A multivariate statistical approach to wrinkling detection in composites.

Non-destructive inspection using ultrasound in materials such as carbon-fibre reinforced polymers (CFRP) is challenging as the ultrasonic wave will scatter from each ply in the structure of the component. This may be improved by using image processing algorithms such as the total focusing method (TFM), however the high level of backscattering within the sample is very likely to obscure a signal arising from a flaw. Detection of wrinkling, or out-of-plane fibre waviness, is especially difficult to automate as no additional scattering is produced (as might be the case with delaminations). Instead, wrinkling changes how a signal is scattered due to the physical displacement of ply layers from their expected location. In this paper, we propose a method of detecting wrinkling by examining the regional variations in image intensity, which are expected to be highly correlated between similar ply layers in the structure. By characterising the 2-dimensional spatial autocorrelation of an area surrounding a given location in the image of pristine components, the distribution of acceptable values is estimated. Wrinkling is observed to correspond with a significant deviation from this distribution, which is readily detected. A comparison is made with an alternative image processing approach identified from the literature, finding that the proposed method has equivalent performance for large wrinkling amplitudes, and better performance for low wrinkling amplitudes.

Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC.

The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play in head and neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find that EphB4 knockdown in cancer cells enhances metastasis in preclinical HNSCC models by augmenting immunosuppressive cells like T regulatory cells (Tregs) within the tumor microenvironment. EphB4 inhibition in cancer cells also amplifies their ability to metastasize through increased expression of genes associated with epithelial mesenchymal transition and hallmark pathways of metastasis. In contrast, vascular ephrinB2 knockout coupled with radiation therapy (RT) enhances anti-tumor immunity, reduces Treg accumulation into the tumor, and decreases metastasis. Notably, targeting the EphB4-ephrinB2 signaling axis with the engineered EphB4 ligands EFNB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggest that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis.

Self-Reporting Therapeutic Protein Nanoparticles.

We present a modular strategy to synthesize nanoparticle sensors equipped with dithiomaleimide-based, fluorescent molecular reporters capable of discerning minute changes in interparticle chemical environments based on fluorescence lifetime analysis. Three types of nanoparticles were synthesized with the aid of tailor-made molecular reporters, and it was found that protein nanoparticles exhibited greater sensitivity to changes in the core environment than polymer nanogels and block copolymer micelles. Encapsulation of the hydrophobic small-molecule drug paclitaxel (PTX) in self-reporting protein nanoparticles induced characteristic changes in fluorescence lifetime profiles, detected via time-resolved fluorescence spectroscopy. Depending on the mode of drug encapsulation, self-reporting protein nanoparticles revealed pronounced differences in their fluorescence lifetime signatures, which correlated with burst- vs diffusion-controlled release profiles observed in previous reports. Self-reporting nanoparticles, such as the ones developed here, will be critical for unraveling nanoparticle stability and nanoparticle-drug interactions, informing the future development of rationally engineered nanoparticle-based drug carriers.

Evaluation of the potential food allergy risks of human lactoferrin expressed in Komagataella phaffii.

Introduction: Prior to the introduction of novel food ingredients into the food supply, safety risk assessments are required, and numerous prediction models have been developed and validated to evaluate safety. Methods: The allergenic risk potential of Helaina recombinant human lactoferrin (rhLF, Effera™), produced in Komagataella phaffii (K. phaffii) was assessed by literature search, bioinformatics sequence comparisons to known allergens, glycan allergenicity assessment, and a simulated pepsin digestion model. Results: The literature search identified no allergenic risk for Helaina rhLF, K. phaffii, or its glycans. Bioinformatics search strategies showed no significant risk for cross-reactivity or allergenicity between rhLF or the 36 residual host proteins and known human allergens. Helaina rhLF was also rapidly digested in simulated gastric fluid and its digestibility profile was comparable to human milk lactoferrin (hmLF), further demonstrating a low allergenic risk and similarity to the hmLF protein. Conclusion: Collectively, these results demonstrate a low allergenic risk potential of Helaina rhLF and do not indicate the need for further clinical testing or serum IgE binding to evaluate Helaina rhLF for risk of food allergy prior to introduction into the food supply.

Smartphone Pupillometry for Detection of Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVES: Vasospasm is a complication of aneurysmal subarachnoid hemorrhage (aSAH) that can change the trajectory of recovery and is associated with morbidity and mortality. Earlier detection of vasospasm could improve patient outcomes. Our objective is to evaluate the accuracy of smartphone-based quantitative pupillometry in the detection of radiographic vasospasm and delayed cerebral ischemia (DCI) after aSAH. MATERIALS AND METHODS: We prospectively collected pupillary light reflex (PLR) parameters from patients with aSAH admitted to a neurocritical care unit at a single hospital twice daily using quantitative smartphone pupillometry recordings. PLR parameters included: Maximum pupil diameter, minimum pupil diameter, percent change in pupil diameter, latency in beginning of pupil constriction to light, mean constriction velocity, maximum constriction velocity, and mean dilation velocity. Two-tailed t-tests for independent samples were performed to determine changes in average concurrent PLR parameter values between the following comparisons: (1) patients with and without radiographic vasospasm (defined by angiography with the need for endovascular intervention) and (2) patients with and without DCI. RESULTS: 49 subjects with aSAH underwent 323 total PLR recordings. For PLR recordings taken with (n=35) and without (n=241) radiographic vasospasm, significant differences were observed in MIN (35.0 ± 7.5 pixels with vasospasm versus 31.6 ± 6.2 pixels without; p=0.002). For PLR recordings taken with (n=43) and without (n=241) DCI, significant differences were observed in MAX (48.9 ± 14.3 pixels with DCI versus 42.5 ± 9.2 pixels without; p<0.001). CONCLUSIONS: Quantitative smartphone pupillometry has the potential to be used to detect radiographic vasospasm and DCI after aSAH.

Chemical modification of hyaluronan oligosaccharides differentially modulates hyaluronan-hyaladherin interactions.

The glycosaminoglycan hyaluronan (HA) is a ubiquitous, non-sulfated polysaccharide with diverse biological roles mediated through its interactions with HA-binding proteins (HABPs). Most HABPs belong to the Link module superfamily, including the major HA receptor, CD44, and secreted protein TSG-6, which catalyzes the covalent transfer of Heavy Chains (HC) from inter-α-inhibitor (IαI) onto HA. The structures of the HA-binding domains (HABD) of CD44 (HABD_CD44) and TSG-6 (Link_TSG6) have been determined and their interactions with HA extensively characterized. The mechanisms of binding are different, with Link_TSG6 interacting with HA primarily via ionic and CH-π interactions, whereas HABD_CD44 binds solely via hydrogen bonds and van der Waals forces. Here we exploit these differences to generate HA oligosaccharides, chemically modified at their reducing ends, that bind specifically and differentially to these target HABPs. Hexasaccharides (HA6AN) modified with 2- or 3-aminobenzoic acid or 2-amino-4-methoxybenzoic acid (HA6-2AA, HA6-3AA, HA6-2A4MBA, respectively) had increased affinities for Link_TSG6 compared to unmodified HA6AN. These modifications did not increase the affinity for CD44_HABD. A model of HA6-2AA (derived from the solution dynamic 3D structure of HA4-2AA) was docked into the Link_TSG6 structure, providing evidence that the 2AA-carboxyl forms a salt bridge with Arginine-81. These modeling results informed a 2nd series of chemical modifications for HA oligosaccharides, which again showed differential binding to the two proteins. Several modifications to HA4 and HA6 were found to convert the oligosaccharide into substrates for HC-transfer, whereas unmodified HA4 and HA6 are not. This study has generated valuable research tools to further understand HA biology.

Heterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice.

Genetic variants in TRIO are associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD) and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal development and connectivity. It remains unclear how discrete TRIO variants differentially impact these neurodevelopmental events. Here, we investigate how heterozygosity for NDD-associated Trio variants - +/K1431M (ASD), +/K1918X (SCZ), and +/M2145T (bipolar disorder, BPD) - impact mouse behavior, brain development, and synapse structure and function. Heterozygosity for different Trio variants impacts motor, social, and cognitive behaviors in distinct ways that align with clinical phenotypes in humans. Trio variants differentially impact head and brain size with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although neuronal structure was only modestly altered in the Trio variant heterozygotes, we observe significant changes in synaptic function and plasticity. We also identified distinct changes in glutamate synaptic release in +/K1431M and +/M2145T cortico-cortical synapses. The TRIO K1431M GEF1 domain has impaired ability to promote GTP exchange on Rac1, but +/K1431M mice exhibit increased Rac1 activity, associated with increased levels of the Rac1 GEF Tiam1. Acute Rac1 inhibition with NSC23766 rescued glutamate release deficits in +/K1431M variant cortex. Our work reveals that discrete NDD-associated Trio variants yield overlapping but distinct phenotypes in mice, demonstrates an essential role for Trio in presynaptic glutamate release, and underscores the importance of studying the impact of variant heterozygosity in vivo.

Baseline dual energy computed tomography urate volume predicts fulfillment of gout remission after two years of urate-lowering therapy.

OBJECTIVE: This study aimed to identify variables that predict gout remission in people with erosive gout receiving urate-lowering therapy. METHODS: We analysed data from a 2-year, double-blind randomized-controlled trial of people with erosive gout, randomized to a serum urate target of <0.20mmol/l or <0.30mmol/l using oral urate-lowering therapies. All participants had dual energy CT (DECT) scans of the feet and ankles at baseline. The proportion of participants achieving gout remission according to the 2016 preliminary gout remission criteria and simplified gout remission criteria (without the patient reported outcomes) was analyzed. Logistic regression models were used to evaluate predictors of gout remission in Year 2. RESULTS: The preliminary gout remission criteria were fulfilled in 11/97 (11%) participants at Year 1 and 21/92 (23%) participants at Year 2. The simplified criteria were fulfilled in 26/97 (27%) participants in Year 1 and 40/92 (44%) participants in Year 2. In multivariable regression models, baseline DECT monosodium urate crystal volume was the only significant independent predictor of gout remission at Year 2, using either criteria. Each one cm3 increase in the baseline DECT monosodium urate crystal volume decreased the odds of fulfilling the 2016 preliminary gout remission criteria (0.65 [95% CI 0.46-0.93], p=0.02), and the simplified gout remission criteria (0.57 [95% CI 0.41-0.78], p<0.001). CONCLUSIONS: In people with erosive gout on urate-lowering therapy, higher baseline DECT monosodium urate crystal volume is associated with lower odds of gout remission after two years of treatment, defined by either the preliminary gout remission criteria or simplified gout remission criteria.

Data Policy Finder: an easily integratable tool connecting data librarians with researchers to navigate publication requirements.

The Data Policy Finder is a searchable database containing librarian-curated information, links, direct quotes from relevant policy sections, and notes to help the researcher search, verify, and plan for their publication data requirements. The Memorial Sloan Kettering Cancer Center Library launched this new resource to help researchers navigate the ever-growing, and widely varying body of publisher policies regarding data, code, and other supplemental materials. The project team designed this resource to encourage growth and collaboration with other librarians and information professionals facing similar challenges supporting their research communities. This resource creates another access point for researchers to connect with data management services and, as an open-source tool, it can be integrated into the workflows and support services of other libraries.

Energetic silicones: synthesis and characterization of pentaoxadiazole-PDMS copolymers.

Standing at the forefront of energetics research is the exploration of energetic binders. To avoid the traditionally used sensitive explosophores, we present the first reported energetic silicone polymers synthesized from a penta-oxadiazole monomer. These polymers exhibit properties that lie between, or exceed, the thermal properties of inert and commonly used energetic binders.

Interhospital variability in hospital admissions for patients with low-risk syncope presenting to the emergency department.

Background: Guidelines and risk scores have sought to standardize the management of syncope in the emergency department (ED), but variation in practice remains. Objective: The purpose of this study was to explore factors associated with admission for patients presenting to the ED with low-risk syncope. Methods: Our study population included adult patients in the Nationwide Emergency Department Sample between 2006 and 2019 who presented to an ED with a primary diagnosis of syncope. Multivariable hierarchical logistic regression analyses determined the association of patient or hospital factors with admission. Reference effect measures methodology assessed the relative contributions of patient, hospital, and unmeasured hospital factors. Results: Of the 3,206,739 qualifying encounters during the study period, 804,398 (25.1%) met low-risk criteria. Of these patients, 20,260 were admitted to the hospital (2.5%). Factors associated with increased odds of admission included increasing age and weekend presentation to the hospital, while female sex, lack of medical insurance, hospital region, teaching status, and higher ED volume decile were associated with lower odds of admission. Reference effect measures methodology demonstrated that unmeasured site variability contributed the widest range of odds for admission (odds ratio [OR] 5th percentile vs 95th percentile 0.23-4.38) compared with the composite patient (OR 0.33-3.68) or hospital (OR 0.65-1.30) factors. Conclusion: Admission patterns for low-risk syncope varies widely across institutions. Unmeasured site variation contributes significantly to the variability in admission rates, suggesting which hospital a patient presents to plays a disproportionate role in admission decisions. Further guidance to reduce practice variation in syncope care in the ED is needed.

Psychiatric Manifestations of Neurological Diseases: A Narrative Review.

Neurological diseases often manifest with psychiatric symptoms, profoundly impacting patients' well-being and treatment outcomes. This comprehensive review examines the psychiatric manifestations associated with Alzheimer's disease, frontotemporal dementia (FTD), Parkinson's disease, multiple sclerosis (MS), stroke, epilepsy, Huntington's disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and multiple system atrophy (MSA). Key psychiatric symptoms include agitation, depression, anxiety, apathy, hallucinations, impulsivity, and aggression across these diseases. In addition, ethical considerations in treating these symptoms are paramount, particularly regarding genetic testing implications, end-of-life discussions, informed consent, and equitable access to innovative treatments. Effective management necessitates interdisciplinary collaboration, personalized interventions, and a focus on patient autonomy. Understanding the psychiatric burden of neurological diseases is crucial for enhancing patients' quality of life. Further research is needed to elucidate underlying mechanisms and develop targeted interventions. This review underscores the importance of comprehensive assessment and ethical treatment practices to address psychiatric manifestations effectively.

Pharmacokinetic Bioequivalence between Generic and Originator Orally Inhaled Drug Products: Validity of Administration of Doses above the Approved Single Maximum Dose.

Pharmacokinetic bioequivalence of orally inhaled drug products is a critical component of the US FDA's "weight of evidence" approach, and it can serve as the sole indicator of safety and effectiveness of follow-on inhalation products approved in Europe and some other geographic areas. The approved labels of the orally inhaled drug products recommend the maximum number of actuations that can be administered in a single dose on one occasion. This single maximum dose may consist of one or more inhalations depending upon the product. Bioequivalence studies for the inhalation drug product registrations in the US and EU have employed single and multiple actuation doses, in some cases over and above the approved single maximum labeled doses, thus, inconsistent with the approved labeling of the reference products. Pharmacokinetics of inhaled drug products after single and multiple doses may be different, with implications for bioequivalence determined at single and multiple doses. Scientific literature indicates that the relative bioavailability of the Test and Reference products may differ between administrations of doses in one and multiple inhalations. Multiple doses not only alter the pharmacokinetics but also may reduce the sensitivity of the bioassay to actual differences between the Test and Reference product performances. Ability of the pharmacokinetic bioassay to accurately determine the extent of difference between two products may also be substantially reduced at high doses. Therefore, in our opinion, pharmacokinetic bioequivalence to support regulatory approvals of inhalation products at doses above the recommended single maximum dose should be avoided. Furthermore, the bioequivalence of products (if any) established at doses exceeding the approved single maximum doses should be revisited to determine if the products maintain bioequivalence when evaluated at the clinically relevant single maximum doses.

Multimodal optical imaging of the oculofacial region using a solid tissue-simulating facial phantom.

Significance: Spatial frequency domain imaging (SFDI) applies patterned near-infrared illumination to quantify the optical properties of subsurface tissue. The periocular region is unique due to its complex ocular adnexal anatomy. Although SFDI has been successfully applied to relatively flat in vivo tissues, regions that have significant height variations and curvature may result in optical property inaccuracies. Aim: We characterize the geometric impact of the periocular region on SFDI imaging reliability. Approach: SFDI was employed to measure the reduced scattering coefficient ( µ s ' ) and absorption coefficient ( µ a ) of the periocular region in a cast facial tissue-simulating phantom by capturing images along regions of interest (ROIs): inferior temporal quadrant (ITQ), inferior nasal quadrant (INQ), superior temporal quadrant (STQ), central eyelid margin (CEM), rostral lateral nasal bridge (RLNB), and forehead (FH). The phantom was placed on a chin rest and imaged nine times from an "en face" or "side profile" position, and the flat back of the phantom was measured 15 times. Results: The measured µ a and µ s ' of a cast facial phantom are accurate when comparing the ITQ, INQ, STQ, and FH to its flat posterior surface. Paired t tests of ITQ, INQ, STQ, and FH µ a and µ s ' concluded that there is not enough evidence to suggest that imaging orientation impacted the measurement accuracy. Regions of extreme topographical variation, i.e., CEM and RLNB, did exhibit differences in measured optical properties. Conclusions: We are the first to evaluate the geometric implications of wide-field imaging along the periocular region using a solid tissue-simulating facial phantom. Results suggest that the ITQ, INQ, STQ, and FH of a generalized face have minimal impact on the SFDI measurement accuracy. Areas with heightened topographic variation exhibit measurement variability. Device and facial positioning do not appear to bias measurements. These findings confirm the need to carefully select ROIs when measuring optical properties along the periocular region.

Persistence and pathway of glyphosate degradation in the coastal wetland soil of central Delaware.

Glyphosate is a globally dominant herbicide. Here, we studied the degradation and microbial response to glyphosate application in a wetland soil in central Delaware for controlling invasive species (Phragmites australis). We applied a two-step solid-phase extraction method using molecularly imprinted polymers designed for the separation and enrichment of glyphosate and aminomethylphosphonic acid (AMPA) from soils before their analysis by ultra-high-performance liquid chromatography (UHPLC) and Q Exactive Orbitrap mass spectrometry methods. Our results showed that approximately 90 % of glyphosate degraded over 100 d after application, with AMPA being a minor (<10 %) product. Analysis of glyphosate-specific microbial genes to identify microbial response and function revealed that the expression of the phnJ gene, which codes C-P lyase enzyme, was consistently dominant over the gox gene, which codes glyphosate oxidoreductase enzyme, after glyphosate application. Both gene and concentration data independently suggested that C-P bond cleavage-which forms sarcosine or glycine-was the dominant degradation pathway. This is significant because AMPA, a more toxic product, is reported to be the preferred pathway of glyphosate degradation in other soil and natural environments. The degradation through a safer pathway is encouraging for minimizing the detrimental impacts of glyphosate on the environment.

Emissive Guanosine Analog Applicable for Real-Time Live Cell Imaging.

A new emissive guanosine analog CF3thG, constructed by a single trifluoromethylation step from the previously reported thG, displays red-shifted absorption and emission spectra compared to its precursor. The impact of solvent type and polarity on the photophysical properties of CF3thG suggests that the electronic effects of the trifluoromethyl group dominate its behavior and demonstrates its susceptibility to microenvironmental polarity changes. In vitro transcription initiations using T7 RNA polymerase, initiated with CF3thG, result in highly emissive 5'-labeled RNA transcripts, demonstrating the tolerance of the enzyme toward the analog. Viability assays with HEK293T cells displayed no detrimental effects at tested concentrations, indicating the safety of the analog for cellular applications. Live cell imaging of the free emissive guanosine analog using confocal microscopy was facilitated by its red-shifted absorption and emission and adequate brightness. Real-time live cell imaging demonstrated the release of the guanosine analog from HEK293T cells at concentration-gradient conditions, which was suppressed by the addition of guanosine.

Pulmonary Embolism Presenting as ST-Elevation Myocardial Infarction: A Report of Two Cases.

Pulmonary embolism (PE) is often underrecognized due to its ability to mimic other conditions; however, ultrasound can provide diagnostic clues to aid in the diagnosis of PE. We describe two patients who presented with symptoms suggestive of cardiac ischemia and had electrocardiograms (EKGs) indicative of anteroseptal myocardial infarction. In both cases, cardiac point-of-care ultrasonography showed signs of large pulmonary emboli, which were then confirmed on computed tomography angiography of the chest. Both patients underwent successful aspiration thrombectomy with rapid resolution of cardiac dysfunction. Point-of-care ultrasonography should be used as an adjunct in patients presenting with anterior ischemia on EKG to evaluate for signs of PE.

The Structure of the LysR-type Transcriptional Regulator, CysB, Bound to the Inducer, N-acetylserine.

In Escherichia coli and Salmonella typhimurium, cysteine biosynthesis requires the products of 20 or more cys genes co-ordinately regulated by CysB. Under conditions of sulphur limitation and in the presence of the inducer, N-acetylserine, CysB binds to cys promoters and activates the transcription of the downstream coding sequences. CysB is a homotetramer, comprising an N-terminal DNA binding domain (DBD) and a C-terminal effector binding domain (EBD). The crystal structure of a dimeric EBD fragment of CysB from Klebsiella aerogenes revealed a protein fold similar to that seen in Lac repressor but with a different symmetry in the dimer so that the mode of DNA binding was not apparent. To elucidate the subunit arrangement in the tetramer, we determined the crystal structure of intact CysB in complex with N-acetylserine. The tetramer has two subunit types that differ in the juxtaposition of their winged helix-turn-helix DNA binding domains with respect to the effector binding domain. In the assembly, the four EBDs form a core with the DNA binding domains arranged in pairs on the surface. N-acetylserine makes extensive polar interactions in an enclosed binding site, and its binding is accompanied by substantial conformational rearrangements of surrounding residues that are propagated to the protein surface where they appear to alter the arrangement of the DNA binding domains. The results are (i) discussed in relation to the extensive mutational data available for CysB and (ii) used to propose a structural mechanism of N-acetylserine induced CysB activation.

Use of Impedance Cardiography to Guide Blood Pressure Lowering Medication Selection: Systematic Review of Randomized Controlled Trials.

BACKGROUND: Blood pressure (BP) control can be difficult to attain due to multiple factors, including choosing and titrating antihypertensive medications. Measurement of hemodynamic parameters using impedance cardiography (ICG) at the point of care may allow better alignment of medication with the mechanism(s) underlying an individual's hypertension. We conducted a systematic review of randomized controlled trials of ICG compared to usual care for attainment of BP control. METHODS: We searched Medline inclusive of year 1946 to January 31, 2024 using a combination of MeSH terms and key words. English-language articles were eligible for inclusion if they described results of a randomized controlled trial designed to compare ICG-guided BP medication selection to usual care (i.e., clinician judgment/guidelines-based alone) among a sample of hypertensive patients. RESULTS: Of 1952 titles screened, six trials met inclusion criteria. The first was published in 2002 from a specialty clinic in the United States, and the most recent in 2021 from a specialty clinic in China. One trial was conducted in a primary care setting. Sample sizes ranged from 102 to 164. Participants randomized to ICG-guided antihypertensive medication had reduced BP in the short-term to a greater extent than those randomized to usual care, with odds ratios for BP control (<140/90 mmHg) at three months ranging from 1.87 to 2.92. This effect was seen in both specialty clinics and in a primary care setting. CONCLUSIONS: Incorporation of ICG in the clinical setting may facilitate medication selection that leads to a greater proportion of patients obtaining BP control in the short-term.