Using patient portals for large-scale recruitment of individuals underrepresented in biomedical research: an evaluation of engagement patterns throughout the patient portal recruitment process at a single site within the All of Us Research Program.

OBJECTIVE: To evaluate the use of patient portal messaging to recruit individuals historically underrepresented in biomedical research (UBR) to the All of Us Research Program (AoURP) at a single recruitment site. MATERIALS AND METHODS: Patient portal-based recruitment was implemented at Columbia University Irving Medical Center. Patient engagement was assessed using patient's electronic health record (EHR) at four recruitment stages: Consenting to be contacted, opening messages, responding to messages, and showing interest in participating. Demographic and socioeconomic data were also collected from patient's EHR and univariate logistic regression analyses were conducted to assess patient engagement. RESULTS: Between October 2022 and November 2023, a total of 59 592 patients received patient portal messages inviting them to join the AoURP. Among them, 24 445 (41.0%) opened the message, 8983 (15.1%) responded, and 3765 (6.3%) showed interest in joining the program. Though we were unable to link enrollment data with EHR data, we estimate about 2% of patients contacted ultimately enrolled in the AoURP. Patients from underrepresented race and ethnicity communities had lower odds of consenting to be contacted and opening messages, but higher odds of showing interest after responding. DISCUSSION: Patient portal messaging provided both patients and recruitment staff with a more efficient approach to outreach, but patterns of engagement varied across UBR groups. CONCLUSION: Patient portal-based recruitment enables researchers to contact a substantial number of participants from diverse communities. However, more effort is needed to improve engagement from underrepresented racial and ethnic groups at the early stages of the recruitment process.

Enamel Remineralisation with a Novel Sodium Fluoride-Infused Bristle Toothbrush.

This study aims to investigate whether toothbrushes with fluoride-infused bristles have any (re)mineralisation effects on bovine enamel. Bovine incisors (N = 160) were extracted, and the buccal side of the crown was cut into dimensions of ~5 mm × 5 mm with a low-speed saw. These specimens were randomly allocated into four groups: half (80 teeth) were stored in demineralising solution (DM), and the other half were stored in deionised water (DW) for 96 h. Then, they were brushed with a force of 2.0 ± 0.1 N for five min with a manual toothbrush with either fluoride-infused (TF) or regular (TR) bristles. Microhardness (Vickers), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS), and scanning electron microscopy (SEM) were used to investigate the surfaces of the bovine enamel specimens before and after brushing. Two-way ANOVA was used to analyse the hardness data, and the pairwise comparison method was used to analyse the Ca/P ratio, for each group at α = 0.05. The results show that brushing with either of these toothbrushes increased the Vickers microhardness on DM and DW enamel (p < 0.001), whereas hydroxyapatite was revealed in all groups by XRD. The DM samples showed a significant increase (p < 0.05) in the Ca/P ratios after brushing with TR and TF. Conversely, under DW conditions, these ratios decreased significantly after brushing. In terms of the F atomic%, TF increased significantly. SEM revealed mineral deposition in the DM groups after toothbrushing. To conclude, toothbrushing effectively induces the microhardness of sound and demineralised enamel, while fluoride-infused bristles might be able to retain fluoride on the enamel surface.

Giant Tunability of Intersubband Transitions and Quantum Hall Quartets in Few-Layer InSe Quantum Wells.

A two-dimensional (2D) quantum electron system is characterized by quantized energy levels, or subbands, in the out-of-plane direction. Populating higher subbands and controlling the intersubband transitions have wide technological applications such as optical modulators and quantum cascade lasers. In conventional materials, however, the tunability of intersubband spacing is limited. Here we demonstrate electrostatic population and characterization of the second subband in few-layer InSe quantum wells, with giant tunability of its energy, population, and spin-orbit coupling strength, via the control of not only layer thickness but also the out-of-plane displacement field. A modulation of as much as 350% or over 250 meV is achievable, underscoring the promise of InSe for tunable infrared and THz sources, detectors, and modulators.

Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa.

The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom's national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3 encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wild-type LAMA3 expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. In vitro lentiviral overexpression of LAMA3A in EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof of concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB.

Autoantigen-Dexamethasone Conjugate-Loaded Liposomes Halt Arthritis Development in Mice.

There is no curative treatment for chronic auto-inflammatory diseases including rheumatoid arthritis, and current treatments can induce off-target side effects due to systemic immune suppression. This work has previously shown that dexamethasone-pulsed tolerogenic dendritic cells loaded with the arthritis-specific antigen human proteoglycan can suppress arthritis development in a proteoglycan-induced arthritis mouse model. To circumvent ex vivo dendritic cell culture, and enhance antigen-specific effects, drug delivery vehicles, such as liposomes, provide an interesting approach. Here, this work uses anionic 1,2-distearoyl-sn-glycero-3-phosphoglycerol liposomes with enhanced loading of human proteoglycan-dexamethasone conjugates by cationic lysine tetramer addition. Antigen-pulsed tolerogenic dendritic cells induced by liposomal dexamethasone in vitro enhanced antigen-specific regulatory T cells to a similar extent as dexamethasone-induced tolerogenic dendritic cells. In an inflammatory adoptive transfer model, mice injected with antigen-dexamethasone liposomes have significantly higher antigen-specific type 1 regulatory T cells than mice injected with antigen only. The liposomes significantly inhibit the progression of arthritis compared to controls in preventative and therapeutic proteoglycan-induced arthritis mouse models. This coincides with systemic tolerance induction and an increase in IL10 expression in the paws of mice. In conclusion, a single administration of autoantigen and dexamethasone-loaded liposomes seems to be a promising antigen-specific treatment strategy for arthritis in mice.

Young duplicate genes show developmental stage- and cell type-specific expression and function in Caenorhabditis elegans.

Gene duplication produces the material that fuels evolutionary innovation. The "out-of-testis" hypothesis suggests that sperm competition creates selective pressure encouraging the emergence of new genes in male germline, but the somatic expression and function of the newly evolved genes are not well understood. We systematically mapped the expression of young duplicate genes throughout development in Caenorhabditis elegans using both whole-organism and single-cell transcriptomic data. Based on the expression dynamics across developmental stages, young duplicate genes fall into three clusters that are preferentially expressed in early embryos, mid-stage embryos, and late-stage larvae. Early embryonic genes are involved in protein degradation and develop essentiality comparable to the genomic average. In mid-to-late embryos and L4-stage larvae, young genes are enriched in intestine, epidermal cells, coelomocytes, and amphid chemosensory neurons. Their molecular functions and inducible expression indicate potential roles in innate immune response and chemosensory perceptions, which may contribute to adaptation outside of the sperm.

Quantum octets in high mobility pentagonal two-dimensional PdSe2.

Two-dimensional (2D) materials have drawn immense interests in scientific and technological communities, owing to their extraordinary properties and their tunability by gating, proximity, strain and external fields. For electronic applications, an ideal 2D material would have high mobility, air stability, sizable band gap, and be compatible with large scale synthesis. Here we demonstrate air stable field effect transistors using atomically thin few-layer PdSe2 sheets that are sandwiched between hexagonal BN (hBN), with large saturation current > 350 µA/µm, and high field effect mobilities of ~ 700 and 10,000 cm2/Vs at 300 K and 2 K, respectively. At low temperatures, magnetotransport studies reveal unique octets in quantum oscillations that persist at all densities, arising from 2-fold spin and 4-fold valley degeneracies, which can be broken by in-plane and out-of-plane magnetic fields toward quantum Hall spin and orbital ferromagnetism.

Monolignol Potential and Insights into Direct Depolymerization of Fruit and Nutshell Remains for High Value Sustainable Aromatics.

The inedible parts of nuts and stone fruits are low-cost and lignin-rich feedstock for more sustainable production of aromatic chemicals in comparison with the agricultural and forestry residues. However, the depolymerization performances on food-related biomass remains unclear, owing to the broad physicochemical variations from the edible parts of the fruits and plant species. In this study, the monomer production potentials of ten major fruit and nutshell biomass were investigated with comprehensive numerical information derived from instrumental analysis, such as plant cell wall chemical compositions, syringyl/guaiacyl (S/G ratios, and contents of lignin substructure linkages (ß-O-4, ß-ß, ß-5). A standardized one-pot reductive catalytic fractionation (RCF) process was applied to benchmark the monomer yields, and the results were statistically analyzed. Among all the tested biomass, mango endocarp provided the highest monolignol yields of 37.1 % per dry substrates. Positive S-lignin (70-84 %) resulted in higher monomer yield mainly due to more cleavable ß-O-4 linkages and less condensed C-C linkages. Strong positive relationships were identified between ß-O-4 and S-lignin and between ß-5 and G-lignin. The analytical, numerical, and experimental results of this study shed lights to process design of lignin-first biorefinery in food-processing industries and waste management works.

The role of BST4 in the pyrenoid of Chlamydomonas reinhardtii.

In many eukaryotic algae, CO2 fixation by Rubisco is enhanced by a CO2-concentrating mechanism, which utilizes a Rubisco-rich organelle called the pyrenoid. The pyrenoid is traversed by a network of thylakoid-membranes called pyrenoid tubules, proposed to deliver CO2. In the model alga Chlamydomonas reinhardtii (Chlamydomonas), the pyrenoid tubules have been proposed to be tethered to the Rubisco matrix by a bestrophin-like transmembrane protein, BST4. Here, we show that BST4 forms a complex that localizes to the pyrenoid tubules. A Chlamydomonas mutant impaired in the accumulation of BST4 (bst4) formed normal pyrenoid tubules and heterologous expression of BST4 in Arabidopsis thaliana did not lead to the incorporation of thylakoids into a reconstituted Rubisco condensate. Chlamydomonas bst4 mutant did not show impaired growth at air level CO2. By quantifying the non-photochemical quenching (NPQ) of chlorophyll fluorescence, we show that bst4 displays a transiently lower thylakoid lumenal pH during dark to light transition compared to control strains. When acclimated to high light, bst4 had sustained higher NPQ and elevated levels of light-induced H2O2 production. We conclude that BST4 is not a tethering protein, but rather is an ion channel involved in lumenal pH regulation possibly by mediating bicarbonate transport across the pyrenoid tubules.

Anthraquinone-Based Silicate Covalent Organic Frameworks as Solid Electrolyte Interphase for High-Performance Lithium-Metal Batteries.

Lithium (Li)-metal batteries (LMBs) possess the highest theoretical energy density among current battery designs and thus have enormous potential for use in energy storage. However, the development of LMBs has been severely hindered by safety concerns arising from dendrite growth and unstable interphases on the Li anode. Covalent organic frameworks (COFs) incorporating either redox-active or anionic moieties on their backbones have high Li-ion (Li+) conductivities and mechanical/chemical stabilities, so are promising for solid electrolyte interphases (SEIs) in LMBs. Here, we synthesized anthraquinone-based silicate COFs (AQ-Si-COFs) that contained both redox-active and anionic sites via condensation of tetrahydroxyanthraquinone with silicon dioxide. The nine Li+-mediated charge/discharge processes enabled the AQ-Si-COF to demonstrate an ionic conductivity of 9.8 mS cm-1 at room temperature and a single-ion-conductive transference number of 0.92. Computational studies also supported the nine Li+ mechanism. We used AQ-Si-COF as the solid electrolyte interphase on the Li anode. The LMB cells with a LiCoO2 cathode attained a maximum reversible capacity of 188 mAh g-1 at 0.25 C during high-voltage operation. Moreover, this LMB cell demonstrated suppressed dendrite growth and stable cyclability, with its capacity decreasing by less than 3% up to 100 cycles. These findings demonstrate the effectiveness of our redox-active and anionic COFs and their practical utility as SEI in LMB.

Interpolated Joint Space Adversarial Training for Robust and Generalizable Defenses.

Adversarial training (AT) is considered to be one of the most reliable defenses against adversarial attacks. However, models trained with AT sacrifice standard accuracy and do not generalize well to unseen attacks. Recent works show generalization improvement with adversarial samples under unseen threat models such as on-manifold threat model or neural perceptual threat model. However, the former requires exact manifold information while the latter requires algorithm relaxation. Motivated by these considerations, we propose a novel threat model called Joint Space Threat Model (JSTM), which exploits the underlying manifold information with Normalizing Flow, ensuring that the exact manifold assumption holds. Under JSTM, we develop novel adversarial attacks and defenses. Specifically, we propose the Robust Mixup strategy in which we maximize the adversity of the interpolated images and gain robustness and prevent overfitting. Our experiments show that Interpolated Joint Space Adversarial Training (IJSAT) achieves good performance in standard accuracy, robustness, and generalization. IJSAT is also flexible and can be used as a data augmentation method to improve standard accuracy and combined with many existing AT approaches to improve robustness. We demonstrate the effectiveness of our approach on three benchmark datasets, CIFAR-10/100, OM-ImageNet and CIFAR-10-C.

Live Cell Imaging by Förster Resonance Energy Transfer Fluorescence to Study Trafficking of PLGA Nanoparticles and the Release of a Loaded Peptide in Dendritic Cells.

Our previous study demonstrated that a selected ß-lactoglobulin-derived peptide (BLG-Pep) loaded in poly(lactic-co-glycolic acid) (PLGA) nanoparticles protected mice against cow's milk allergy development. However, the mechanism(s) responsible for the interaction of the peptide-loaded PLGA nanoparticles with dendritic cells (DCs) and their intracellular fate was/were elusive. Förster resonance energy transfer (FRET), a distance-dependent non-radioactive energy transfer process mediated from a donor to an acceptor fluorochrome, was used to investigate these processes. The ratio of the donor (Cyanine-3)-conjugated peptide and acceptor (Cyanine-5) labeled PLGA nanocarrier was fine-tuned for optimal (87%) FRET efficiency. The colloidal stability and FRET emission of prepared NPs were maintained upon 144 h incubation in PBS buffer and 6 h incubation in biorelevant simulated gastric fluid at 37 °C. A total of 73% of Pep-Cy3 NP was internalized by DCs as quantified using flow cytometry and confirmed using confocal fluorescence microscopy. By real-time monitoring of the change in the FRET signal of the internalized peptide-loaded nanoparticles, we observed prolonged retention (for 96 h) of the nanoparticles-encapsulated peptide as compared to 24 h retention of the free peptide in the DCs. The prolonged retention and intracellular antigen release of the BLG-Pep loaded in PLGA nanoparticles in murine DCs might facilitate antigen-specific tolerance induction.

Polyplex designs for improving the stability and safety of RNA therapeutics.

Nanoparticle-based delivery systems have contributed to the recent clinical success of RNA therapeutics, including siRNA and mRNA. RNA delivery using polymers has several distinct properties, such as enabling RNA delivery into extra-hepatic organs, modulation of immune responses to RNA, and regulation of intracellular RNA release. However, delivery systems should overcome safety and stability issues to achieve widespread therapeutic applications. Safety concerns include direct damage to cellular components, innate and adaptive immune responses, complement activation, and interaction with surrounding molecules and cells in the blood circulation. The stability of the delivery systems should balance extracellular RNA protection and controlled intracellular RNA release, which requires optimization for each RNA species. Further, polymer designs for improving safety and stability often conflict with each other. This review covers advances in polymer-based approaches to address these issues over several years, focusing on biological understanding and design concepts for delivery systems rather than material chemistry.

A phase-separated CO2-fixing pyrenoid proteome determined by TurboID in Chlamydomonas reinhardtii.

Phase separation underpins many biologically important cellular events such as RNA metabolism, signaling, and CO2 fixation. However, determining the composition of a phase-separated organelle is often challenging due to its sensitivity to environmental conditions, which limits the application of traditional proteomic techniques like organellar purification or affinity purification mass spectrometry to understand their composition. In Chlamydomonas reinhardtii, Rubisco is condensed into a crucial phase-separated organelle called the pyrenoid that improves photosynthetic performance by supplying Rubisco with elevated concentrations of CO2. Here, we developed a TurboID-based proximity labeling technique in which proximal proteins in Chlamydomonas chloroplasts are labeled by biotin radicals generated from the TurboID-tagged protein. By fusing 2 core pyrenoid components with the TurboID tag, we generated a high-confidence pyrenoid proxiome that contains most known pyrenoid proteins, in addition to new pyrenoid candidates. Fluorescence protein tagging of 7 previously uncharacterized TurboID-identified proteins showed that 6 localized to a range of subpyrenoid regions. The resulting proxiome also suggests new secondary functions for the pyrenoid in RNA-associated processes and redox-sensitive iron-sulfur cluster metabolism. This developed pipeline can be used to investigate a broad range of biological processes in Chlamydomonas, especially at a temporally resolved suborganellar resolution.

Evidence for Dirac flat band superconductivity enabled by quantum geometry.

In a flat band superconductor, the charge carriers' group velocity vF is extremely slow. Superconductivity therein is particularly intriguing, being related to the long-standing mysteries of high-temperature superconductors1 and heavy-fermion systems2. Yet the emergence of superconductivity in flat bands would appear paradoxical, as a small vF in the conventional Bardeen-Cooper-Schrieffer theory implies vanishing coherence length, superfluid stiffness and critical current. Here, using twisted bilayer graphene3-7, we explore the profound effect of vanishingly small velocity in a superconducting Dirac flat band system8-13. Using Schwinger-limited non-linear transport studies14,15, we demonstrate an extremely slow normal state drift velocity vn ≈ 1,000 m s-1 for filling fraction ν between -1/2 and -3/4 of the moiré superlattice. In the superconducting state, the same velocity limit constitutes a new limiting mechanism for the critical current, analogous to a relativistic superfluid16. Importantly, our measurement of superfluid stiffness, which controls the superconductor's electrodynamic response, shows that it is not dominated by the kinetic energy but instead by the interaction-driven superconducting gap, consistent with recent theories on a quantum geometric contribution8-12. We find evidence for small Cooper pairs, characteristic of the Bardeen-Cooper-Schrieffer to Bose-Einstein condensation crossover17-19, with an unprecedented ratio of the superconducting transition temperature to the Fermi temperature exceeding unity and discuss how this arises for ultra-strong coupling superconductivity in ultra-flat Dirac bands.

Acute Fasting Modulates Food-Seeking Behavior and Neural Signaling in the Piriform Cortex.

It is well known that the state of hunger can modulate hormones and hypothalamic neural circuits to drive food-seeking behavior and consumption. However, the role the sensory cortex plays in regulating foraging is much less explored. Here, we investigated whether acute fasting in mice can alter an odor-guided foraging behavior and how it can alter neurons and synapses in the (olfactory) piriform cortex (PC). Acute hunger enhances the motivation of a mouse to search for food pellets and increases food intake. The foraging behavior strongly activates the PC, as revealed by c-Fos immunostaining. The activation of PC is accompanied by an increase in excitation-inhibition ratio of synaptic density. Fasting also enhances the phosphorylation of AMP kinase, a biochemical energy regulator. Taken together, our results uncover a new regulatory brain region and implicate the PC in controlling foraging behavior.

An artificial intelligence-enabled smartphone app for real-time pressure injury assessment.

The management of chronic wounds in the elderly such as pressure injury (also known as bedsore or pressure ulcer) is increasingly important in an ageing population. Accurate classification of the stage of pressure injury is important for wound care planning. Nonetheless, the expertise required for staging is often not available in a residential care home setting. Artificial-intelligence (AI)-based computer vision techniques have opened up opportunities to harness the inbuilt camera in modern smartphones to support pressure injury staging by nursing home carers. In this paper, we summarise the recent development of smartphone or tablet-based applications for wound assessment. Furthermore, we present a new smartphone application (app) to perform real-time detection and staging classification of pressure injury wounds using a deep learning-based object detection system, YOLOv4. Based on our validation set of 144 photos, our app obtained an overall prediction accuracy of 63.2%. The per-class prediction specificity is generally high (85.1%-100%), but have variable sensitivity: 73.3% (stage 1 vs. others), 37% (stage 2 vs. others), 76.7 (stage 3 vs. others), 70% (stage 4 vs. others), and 55.6% (unstageable vs. others). Using another independent test set, 8 out of 10 images were predicted correctly by the YOLOv4 model. When deployed in a real-life setting with two different ambient brightness levels with three different Android phone models, the prediction accuracy of the 10 test images ranges from 80 to 90%, which highlight the importance of evaluation of mobile health (mHealth) application in a simulated real-life setting. This study details the development and evaluation process and demonstrates the feasibility of applying such a real-time staging app in wound care management.

Thickness- and Twist-Angle-Dependent Interlayer Excitons in Metal Monochalcogenide Heterostructures.

Interlayer excitons, or bound electron-hole pairs whose constituent quasiparticles are located in distinct stacked semiconducting layers, are being intensively studied in heterobilayers of two-dimensional semiconductors. They owe their existence to an intrinsic type-II band alignment between both layers that convert these into p-n junctions. Here, we unveil a pronounced interlayer exciton (IX) in heterobilayers of metal monochalcogenides, namely, γ-InSe on ε-GaSe, whose pronounced emission is adjustable just by varying their thicknesses given their number of layers dependent direct band gaps. Time-dependent photoluminescense spectroscopy unveils considerably longer interlayer exciton lifetimes with respect to intralayer ones, thus confirming their nature. The linear Stark effect yields a bound electron-hole pair whose separation d is just (3.6 ± 0.1) Å with d being very close to dSe = 3.4 Å which is the calculated interfacial Se separation. The envelope of IX is twist-angle-dependent and describable by superimposed emissions that are nearly equally spaced in energy, as if quantized due to localization induced by the small moiré periodicity. These heterostacks are characterized by extremely flat interfacial valence bands making them prime candidates for the observation of magnetism or other correlated electronic phases upon carrier doping.

Light sources with bias tunable spectrum based on van der Waals interface transistors.

Light-emitting electronic devices are ubiquitous in key areas of current technology, such as data communications, solid-state lighting, displays, and optical interconnects. Controlling the spectrum of the emitted light electrically, by simply acting on the device bias conditions, is an important goal with potential technological repercussions. However, identifying a material platform enabling broad electrical tuning of the spectrum of electroluminescent devices remains challenging. Here, we propose light-emitting field-effect transistors based on van der Waals interfaces of atomically thin semiconductors as a promising class of devices to achieve this goal. We demonstrate that large spectral changes in room-temperature electroluminescence can be controlled both at the device assembly stage -by suitably selecting the material forming the interfaces- and on-chip, by changing the bias to modify the device operation point. Even though the precise relation between device bias and kinetics of the radiative transitions remains to be understood, our experiments show that the physical mechanism responsible for light emission is robust, making these devices compatible with simple large areas device production methods.

EHR Data Quality Assessment Tools and Issue Reporting Workflows for the 'All of Us' Research Program Clinical Data Research Network.

The All of Us (AoU) Research Program aggregates electronic health records (EHR) data from 300,00+ participants spanning 50+ distinct data sites. The diversity and size of AoU's data network result in multifaceted obstacles to data integration that may undermine the usability of patient EHR. Consequently, the AoU team implemented data quality tools to regularly evaluate and communicate EHR data quality issues at scale. The use of systematic feedback and educational tools ultimately increased site engagement and led to quantitative improvements in EHR quality as measured by program- and externally-defined metrics. These improvements enabled the AoU team to save time on troubleshooting EHR and focus on the development of alternate mechanisms to improve the quality of future EHR submissions. While this framework has proven effective, further efforts to automate and centralize communication channels are needed to deepen the program's efforts while retaining its scalability.