle cells, mouse C2C12 myoblast progenitor cell‐derived myotubes, and neonatal rat cardiomyocytes. We induced CIC by incubating striated muscle cells with pro‐inflammatory cytokines TNF‐α and IFN‐γ. To understand the physiological effects of CIC, we probed the contractile properties of muscle cells following electrical stimulation and measured intracellular calcium transients. Effects of CIC on sarcomere organization were monitored by confocal microscopy. Large‐scale quantitative proteomics and RNA sequencing assays enabled us to examine molecular mechanisms underlying CIC. Using chromatin immunoprecipitation experiments, chromatin signalling and modulation of epigenetic marks on muscle‐specific genes were investigated. Results Here, we observed a drastic loss of striated muscle cell contraction in CIC, primarily, due to acutely disorganized sarcomere structures and impeded calcium handling process. In calcium transients, the extent of calcium (Ca ²⁺ ) release, as indicated by the calcium amplitude during the excitation–contraction coupling (ECC) process, was reduced (19.6 ± 2.35% in control to 8.6 ± 1.52% in CIC, p = 4.8 * 10 ⁻¹¹ ). Kinetics of calcium transients, i.e., the Ca ²⁺ release rate (26 ± 0.5 ms in control to 29 ± 5.1 ms in CIC, median p = 0.014), and calcium re‐uptake rate (137 ± 13 ms in control to 185 ± 24 ms in CIC, p = 0.032) were both prolonged. Proteomic analysis showed altered proteostasis in CIC, particularly related to sarcomere and sarcoplasmic reticulum (SR). Transcriptomic analysis unravelled upstream deregulation of global transcriptional events for sarcomeric and SR genes. Mechanistically, chromatin loading of transcriptionally active RNA Polymerase II on muscle‐specific genes, including Myh1 and Atp2a1 , was impeded. This was due to diminished transcriptionally active epigenetic marks H3K4 trimethylation on Myh1 and Atp2a1 , resulted in lower transcriptional activity of these muscle‐specific genes in CIC and ultimately reduced MyHC‐IId molecular motor protein and SERCA1 protein levels. Conclusions Our top‐down approach elucidated that the altered transcriptional mechanism and proteomic state perturbed functionally related machinery responsible for calcium handling and sarcomere organization in CIC. Knowledge of the underlying cause of muscle mass loss and compromised muscle function is key for developing therapeutic solutions to ameliorate cachectic conditions.

This study aims to advance the field of additive manufacturing of NiTi shape memory alloys by providing a comprehensive functional analysis of a complex NiTi structure fabricated using laser powder bed fusion. While most of the literature on additive manufacturing of NiTi has been focused on the pseudoelastic effect, this research explores both pseudoelastic and shape memory effect. The selected geometry is origami inspired with wall thickness of 0.45 mm. Samples were fabricated through an AM400 of Renishaw starting with a NiTi powder with 50.8 at. % of Ni and followed a double-stage heat treatment, at 950 °C for 5.5 h and 450 °C for 15 min. The heat-treated cells were characterized to assess at first the phase transformation temperatures through thermal analysis and then both the pseudoelastic and the shape memory effects (analyzing both free and under load shape recovery), with maximum load ranging from 600 to 1500 N for pseudoelasticity, from 600 to 1000 N for free shape recovery and from 600 to 1200 N for actuation tests. Actuation tests were conducted by heating the loaded samples from room temperature to 85 °C and from Mf to 85 °C, thereby examining the material’s actuation response with the cold phase corresponding to the R-phase and martensite phase, respectively. Results were promising for all the tests performed. The pseudoelastic response highlights a loss factor of 0.0263 under the load of 1200 N. Moreover, maximum strokes of approximately 3 mm and 3.2 mm were observed in free shape recovery and actuation tests, respectively. Finally, it was found that the proposed origami-inspired structure, featuring two distinct shaped zones with varying rigidity, offers the advantage of preventing abrupt collapse and fracture during failure tests.

Background In external x‐ray radiation therapy, the administered dose distribution can deviate from the planned dose due to alterations in patient positioning, changes in intra‐fraction anatomy, and the limited precision of the beam delivery system in spatial terms. Adaptive radiation therapy (ART) can potentially improve dose delivery accuracy by re‐optimizing the treatment plan before each fraction, maximizing the dose to the target volume while minimizing exposure to surrounding radiosensitive organs. However, to effectively implement ART, the stages of the radiation therapy pipeline, including image acquisition, segmentation, physician directive generation, and treatment plan generation, must be optimized for maximum speed and accuracy to ensure feasibility prior to each treatment fraction. In this work, we focus on image segmentation. By reducing the segmentation computation time, one can reproduce the planning process for each session, enabling routine customization for individual patients, achieving safe dose escalation, better cancer control, and reduced risk of severe radiotoxicity. Purpose The aim of this study is to develop a fast point‐cloud‐based segmentation model with novel in‐silico‐aided data augmentation and demonstrate it on pelvic computed tomography (CT) patient data used in prostate cancer (PCa) treatment. This model can be implemented during ART because it requires only a few seconds to perform organ segmentation. Methods In this study, a dataset of pelvic CT images was obtained from Order of St. Francis (OSF) Healthcare Hospital (Peoria, IL, USA), comprising 38 images in total. These were divided into 25 for training, seven for validation, and six for testing the developed model. A novel point‐cloud‐based model was used to reduce the prostate segmentation time, cross‐validation was implemented to ensure the robustness of the model. The developed point‐cloud‐based network is a novel deep‐learning (DL) model that adds a loss function that combines region‐based with a new boundary loss function. The region‐based loss enables the identification of large volumes while the boundary loss, whose relative weight increases with the epochs, increases the network training ability of uneven surfaces, like the interface between the prostate bladder and rectum, which are challenging to resolve. We introduced a new data‐augmentation approach to expand the training set. This fully automated method generates synthetic 3‐D CT images by creating relevant organs in the extended cardiac‐torso (XCAT) computational phantom. The Dice similarity coefficient was used as an assessment metric and compared to state‐of‐the‐art segmentation models. The doses to the prostate and organs at risk (i.e., bladder and rectum) were also calculated for both our automated segmentation and manual expert segmentation to evaluate the practical feasibility of the point‐cloud‐based approach. Results Our model achieves the segmentation results (Dice coefficient) of 0.92 ±$\pm$ 0.04, 0.89 ±$\pm$ 0.05, and 0.84 ±$\pm$ 0.07 for bladder, prostate, and rectum, respectively. The accuracy of the prostate segmentation outperforms the voxel‐based segmentation models reported in the literature. More importantly, the average segmentation time of the point‐cloud model for a single 3‐D CT data set was 1.8 times faster than 2‐D fully convolutional network (FCN), and 11 times faster than 3‐D U‐Net. The improved loss function and in‐silico‐based training data augmentation approach effectively enabled the model to learn features of outlier data sets, thereby improving the model's robustness across diverse images. The developed fast and robust point‐cloud segmentation model can potentially be applied to ART to improve the treatment workflow. Conclusions Our proposed method demonstrates favorable performance in the segmentation of X‐ray CT data. Results confirmed that the point‐cloud‐model is faster than voxel‐based segmentation algorithms while achieving comparable or better segmentation results. The segmentation approach can be integrated into ART workflow, ultimately reducing the workload of clinicians and radiologists.

Siderophore production, along with heme scavenging by hemophores, is one of the main mechanisms exploited by bacteria to achieve an adequate iron supply. Staphylococcus aureus produces two main siderophores, staphyloferrin A (SA) and staphyloferrin B (SB), with the latter produced only by the most invasive, coagulase‐positive S. aureus strains. Along the seven steps of the SB biosynthetic pathway, N‐(2‐amino‐2‐carboxyethyl)‐l‐glutamate synthase (SbnA) catalyzes the crucial formation of the intermediate N‐(2‐amino‐2‐carboxyethyl)‐l‐glutamate from O‐phospho‐L‐serine and glutamate. Our functional characterization of the enzyme highlighted that citrate inhibits SbnA with an inhibitory constant (Ki) in the order of magnitude of the physiological concentration of the metabolite. We searched for inhibitors of SbnA within citrate analogues and identified 2‐phenylmaleic acid (2‐PhMA) as the best hit, with a Ki of 16 ± 2 μm and a mechanism of inhibition that is competitive with O‐phospho‐L‐serine for active site binding. The methyl ester of 2‐PhMA at a 2 mm concentration was effective in inhibiting siderophore biosynthesis in S. aureus. These results pave the way for the discovery of promising inhibitors of iron acquisition that might find application as innovative antimicrobials.

Allosteric modulation of cannabinoid receptor type 1 (CB1R) offers a promising alternative to conventional therapeutic approaches using orthosteric ligands (OLs). Currently, CB1R allosteric modulators (AMs) are characterized based on their ability to modulate binding or functional response of OLs, preventing isolation of individual contributions by allosteric and orthosteric ligands. Herein, we develop the first allosteric fluoroprobe and attendant FRET‐based assay allowing for the direct profiling of CB1R AMs without coincubation with an OL. Our allosteric tracer enables differentiation of allosteric and orthosteric ligands as well as their pharmacological profiling at CB1R. The utility of this work is highlighted by addressing ambiguities surrounding the binding of cannabidiol (CBD). CBD was found to interact with both allosteric and orthosteric sites of CB1R with comparable affinity (pKi=5.34 and 5.67, respectively).

Climate change is predicted to drive geographical range shifts that will result in changes in species diversity and functional composition and have potential repercussions for ecosystem functioning. However, the effect of these changes on species composition and functional diversity (FD) remains unclear, especially for mammals, specifically bats. We used species distribution models and a comprehensive ecological and morphometrical trait database to estimate how projected future climate and land‐use changes could influence the distribution, composition, and FD of the European bat community. Future bat assemblages were predicted to undergo substantial shifts in geographic range and trait structure. Range suitability decreased substantially in southern Europe and increased in northern latitudes. Our findings highlight the potential for climate change to drive shifts in bat FD, which has implications for ecosystem function and resilience at a continental scale. It is important to incorporate FD in conservation strategies. These efforts should target species with key functional traits predicted to be lost and areas expected to experience losses in FD. Conservation strategies should include habitat and roost protection, enhancing landscape connectivity, and international monitoring to preserve bat populations and their ecosystem services.

The p75NTR receptor, a member of the tumor necrosis factor (TNF) receptor superfamily, can participate in signaling pathways either by forming heteromeric complexes with other receptors, such as the Trk family (tropomyosin receptor kinases), or by functioning independently. p75NTR was investigated prevalently in the brain and retina of mammals, whereas almost nothing is known about its conservation among species. Here, we reconstructed the phylogenetic arb of p75NTR and described for the first time the p75NTR expression in the brain of the basal vertebrate Chondrichthyan Scyliorhinus canicula ( S. canicula ), uncovering the existing parallelism between ancient vertebrates and mammals. p75NTR functional conservation among vertebrates was further investigated by cloning the S. canicula nerve growth factor (NGF) and performing the canonical posterior commissure (PC)‐12 differentiation assay, which results in standard neurite‐like production. We then investigated the S. canicula p75NTR, which proves to be capable of complementing a specific clone of PC‐12 lacking p75NTR (PC‐12 p75NTR ⁻ / ⁻ ). All together, our results highlighted the expression and functional conservation of p75NTR among vertebrates during the evolution.

In the diverse landscape of African hominids, the obligate relationship between the host and its microbiome narrates signals of adaptation and co-evolution. Sequencing 546 African hominid metagenomes, including those from indigenous Hadza and wild chimpanzees, identified similar bacterial richness and diversity surpassing those of westernized populations. While hominids share core bacterial communities, they also harbor distinct, population-specific bacterial taxa tailored to specific diets, ecology and lifestyles, differentiating non-indigenous and indigenous humans and chimpanzees. Even amongst shared bacterial communities, several core bacteria have co-diversified to fulfil unique dietary degradation functions within their host populations. These co-evolutionary trends extend to non-bacterial elements, such as mitochondrial DNA, antimicrobial resistance, and parasites. Our findings indicate that microbiome-host co-adaptations have led to both taxonomic and within taxa functional displacements to meet host physiological demands. The microbiome, in turn, transcends its taxonomic interchangeable role, reflecting the lifestyle, ecology and dietary history of its host.

Background Despite the growing popularity of osteopathy in France, little is known about how French osteopaths conceptualise key aspects of their practice, including skills, knowledge, and decision-making. This study aimed to adapt and validate the Osteopaths' Therapeutic Approaches Questionnaire (Osteo-TAQ) for use in a French osteopathic population (Osteo-TAQfr) and to examine the professional profile and core elements of clinical practice among French osteopaths. The first objective was to establish the psychometric properties of the Osteo-TAQfr within a French osteopathic population. The second aim was to explore French osteopaths’ conceptions of practice and their approach to patient care, thereby contributing to a broader understanding of the profession in France and its relevance within the discourse on allied health professions (AHPs). Methods A cross-sectional study was conducted to (1) adapt and validate the French version of the Osteopaths' Therapeutic Approaches Questionnaire (Osteo-TAQfr) and (2) explore osteopaths’ conceptions of practice in France. The translation and cultural adaptation process was informed by cognitive interviews to ensure linguistic and contextual appropriateness. Exploratory Factor Analysis (EFA) was performed to assess the factor structure in the French osteopathic context and Confirmatory Factor Analysis (CFA) was used to test the validity of previously established constructs—Professional Artistry (PA) and Technical Rationality (TR). Internal consistency was evaluated using McDonald’s omega (ω). Results The survey yielded 1,703 complete responses. Analysis supported a two-factor model with PA andTR subscales, both showing strong reliability estimations (PA ω = 0.882; TR ω = 0.873). Minor theory-informed adjustments improved model fit. A moderate negative correlation was observed between the PA and TR subscales (r=-0.407). Respondents with additional health professions qualifications scored lower on the PA subscale and higher on the TR subscale. Conclusions The Osteo-TAQfr is an original tool that assesses conceptions of osteopathic practice in France. Findings reveal a predominance of TR among French osteopaths, characterised by biomedical, technique-driven approaches. These results have significant implications for aligning osteopathic education and practice with contemporary AHP paradigms, including patient-centred care and interdisciplinary collaboration. Further research should explore the transferability of the Osteo-TAQ across other healthcare systems and its potential impact on clinical outcomes and professional development.

Smart fabrics with health protection, motion monitoring, and perception capabilities effectively managed and optimized human health, significantly promoting the development of smart health. However, it remains challenging to achieve the multifunctional and mechanical robustness required for use in multiple scenarios without destroying the characteristics of the softness and air permeability. Here, a cross‐scale regulation strategy is presented based on the chemical coupling‐physical twisting to develop a multiscale twisted core‐shell structure yarn. Benefiting from the strong interfacial interactions and the coaxial twisted wrapping structure, the multi‐component functional particles are highly stably integrated into the yarn while achieving ultra‐high strength (≈0.662 GPa). The resulting fabric exhibits good impact resistance (attenuate > 40% of impact force), superior air permeability (387.37 mm s⁻¹), excellent eletromagnetic interference (EMI) shielding (36.1 dB), IR thermal camouflage, high triboelectric output (Voc ≈39.1 V), and the ability to sensitively perceive environment safety and monitor human health in real‐time. This study effectively addresses the long‐lasting challenge of balancing functionality and comfort and offers a new perspective for developing next‐generation advanced wearable multifunctional protective smart fabrics.

A fast and weakly stable method for computing the zeros of a particular class of hypergeometric polynomials is presented. The studied hypergeometric polynomials satisfy a higher order differential equation and generalize Laguerre polynomials. The theoretical study of the asymptotic distribution of the spectrum of these polynomials is an active research topic. In this article we do not contribute to the theory, but provide a practical method to contribute to further and better understanding of the asymptotic behavior. The polynomials under consideration fit into the class of Sobolev orthogonal polynomials, satisfying a four--term recurrence relation. This allows computing the roots via a generalized eigenvalue problem. After condition enhancing similarity transformations, the problem is transformed into the computation of the eigenvalues of a comrade matrix, which is a symmetric tridiagonal modified by a rank--one matrix. The eigenvalues are then retrieved by relying on an existing structured rank based fast algorithm. Numerical examples are reported studying the accuracy, stability and conforming the efficiency for various parameter settings of the proposed approach. AMS Classification: 33C20, 65F15, 65F35