Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability.

While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here, we describe an immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N terminus of the ebolavirus glycoproteins (GPs) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets. Analysis of memory B cells from the immunized macaque suggests that elicitation of broadly neutralizing antibodies (bNAbs) for ebolaviruses is possible but difficult, potentially due to the rarity of bNAb clones and their precursors. Unexpectedly, germline-reverted CA45, while exhibiting negligible binding to full-length GP, bound a proteolytically remodeled GP with picomolar affinity, suggesting that engineered ebolavirus vaccines could trigger rare bNAb precursors more robustly. These findings have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails.

Ubiquitous coexisting electron-mode couplings in high-temperature cuprate superconductors.

In conventional superconductors, electron-phonon coupling plays a dominant role in generating superconductivity. In high-temperature cuprate superconductors, the existence of electron coupling with phonons and other boson modes and its role in producing high-temperature superconductivity remain unclear. The evidence of electron-boson coupling mainly comes from angle-resolved photoemission (ARPES) observations of [Formula: see text]70-meV nodal dispersion kink and [Formula: see text]40-meV antinodal kink. However, the reported results are sporadic and the nature of the involved bosons is still under debate. Here we report findings of ubiquitous two coexisting electron-mode couplings in cuprate superconductors. By taking ultrahigh-resolution laser-based ARPES measurements, we found that the electrons are coupled simultaneously with two sharp modes at [Formula: see text]70meV and [Formula: see text]40meV in different superconductors with different dopings, over the entire momentum space and at different temperatures above and below the superconducting transition temperature. These observations favor phonons as the origin of the modes coupled with electrons and the observed electron-mode couplings are unusual because the associated energy scales do not exhibit an obvious energy shift across the superconducting transition. We further find that the well-known "peak-dip-hump" structure, which has long been considered a hallmark of superconductivity, is also omnipresent and consists of "peak-double dip-double hump" finer structures that originate from electron coupling with two sharp modes. These results provide a unified picture for the [Formula: see text]70-meV and [Formula: see text]40-meV energy scales and their evolutions with momentum, doping and temperature. They provide key information to understand the origin of these energy scales and their role in generating anomalous normal state and high-temperature superconductivity.

The interaction between the histone acetyltransferase complex Hat1-Hat2 and transcription factor AmyR provides a molecular brake to regulate amylase gene expression.

The chromatin structure is generally regulated by chromatin remodelers and histone modifiers, which affect DNA replication, repair, and levels of transcription. The first identified histone acetyltransferase was Hat1/KAT1, which belongs to lysine (K) acetyltransferases. The catalytic subunit Hat1 and the regulatory subunit Hat2 make up the core HAT1 complex. In this study, the results of tandem affinity purification and mass spectrometry and bimolecular fluorescence complementation proved that the Penicillium oxalicum PoHat1-Hat2 is the transcriptional cofactor of the sequence-specific transcription factor PoAmyR, a transcription activator essential for the transcription of amylase gene. ChIP-qPCR results demonstrated that the complex PoHat1-Hat2 is recruited by PoAmyR to the promoters of prominent amylase genes Poamy13A and Poamy15A and performs histone H4 lysine12 acetylation. The result of the yeast two-hybrid test indicated that PoHat2 is the subunit that directly interacts with PoAmyR. PoHat1-Hat2 acts as the molecular brake of the PoAmyR-regulating transcription of amylase genes. A putative model for amylase gene regulation by PoAmyR-Hat2-Hat1 was constructed. Our paper is the first report that the Hat1-Hat2 complex acts as a cofactor for sequence-specific TF to regulate gene expression and explains the mechanism of TF AmyR regulating amylase genes expression.

A novel strategy to induce penile erection during penile doppler ultrasound: oral sildenafil administration plus alprostadil injection.

OBJECTIVES: To evaluate the efficacy of a novel approach to achieve the optimal penile erection during the penile doppler ultrasound (PDU) examination, which was oral sildenafil combined alprostadil injection. MATERIALS AND METHODS: A total of 60 ED patients were enrolled in our prospective study, and they were randomly assigned to two group with different PDU order. The approaches assisted the PDU included two models, mode A meaning injection of 15 µg alprostadil and model B meaning oral sildenafil 100 mg plus injection of 15 µg alprostadil. The PDU parameters were measured continuously before induced erection, and 5, 10, 15, 20, 25 min. RESULTS: Each group included 30 ED patients with similar clinical characteristics. After pooling the results together, the PSV, EDV, and RI were all improved significantly, when adding the oral sildenafil administration to assist PDU. Also, the clinical response of oral sildenafil administration plus alprostadil injection was better than that in alprostadil injection alone (p = 0.016). The arterial ED were decreased from 31.67% to 15.00% with the P value 0.031, and the mixed ED was also decreased statistically (23.33% vs 8.33%, p = 0.024). CONCLUSION: Oral sildenafil administration plus alprostadil injection could improve the diagnostic accuracy of PDU.

Probabilistic Estimation of Airborne Micro- and Nanoplastic Intake in Humans.

Little research exists on the magnitude, variability, and uncertainty of human exposure to airborne micro- and nanoplastics (AMNPs), despite their critical role in human exposure to MNPs. We probabilistically estimate the global intake of AMNPs through three main pathways: indoor inhalation, outdoor inhalation, and ingestion during indoor meals, for both children and adults. The median inhalation of AMPs is 1,207.7 (90% CI, 42.5-8.48 × 104) and 1,354.7 (90% CI, 47.4-9.55 × 104) N/capita/day for children and adults, respectively. The annual intake of AMPs is 13.18 mg/capita/a for children and 19.10 mg/capita/a for adults, which is approximately one-fifth and one-third of the mass of a standard stamp, assuming a consistent daily intake of medians. The majority of AMP number intake occurs through inhalation, while the ingestion of deposited AMPs during meals contributes the most in terms of mass. Furthermore, the median ANP intake through outdoor inhalation is 9,638.1 N/day (8.23 × 10-6 µg/d) and 5,410.6 N/day (4.62 × 10-6 µg/d) for children and adults, respectively, compared to 5.30 × 105 N/day (5.79 × 10-4 µg/d) and 6.00 × 105 N/day (6.55 × 10-4 µg/d) via indoor inhalation. Considering the increased toxicity of smaller MNPs, the significant number of ANPs inhaled warrants great attention. Collaborative efforts are imperative to further elucidate and combat the current MPN risks.

The effective prolongation of the excited-state carrier lifetime of CsPbI2Br with applying strain.

In recent years, all-inorganic perovskites CsPbX3 (X = Cl, Br, I) have emerged as excellent candidates for solar cells due to their remarkable thermal stability and suitable bandgaps. Among them, CsPbI2Br is a hotspot in perovskite material research currently. Non-radiative electron-hole recombination often leads to significant energy losses, impacting the efficiency of solar cells, so a thorough understanding of carrier recombination mechanisms is crucial. Our work investigated the carrier recombination dynamics in detail and proved that strains can effectively reduce nonradiative recombination. In this study, using first-principles calculations combined with nonadiabatic (NA) molecular dynamics (MD), we demonstrate that applying 2% tensile and 2% compressive strains to CsPbI2Br can modify the bandgap, induce moderate disorder, reduce the overlap of electron-hole wavefunctions, decrease NA coupling, and shorten decoherence time, thereby minimizing non-radiative recombination and extending the carrier lifetime. Especially the 2% tensile strain exhibits more effective control performance, significantly reducing non-radiative electron-hole recombination and extending the charge carrier lifetime to 14.59 ns, nearly five times that of the pristine CsPbI2Br system (3.12 ns). This study reveals the impact mechanism of strain on carrier behavior in perovskite solar cells, providing a new non-chemical strategy for modulating the lifetime of photo-generated carriers and enhancing the efficiency of all-inorganic perovskite solar cells.

Associations between alcohol taxes and varied health outcomes among women of reproductive age and infants.

OBJECTIVE: No studies have examined whether alcohol taxes may be relevant for reducing harms related to pregnant people's drinking. METHOD: We examined how beverage-specific ad valorem, volume-based, and sales taxes are associated with outcomes across three data sets. Drinking outcomes came from women of reproductive age in the 1990-2020 US National Alcohol Surveys (N = 11 659 women $\le$ 44 years); treatment admissions data came from the 1992-2019 Treatment Episode Data Set: Admissions (N = 1331 state-years; 582 436 pregnant women admitted to treatment); and infant and maternal outcomes came from the 2005-19 Merative Marketscan® database (1 432 979 birthing person-infant dyads). Adjusted analyses for all data sets included year fixed effects, state-year unemployment and poverty, and accounted for clustering by state. RESULTS: Models yield no robust significant associations between taxes and drinking. Increased spirits ad valorem taxes were robustly associated with lower rates of treatment admissions [adjusted IRR = 0.95, 95% CI: 0.91, 0.99]. Increased wine and spirits volume-based taxes were both robustly associated with lower odds of infant morbidities [wine aOR = 0.98, 95% CI: 0.96, 0.99; spirits aOR = 0.99, 95% CI: 0.98, 1.00] and lower odds of severe maternal morbidities [wine aOR = 0.91, 95% CI: 0.86, 0.97; spirits aOR = 0.95, 95% CI: 0.92, 0.97]. Having an off-premise spirits sales tax was also robustly related to lower odds of severe maternal morbidities [aOR = 0.78, 95% CI: 0.64, 0.96]. CONCLUSIONS: Results show protective associations between increased wine and spirits volume-based and sales taxes with infant and maternal morbidities. Policies that index tax rates to inflation might yield more public health benefits, including for pregnant people and infants.

On cognitive epidemic models: spatial segregation versus nonpharmaceutical interventions.

Fick's law and the Fokker-Planck law of diffusion are applied to manifest the cognitive dispersal of individuals in two reaction-diffusion SEIR epidemic models, where the disease transmission is illustrated by nonlocal infection mechanisms in heterogeneous environments. Building upon the well-posedness of solutions, threshold dynamics are discussed in terms of the basic reproduction numbers for the two cognitive epidemic models. The numerical investigation reveals that the Fokker-Planck law can better describe the diffusion of individuals by taking different dispersal strategies of exposed individuals in our cognitive epidemic models, and provides some insights on spatial segregation and nonpharmaceutical interventions: (i) spatial segregation occurs in the random diffusion model when the nonlocal infection radius is small, while it appears in the symmetric diffusion model when the radius is large; (ii) nonpharmaceutical interventions on restricting the dispersal of exposed and infected individuals do not contribute to reducing the infection proportion, but rather eliminate the disease in a region, which expands as the nonlocal infection radius increases. We additionally find that the final infection size in the random diffusion model is significantly smaller than that in the symmetric diffusion model and decreases as the nonlocal infection radius increases.

PTPN7 mediates macrophage-polarization and determines immunotherapy in gliomas: A single-cell sequencing analysis.

BACKGROUND: Protein tyrosine phosphatase non-receptor type 7 (PTPN7) is a signaling molecule that regulates a multitude of cellular processes, spanning cell proliferation, cellular differentiation, the mitotic cycle, and oncogenic metamorphosis. However, the characteristic of PTPN7 in the glioma microenvironment has yet to be elucidated. METHODS: The prognostic value, genomic features, immune characteristics, chemotherapy prediction, and immunotherapy prediction of PTPN7 were systematically explored at the bulk sequencing level. The cell evolution trajectory, cell communication pattern, and cell metabolic activity related to PTPN7 were systematically explored at the single-cell sequencing level. HMC3 and M0 cells were cocultured with U251 and T98G cells, and flow cytometry was carried out to investigate the polarization of HMC3 and M0. Transwell assay and CCK-8 assay were performed to explore the migration and proliferation activity of U251 and T98G. RESULTS: The expression level of PTPN7 is significantly elevated in glioma and indicates malignant features. PTPN7 expression predicts worse prognosis of glioma patients. PTPN7 is associated with genome alteration and immune infiltration. Besides, PTPN7 plays a crucial role in modulating metabolic and immunogenic processes, particularly by influencing the activity of microglia and macrophages through multiple signaling pathways involved in cellular communication. Specifically, PTPN7 actively mediates inflammation-resolving-polarization of macrophages and microglia and protects glioma from immune attack. PTPN7 could also predict the response of immunotherapy. CONCLUSIONS: PTPN7 is critically involved in inflammation-resolving-polarization mediated by macrophage and microglia and promotes the immune escape of glioma cells.

Magnetic Real Chern Insulator in 2D Metal-Organic Frameworks.

Real Chern insulators have attracted great interest, but so far, their material realization is limited to nonmagnetic crystals and systems without spin-orbit coupling. Here, we reveal the magnetic real Chern insulator (MRCI) state in a recently synthesized metal-organic framework material Co3(HITP)2. Its ground state with in-plane ferromagnetic ordering hosts a nontrivial real Chern number, enabled by the C2zT symmetry and robustness against spin-orbit coupling. Distinct from previous nonmagnetic examples, the topological corner zero modes of MRCIs are spin-polarized. Furthermore, under small tensile strains, the material undergoes a topological phase transition from the MRCI to a magnetic double-Weyl semimetal phase, via a pseudospin-1 critical state. Similar physics can also be found in closely related materials Mn3(HITP)2 and Fe3(HITP)2, which also exist. Possible experimental detections and implications of an emerging magnetic flat band in the system are discussed.

A Pan-Ebolavirus Monoclonal Antibody Cocktail Provides Protection Against Ebola and Sudan Viruses.

Filoviruses, including ebolaviruses and marburgviruses, can cause severe and often fatal disease in humans. Over the past several years, antibody therapy has emerged as a promising strategy for the treatment of filovirus disease. Here, we describe 2 distinct cross-reactive monoclonal antibodies (mAbs) isolated from mice immunized with recombinant vesicular stomatitis virus-based filovirus vaccines. Both mAbs recognized the glycoproteins of multiple different ebolaviruses and exhibited broad but differential in vitro neutralization activities against these viruses. By themselves, each mAb provided partial to full protection against Ebola virus in mice, and in combination, the mAbs provided 100% protection against Sudan virus challenge in guinea pigs. This study identified novel mAbs that were elicited through immunization and able to provide protection from ebolavirus infection, thus enriching the pool of candidate therapeutics for treating Ebola disease.

Amyloid-ß accumulation in relation to functional connectivity in aging: A longitudinal study.

The brain undergoes many changes at pathological and functional levels in healthy aging. This study employed a longitudinal and multimodal imaging dataset from the OASIS-3 study (n = 300) and explored possible relationships between amyloid beta (Aß) accumulation and functional brain organization over time in healthy aging. We used positron emission tomography (PET) with Pittsburgh compound-B (PIB) to quantify the Aß accumulation in the brain and resting-state functional MRI (rs-fMRI) to measure functional connectivity (FC) among brain regions. Each participant had at least 2 to 3 follow-up visits. A linear mixed-effect model was used to examine longitudinal changes of Aß accumulation and FC throughout the whole brain. We found that the limbic and frontoparietal networks had a greater annual Aß accumulation and a slower decline in FC in aging. Additionally, the amount of the Aß deposition in the amygdala network at baseline slowed down the decline in its FC in aging. Furthermore, the functional connectivity of the limbic, default mode network (DMN), and frontoparietal networks accelerated the Aß propagation across their functionally highly connected regions. The functional connectivity of the somatomotor and visual networks accelerated the Aß propagation across the brain regions in the limbic, frontoparietal, and DMN networks. These findings suggested that the slower decline in the functional connectivity of the functional hubs may compensate for their greater Aß accumulation in aging. The Aß propagation from one brain region to the other may depend on their functional connectivity strength.

Magnetic Electrides: High-Throughput Material Screening, Intriguing Properties, and Applications.

Electrides are a unique class of electron-rich materials where excess electrons are localized in interstitial lattice sites as anions, leading to a range of unique properties and applications. While hundreds of electrides have been discovered in recent years, magnetic electrides have received limited attention, with few investigations into their fundamental physics and practical applications. In this work, 51 magnetic electrides (12 antiferromagnetic, 13 ferromagnetic, and 26 interstitial-magnetic) were identified using high-throughput computational screening methods and the latest Materials Project database. Based on their compositions, these magnetic electrides can be classified as magnetic semiconductors, metals, or half-metals, each with unique topological states and excellent catalytic performance for N2 fixation due to their low work functions and excess electrons. The novel properties of magnetic electrides suggest potential applications in spintronics, topological electronics, electron emission, and as high-performance catalysts. This work marks the beginning of a new era in the identification, investigation, and practical applications of magnetic electrides.

Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials.

Despite centuries since the discovery and study of cancer, cancer is still a lethal and intractable health issue worldwide. Cancer-associated fibroblasts (CAFs) have gained much attention as a pivotal component of the tumor microenvironment. The versatility and sophisticated mechanisms of CAFs in facilitating cancer progression have been elucidated extensively, including promoting cancer angiogenesis and metastasis, inducing drug resistance, reshaping the extracellular matrix, and developing an immunosuppressive microenvironment. Owing to their robust tumor-promoting function, CAFs are considered a promising target for oncotherapy. However, CAFs are a highly heterogeneous group of cells. Some subpopulations exert an inhibitory role in tumor growth, which implies that CAF-targeting approaches must be more precise and individualized. This review comprehensively summarize the origin, phenotypical, and functional heterogeneity of CAFs. More importantly, we underscore advances in strategies and clinical trials to target CAF in various cancers, and we also summarize progressions of CAF in cancer immunotherapy.

The complex Tup1-Cyc8 bridges transcription factor ClrB and putative histone methyltransferase LaeA to activate the expression of cellulolytic genes.

The degradation of lignocellulosic biomass by cellulolytic enzymes is involved in the global carbon cycle. The hydrolysis of lignocellulosic biomass into fermentable sugars is potential as an excellent industrial resource to produce a variety of chemical products. The production of cellulolytic enzymes is regulated mainly at the transcriptional level in filamentous fungi. Transcription factor ClrB and the putative histone methyltransferase LaeA, are both necessary for the expression of cellulolytic genes. However, the mechanism by which transcription factors and methyltransferase coordinately regulate cellulolytic genes is still unknown. Here, we reveal a transcriptional regulatory mechanism involving Penicillium oxalicum transcription factor ClrB (PoClrB), complex Tup1-Cyc8, and putative histone methyltransferase LaeA (PoLaeA). As the transcription factor, PoClrB binds the targeted promoters of cellulolytic genes, recruits PoTup1-Cyc8 complex via direct interaction with PoTup1. PoTup1 interacts with PoCyc8 to form the coactivator complex PoTup1-Cyc8. Then, PoTup1 recruits putative histone methyltransferase PoLaeA to modify the chromatin structure of the upstream region of cellulolytic genes, thereby facilitating the binding of transcription machinery to activating the corresponding cellulolytic gene expression. Our results contribute to a better understanding of complex transcriptional regulation mechanisms of cellulolytic genes and will be valuable for lignocellulosic biorefining.

Strategies to Improve Multi-enzyme Compatibility and Coordination in One-Pot SHERLOCK.

While molecular diagnostics generally require heating elements that supply high temperatures such as 95 °C in polymerase chain reaction and 60-69 °C in loop-mediated isothermal amplification, the recently developed CRISPR-based SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) platform can operate at 37 °C or a similar ambient temperature. This unique advantage may be translated into highly energy-efficient or equipment-free molecular diagnostic systems with unrestricted deployability. SHERLOCK is characterized by ultra-high sensitivity when performed in a traditional two-step format. For RNA sensing, the first step combines reverse transcription with recombinase polymerase amplification, while the second step consists of T7 transcription and CRISPR-Cas13a detection. The sensitivity drops dramatically, however, when all these components are combined into a single reaction mixture, and it largely remains an unmet need in the field to establish a high-performance one-pot SHERLOCK assay. An underlying challenge, conceivably, is the extremely complex nature of a one-pot formulation, crowding a large number of reaction types using at least eight enzymes/proteins. Although previous work has made substantial improvements by serving individual enzymes/reactions with accommodating conditions, we reason that the interactions among different enzymatic reactions could be another layer of complicating factors. In this study, we seek optimization strategies by which inter-enzymatic interference may be eliminated or reduced and cooperation created or enhanced. Several such strategies are identified for SARS-CoV-2 detection, each leading to a significantly improved reaction profile with faster and stronger signal amplification. Designed based on common molecular biology principles, these strategies are expected to be customizable and generalizable with various buffer conditions or pathogen types, thus holding broad applicability for integration into future development of one-pot diagnostics in the form of a highly coordinated multi-enzyme reaction system.

Honeycomb Electron Lattice Induced Dirac Fermion with Trigonal Warping in Bilayer Electrides.

Emergent fermions arising from the excess electrons of electrides provide a new perspective for exploring semimetal states with unique Fermi surface geometries. In this study, a class of unique two-dimensional (2D) highly anisotropic Dirac fermions is designed using a sandwich structure. Based on the structural design and first-principles calculations, 2D electride MB (M = Ca/Sr, B = Cl/Br/I) is an ideal candidate material. The excess electrons of the bilayer MB could be stably localized in the interstitial cavities, constructing a natural zigzag honeycomb electron sublattice that further forms a Dirac fermion. Compared with traditional Dirac semimetals, 2D Dirac electrides exhibited rich physical properties: i) The Fermi surface shows trigonal warping in low-energy regions. In particular, the geometry of the Fermi surface determines the high anisotropy of the Fermi velocity. ii) A pair of Dirac fermions are protected by three-fold rotational symmetry and exhibit strong robustness. iii) Electride MB possesses a lower work function that strongly correlates with the surface area of the emission channel. Based on these properties, an electron-emitting device with multifunctional applications is fabricated. Therefore, this study provides an ideal platform for studying potential entanglement between structures, electrides, and topological states.

Delay from Screening to Diagnosis in Autism Spectrum Disorder: Results from a Large National Health Research Network.

To examine delay from developmental screening to autism diagnosis, we used real-world health care data from a national research network to estimate the time between these events. We found an average delay of longer than 2 years from first screening to diagnosis, with no significant differences observed by sex, race, or ethnicity.

High-sensitivity non-cooled near-infrared detector based on lithium niobate surface acoustic wave resonators combined with MXene Ti3C2Tx quantum dot thin films.

In this study, we propose the design of a surface acoustic wave (SAW) near-infrared sensor combined with an MXene quantum dot thin film to improve the infrared absorption efficiency at near-infrared wavelengths. A YZ-cut lithium niobate (LiNbO3) SAW resonator is fabricated as an infrared sensing unit with a resonant frequency shift reflecting the change in infrared radiation. It was observed that the responsivity of the near-infrared sensor (with a base frequency of 460 MHz) increased by approximately 88.89%. Thus, the proposed device exhibits high-performance infrared detection. Owing to the passive wireless capability of the device, it has wide applications.

A Versatile Strategy of Designing Gold Nanoparticle-cDNA Nanoprobes in Developing Aptamer-Based Lateral Flow Assay for Small-Molecule Detection.

Aptamer-based lateral flow assay (Apt-LFA) has shown promising applications for small-molecule detection. However, the design of the AuNP (gold nanoparticle)-cDNA (complementary DNA) nanoprobe is still a big challenge due to the moderate affinity of the aptamer to small molecules. Herein, we report a versatile strategy to design a AuNPs@polyA-cDNA (poly A, a repeat sequence with 15 A bases) nanoprobe for small-molecule Apt-LFA. The AuNPs@polyA-cDNA nanoprobe contains a polyA anchor blocker, complementary DNA segment to DNA on the control line (cDNAc), partial complementary DNA segment with aptamer (cDNAa), and auxiliary hybridization DNA segment (auxDNA). Using adenosine 5'-triphosphate (ATP) as a model target, we optimized the length of auxDNA and cDNAa and achieved a sensitive detection of ATP. In addition, kanamycin was used as a model target to verify the universality of the concept. Therefore, this strategy can be easily extended to other small molecules; therefore, high application potential in Apt-LFAs can be envisaged.