irGSEA: the integration of single-cell rank-based gene set enrichment analysis.

irGSEA is an R package designed to assess the outcomes of various gene set scoring methods when applied to single-cell RNA sequencing data. This package incorporates six distinct scoring methods that rely on the expression ranks of genes, emphasizing relative expression levels over absolute values. The implemented methods include AUCell, UCell, singscore, ssGSEA, JASMINE and Viper. Previous studies have demonstrated the robustness of these methods to variations in dataset size and composition, generating enrichment scores based solely on the relative gene expression of individual cells. By employing the robust rank aggregation algorithm, irGSEA amalgamates results from all six methods to ascertain the statistical significance of target gene sets across diverse scoring methods. The package prioritizes user-friendliness, allowing direct input of expression matrices or seamless interaction with Seurat objects. Furthermore, it facilitates a comprehensive visualization of results. The irGSEA package and its accompanying documentation are accessible on GitHub (https://github.com/chuiqin/irGSEA).

Revealing the reconstruction mechanism of AgPd nanoalloys under fluorination based on a multiscale deep learning potential.

The design of heterogeneous catalysts generally involves optimizing the reactivity descriptor of adsorption energy, which is inevitably governed by the structure of surface-active sites. A prerequisite for understanding the structure-properties relationship is the precise identification of real surface-active site structures, rather than relying on conceived structures derived from bulk alloy properties. However, it remains a formidable challenge due to the dynamic nature of nanoalloys during catalytic reactions and the lack of accurate and efficient interatomic potentials for simulations. Herein, a generalizable deep-learning potential for the Ag-Pd-F system is developed based on a dataset encompassing the bulk, surface, nanocluster, amorphous, and point defected configurations with diverse compositions to achieve a comprehensive description of interatomic interactions, facilitating precise prediction of adsorption energy, surface energy, formation energy, and diffusion energy barrier and is utilized to investigate the structural evolutions of AgPd nanoalloys during fluorination. The structural evolutions involve the inward diffusion of F, the outward diffusion of Ag in Ag@Pd nanoalloys, the formation of surface AgFx species in mixed and Janus AgPd nanoalloys, and the shape deformation from cuboctahedron to sphere in Ag and Pd@Ag nanoalloys. Moreover, the effects of atomic diffusion and dislocation formation and migration on the reconstructing pathway of nanoalloys are highlighted. It is demonstrated that the stress relaxation upon F adsorption serves as the intrinsic driving factor governing the surface reconstruction of AgPd nanoalloys.

Plasmon-driven methanol oxidation on PtAg nanoalloys prepared by improved pulsed laser deposition.

The methanol oxidation reaction (MOR) is crucial in many energy-conversion devices. Although intensive efforts have been devoted to improving the MOR catalytic activity of Pt-based catalysts by treatment or alloying, enhancing the MOR catalyst performance utilizing solar energy has been less investigated. PtAg nanoalloys, combining the intrinsic catalytic activity of Pt toward the MOR with the visible spectrum plasmonic response of Ag, are expected to be a good MOR catalyst for solar energy, however, it remains challenging to incorporate these immiscible elements into a nanoalloy in a controlled way using conventional synthetic techniques. Herein, we proposed a general strategy for alloying silver and platinum elements into single-phase solid-solution nanoparticles with arbitrarily desired composition by bonding pure Pt targets with pure Ag strips in an improved pulsed laser deposition. The as-prepared PtAg nanoalloys show two crystalline phases and an average particle size of about 4 nm. To prove utility, we use the PtAg nanoalloys as support-free MOR catalysts anchored on the surface of a glassy carbon electrode solidly and uniformly. The PtAg nanoalloys exhibit a mass catalytic activity of 3.6 A mg-1, which is 4.5 times higher than that of the commercial Pt/C catalyst. Besides, the PtAg nanoalloys exhibit a promising regenerability after reactivation by cyclic voltammetry. Furthermore, the MOR catalytic activity of PtAg nanoalloys increased by 16% under irradiation by simulated sunlight, which is attributed to the surface plasmon resonance as ascertained from the UV-vis absorption spectra and photocurrent response experiments. These studies are believed to provide a new strategy for the enhancement of MOR catalytic activity with visible light as the driving force.

Structural transformations in single-crystalline AgPd nanoalloys from multiscale deep potential molecular dynamics.

AgPd nanoalloys often undergo structural evolution during catalytic reactions; the mechanism underlying such restructuring remains largely unknown due to the use of oversimplified interatomic potentials in simulations. Herein, a deep-learning potential is developed for AgPd nanoalloys based on a multiscale dataset spanning from nanoclusters to bulk configurations, exhibits precise predictions of mechanical properties and formation energies with near-density functional theory accuracy, calculates the surface energies closer to experimental values compared to those obtained by Gupta potentials, and is applied to investigate the shape reconstruction of single-crystalline AgPd nanoalloys from cuboctahedron (Oh) to icosahedron (Ih) geometries. The Oh to Ih shape restructuring is thermodynamically favorable and occurs at 11 and 92 ps for Pd55@Ag254 and Ag147@Pd162 nanoalloys, respectively. During the shape reconstruction of Pd@Ag nanoalloys, concurrent surface restructuring of the (100) facet and internal multi-twinned phase change are observed with collaborative displacive characters. The presence of vacancies can influence the final product and reconstructing rate of Pd@Ag core-shell nanoalloys. The Ag outward diffusion on Ag@Pd nanoalloys is more pronounced in Ih geometry compared to Oh geometry and can be further accelerated by the Oh to Ih deformation. The deformation of single-crystalline Pd@Ag nanoalloys is characterized by a displacive transformation involving the collaborative displacement of a large number of atoms, distinguishing it from the diffusion-coupled transformation of Ag@Pd nanoalloys.

Expression liabilities in a four-chain bispecific molecule.

Multispecific antibodies, often composed of three to five polypeptide chains, have become increasingly relevant in the development of biotherapeutics. These molecules have mechanisms of action that include redirecting T cells to tumors and blocking multiple pathogenic mediators simultaneously. One of the major challenges for asymmetric multispecific antibodies is generating a high proportion of the correctly paired antibody during production. To understand the causes and effects of chain mispairing impurities in a difficult to express multispecific hetero-IgG, we investigated consequences of individual and pairwise chain expression in mammalian transient expression hosts. We found that one of the two light chains (LC) was not secretion competent when transfected individually or cotransfected with the noncognate heavy chain (HC). Overexpression of this secretion impaired LC reduced cell growth while inducing endoplasmic reticulum stress and CCAAT/enhancer-binding protein homologous protein (CHOP) expression. The majority of this LC was observed as monomer with incomplete intrachain disulfide bonds when expressed individually. Russell bodies (RB) were induced when this LC was co-expressed with the cognate HC. Moreover, one HC paired promiscuously with noncognate LC. These results identify the causes for the low product quality observed from stable cell lines expressing this heteroIgG and suggest mitigation strategies to improve overall process productivity of the correctly paired multispecific antibody. The approach described here provides a general strategy for identifying the molecular and cellular liabilities associated with difficult to express multispecific antibodies.

Catalytic activity of palladium-doped silver dilute nanoalloys for formate oxidation from a theoretical perspective.

The large-scale practical application of formate oxidation reaction (FOR) catalysts is hindered by their low activity and high cost. Herein, for the first time, a series of Pd-doped Ag dilute nanoalloys is demonstrated to have high catalytic activity in FOR with reduced consumption of Pd metals through density functional theory calculations, where the effects of potential, solvent and spin on catalytic performance are discussed. The Pd1Ag(111) single-atom alloy (SAA) exhibits higher FOR catalytic activity as reflected by the low limiting potential of 0.026 eV for the direct association path and a value of 0.084 eV for the direct dissociation path, and the lowest activation energy of 0.774 eV for the rate-determining-step in the direct dissociation path compared with Pd2Ag(111) and Pd3Ag(111) dilute alloys. Pd1Ag(111) SAA exhibits an extremely narrow sharp peak in the partial density of states from -0.75 to -2.0 eV, which is due to the free-atom-like electronic structure of the single Pd atom. The isolated Pd single atom is more stable by -0.041 and -0.097 eV, respectively, than the aggregated Pd2 and Pd3 atom clusters on the Ag(111) surface, which verifies the potential application of Pd1Ag(111) SAA in experiments. Overall, this work further elucidates the theoretical profile of FOR and provides a new strategy for designing the catalytic reaction at the atomic level.

Tracking and transforming neocortical progenitors by CRISPR/Cas9 gene targeting and piggyBac transposase lineage labeling.

The ability to induce targeted mutations in somatic cells in developing organisms and then track the fates of those cells is a powerful approach both for studying neural development and for modeling human disease. The CRISPR/Cas9 system allows for such targeted mutagenesis, and we therefore tested it in combination with a piggyBac transposase lineage labeling system to track the development of neocortical neural progenitors with targeted mutations in genes linked to neurodevelopmental disruptions and tumor formation. We show that sgRNAs designed to target PTEN successfully decreased PTEN expression, and led to neuronal hypertrophy and altered neuronal excitability. Targeting NF1, by contrast, caused increased astrocytogenesis at the expense of neurogenesis, and combined targeting of three tumor suppressors (PTEN, NF1 and P53) resulted in formation of glioblastoma tumors. Our results demonstrate that CRISPR/Cas9 combined with piggyBac transposase lineage labeling can produce unique models of neurodevelopmental disruption and tumors caused by somatic mutation in neural progenitors.

Knockdown of Dyslexia-Gene Dcdc2 Interferes with Speech Sound Discrimination in Continuous Streams.

UNLABELLED: Dyslexia is the most common developmental language disorder and is marked by deficits in reading and phonological awareness. One theory of dyslexia suggests that the phonological awareness deficit is due to abnormal auditory processing of speech sounds. Variants in DCDC2 and several other neural migration genes are associated with dyslexia and may contribute to auditory processing deficits. In the current study, we tested the hypothesis that RNAi suppression of Dcdc2 in rats causes abnormal cortical responses to sound and impaired speech sound discrimination. In the current study, rats were subjected in utero to RNA interference targeting of the gene Dcdc2 or a scrambled sequence. Primary auditory cortex (A1) responses were acquired from 11 rats (5 with Dcdc2 RNAi; DC-) before any behavioral training. A separate group of 8 rats (3 DC-) were trained on a variety of speech sound discrimination tasks, and auditory cortex responses were acquired following training. Dcdc2 RNAi nearly eliminated the ability of rats to identify specific speech sounds from a continuous train of speech sounds but did not impair performance during discrimination of isolated speech sounds. The neural responses to speech sounds in A1 were not degraded as a function of presentation rate before training. These results suggest that A1 is not directly involved in the impaired speech discrimination caused by Dcdc2 RNAi. This result contrasts earlier results using Kiaa0319 RNAi and suggests that different dyslexia genes may cause different deficits in the speech processing circuitry, which may explain differential responses to therapy. SIGNIFICANCE STATEMENT: Although dyslexia is diagnosed through reading difficulty, there is a great deal of variation in the phenotypes of these individuals. The underlying neural and genetic mechanisms causing these differences are still widely debated. In the current study, we demonstrate that suppression of a candidate-dyslexia gene causes deficits on tasks of rapid stimulus processing. These animals also exhibited abnormal neural plasticity after training, which may be a mechanism for why some children with dyslexia do not respond to intervention. These results are in stark contrast to our previous work with a different candidate gene, which caused a different set of deficits. Our results shed some light on possible neural and genetic mechanisms causing heterogeneity in the dyslexic population.

Engineering Bimetallic Ag-Cu Nanoalloys for Highly Efficient Oxygen Reduction Catalysts: A Guideline for Designing Ag-Based Electrocatalysts with Activity Comparable to Pt/C-20.

Development of highly active and stable Pt-free oxygen reduction reaction catalysts from earth-abundant elements remains a grand challenge for highly demanded metal-air batteries. Ag-based alloys have many advantages over platinum group catalysts due to their low cost, high stability, and acceptable oxygen reduction reaction (ORR) performance in alkaline solutions. Nevertheless, compared to commercial Pt/C-20%, their catalytic activity still cannot meet the demand of commercialization. In this study, a kind of catalysts screening strategy on Agx Cu100-x nanoalloys is reported, containing the surface modification method, studies of activity enhancement mechanism, and applied research on zinc-air batteries. The results exhibit that the role of selective dealloying (DE) or galvanic displacement (GD) is limited by the "parting limitation", and this "parting limitation" determines the surface topography, position of d-band center, and ORR performance of Agx Cu100-x alloys. The GD-Ag55 Cu45 and DE-Ag25 Cu75 catalysts alloys present excellent ORR performance that is comparable to Pt/C-20%. The relationship between electronic perturbation and specific activity demonstrates that positive shift of the d-band center (≈0.12 eV, relative to Ag) for GD-Ag55 Cu45 is beneficial for ORR, which is contrary to Pt-based alloys (negative shift, ≈0.1 eV). Meanwhile, extensive electrochemical and electronic structure characterization indicates that the high work function of GD-Ag55 Cu45 (4.8 eV) is the reason behind their excellent durability for zinc-air batteries.

Activity Trends of Binary Silver Alloy Nanocatalysts for Oxygen Reduction Reaction in Alkaline Media.

The electrocatalytic activity of Pt-based alloys exhibits a strong dependence on their electronic structures, but a relationship between electronic structure and oxygen reduction reaction (ORR) activity in Ag-based alloys is still not clear. Here, a vapor deposition based approach is reported for the preparation of Ag75 M25 (M = Cu, Co, Fe, and In) and Agx Cu100-x (x = 0, 25, 45, 50, 55, 75, 90, and 100) nanocatalysts and their electronic structures are determined by valence band spectra. The relationship of the d-band center and ORR activity exhibits volcano-shape behaviors, where the maximum catalytic activity is obtained for Ag75 Cu25 alloys. The ORR enhancement of Ag75 Cu25 alloys originates from the 0.12 eV upshift in d-band center relative to pure Ag, which is different from the downshift in the d-band center in Pt-based alloys. The activity trend for these Ag75 M25 alloys is in the order of Ag75 Cu25 > Ag75 Fe25 > Ag75 Co25 . These results provide an insight to understand the activity and stability enhancement of Ag75 Cu25 and Ag50 Cu50 catalysts by alloying.

Evaluation of the boson chemiluminescence immunoassay as a first-line screening test in the ECDC algorithm for syphilis serodiagnosis in a population with a high prevalence of syphilis.

We developed a new Boson chemiluminescence immunoassay (CIA) and evaluated its application with cross-sectional analyses. Our results indicated that the Boson CIA demonstrated strong discriminatory power in diagnosing syphilis and that it can be used as a first-line screening test for syphilis serodiagnosis using the European Centre for Disease Prevention and Control algorithm or as a confirmatory test when combined with a patient's clinical history.

Fate mapping by piggyBac transposase reveals that neocortical GLAST+ progenitors generate more astrocytes than Nestin+ progenitors in rat neocortex.

Progenitors within the neocortical ventricular zone (VZ) first generate pyramidal neurons and then astrocytes. We applied novel piggyBac transposase lineage tracking methods to fate-map progenitor populations positive for Nestin or glutamate and aspartate transpoter (GLAST) promoter activities in the rat neocortex. GLAST+ and Nestin+ progenitors at embryonic day 13 (E13) produce lineages containing similar rations of neurons and astrocytes. By E15, the GLAST+ progenitor population diverges significantly to produce lineages with 5-10-fold more astrocytes relative to neurons than generated by the Nestin+ population. To determine when birth-dated progeny within GLAST+ and Nestin+ populations diverge, we used a Cre/loxP fate-mapping system in which plasmids are lost after a cell division. By E18, birth-dated progeny of GLAST+ progenitors give rise to 2-3-fold more neocortical astrocytes than do Nestin+ progenitors. Finally, we used a multicolor clonal labeling method to show that the GLAST+ population labeled at E15 generates astrocyte progenitors that produce larger, spatially restricted, clonal clusters than the Nestin+ population. This study provides in vivo evidence that by mid-corticogenesis (E15), VZ progenitor populations have significantly diversified in terms of their potential to generate astrocytes and neurons.

Analysis of 3 algorithms for syphilis serodiagnosis and implications for clinical management.

BACKGROUND: Algorithms for the diagnosis of syphilis continue to be a source of great controversy, and numerous test interpretations have perplexed many clinicians. METHODS: We conducted a cross-sectional study of 24 124 subjects to analyze 3 syphilis testing algorithms: traditional algorithm, reverse algorithm, and the European Centre for Disease Prevention and Control (ECDC) algorithm. Every serum sample was simultaneously evaluated using the rapid plasma reagin, Treponema pallidum particle agglutination, and chemiluminescence immunoassay tests. With the results of clinical diagnoses of syphilis as a gold standard, we evaluated the diagnostic accuracy of the 3 syphilis testing algorithms. The κ coefficient was used to compare the concordance between the reverse algorithm and the ECDC algorithm. RESULTS: Overall, 2749 patients in our cohort were diagnosed with syphilis. The traditional algorithm had the highest negative likelihood ratio (0.24), a missed diagnosis rate of 24.2%, and only 75.81% sensitivity. However, both the reverse and ECDC algorithms had higher diagnostic efficacy than the traditional algorithm. Their sensitivity, specificity, and accuracy were 99.38%-99.85%, 99.98%-100.00%, and 99.93%-99.96%, respectively. Moreover, the overall percentage of agreement and κ value between the reverse and the ECDC algorithms were 99.9% and 0.996, respectively. CONCLUSIONS: Our research supported use of the ECDC algorithm, in which syphilis screening begins with a treponemal immunoassay that is followed by a second, different treponemal assay as a confirmatory test in high-prevalence populations. In addition, our results indicated that nontreponemal assay is unnecessary for syphilis diagnosis but can be recommended for determining serological activity and the effect of syphilis treatment.

Incidence and risk factors for the prozone phenomenon in serologic testing for syphilis in a large cohort.

BACKGROUND: The prozone phenomenon is known to be associated with high antibody titers; other associations, such as host factors, have not been elucidated. METHODS: A retrospective analysis was conducted to evaluate the incidence of the prozone phenomenon of the syphilis rapid plasma reagin (RPR) test among 46 856 clinical samples, between June 2010 and June 2013. Logistic regression was used to analyze the risk factors of the prozone phenomenon. RESULTS: Our results showed that the incidence of the prozone phenomenon was low (0.83%) and could occur during any clinical phase, particularly during primary and secondary syphilis. Pregnancy and neurosyphilis were associated with the prozone phenomenon; sex, age, and whether the patient had been treated were not. The results also revealed that the prozone phenomenon not only occurred in patients with a high titer but also could occur in patients with a moderate/low titer. In fact, almost 31% of the patients with the prozone phenomenon had titers ≤1:16. CONCLUSIONS: The prozone phenomenon in the RPR test was associated with the phase of syphilis, pregnancy, and neurosyphilis as well as a range of RPR titers between 1:8 and 1:512. This latter finding is in contrast to previous reports that the prozone phenomenon is associated with very high RPR titers.

Atomic mechanism of predictable phase transition in dual-phase H2 Ti3 O7 /TiO2 (B) nanofiber: an in situ heating TEM investigation.

The phase transition from H(2)Ti(3)O(7) to TiO(2) (B) in a 1D single nanocrystal of H(2)Ti(3)O(7) was observed by in situ heating in a transmission electron microscope experimentally. The results indicate a typical monoclinic-to-monoclinic crystallographic orientation relationship between the two phases. Moreover, the fundamental building blocks and invariant deformation element model were both adopted to reveal the atomic mechanism and predict the crystallographic orientation relationship quantitatively for the phase transition. The prediction was precisely consistent with TEM results.

Neuropsychiatric disorders secondary to neurosyphilis in elderly people: one theme not to be ignored.

BACKGROUND: Neurosyphilis (NS) may present with neuropsychiatric disorders characterized by cognitive impairment, personality disorders, and confusion, among others. Very few studies have focused on neuropsychiatric disorders secondary to NS in elderly people. METHOD: A retrospective chart review was performed to characterize the psychiatric findings, clinical signs and symptoms, laboratory findings, and brain magnetic resonance imaging results of ten elderly inpatients with NS. RESULTS: In these ten patients, the most common presenting symptoms included a wide variety of psychiatric manifestations. The serum rapid plasma regain (RPR) and Treponema pallidum particle agglutination assay (TPPA) of the ten patients were positive, with positive CSF TPPA and RPR rates of 100% and 60%, respectively. In addition, 90% of the patients demonstrated abnormal imaging, including cerebral atrophy, infarct ischemic stroke, and hydrocephalus. CONCLUSIONS: Our findings support the importance of serological tests for syphilis as a routine component of the evaluation of patients with clinically evident neurological or psychiatric symptoms. If the serology is positive, all of the patients should be examined with a lumbar puncture. Moreover, psychiatric illnesses secondary to NS in the elderly also deserve medical attention.