Au nanoparticles (NPs) with protecting organothiolate ligands and core diameters smaller than 2 nm are interesting materials because their size-dependent properties range from metal-like to ...molecule-like. This Account focuses on the most thoroughly investigated of these NPs, Au25L18. Future advances in nanocluster catalysis and electronic miniaturization and biological applications such as drug delivery will depend on a thorough understanding of nanoscale materials in which molecule-like characteristics appear. This Account tells the story of Au25L18 and its associated synthetic, structural, mass spectrometric, electron transfer, optical spectroscopy, and magnetic resonance results. We also reference other Au NP studies to introduce helpful synthetic and measurement tools. Historically, nanoparticle sizes have been described by their diameters. Recently, researchers have reported actual molecular formulas for very small NPs, which is chemically preferable to solely reporting their size. Au25L18 is a success story in this regard; however, researchers initially mislabeled this NP as Au28L16 and as Au38L24 before correctly identifying it by electrospray-ionization mass spectrometry. Because of its small size, this NP is amenable to theoretical investigations. In addition, Au25L18’s accessibility in pure form and molecule-like properties make it an attractive research target. The properties of this NP include a large energy gap readily seen in cyclic voltammetry (related to its HOMO−LUMO gap), a UV−vis absorbance spectrum with step-like fine structure, and NIR fluorescence emission. A single crystal structure and theoretical analysis have served as important steps in understanding the chemistry of Au25L18. Researchers have determined the single crystal structure of both its “native” as-prepared form, a N((CH2)7CH3)4 1+Au25(SCH2CH2Ph)18 1− salt, and of the neutral, oxidized form Au25(SCH2CH2Ph)18 0. A density functional theory (DFT) analysis correctly predicted essential elements of the structure. The NP is composed of a centered icosahedral Au13 core stabilized by six Au2(SR)3 semirings. These semirings present interesting implications regarding other small Au nanoparticle clusters. Many properties of the Au25 NP result from these semiring structures. This overview of the identification, structure determination, and analytical properties of perhaps the best understood Au nanoparticle provides results that should be useful for further analyses and applications. We also hope that the story of this nanoparticle will be useful to those who teach about nanoparticle science.
Summary Background Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and ...pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging–Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. Findings On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β −4·0, 95% CI −5·5 to −2·6; p<0·0001; R2 0·22, p<0·0001) and with survival (–2·0, −3·2 to −0·8; 0·003; 0·15, <0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology. Funding US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).
The structure and dynamics of bacterial communities in the airways of persons with cystic fibrosis (CF) remain largely unknown. We characterized the bacterial communities in 126 sputum samples ...representing serial collections spanning 8–9 y from six age-matched male CF patients. Sputum DNA was analyzed by bar-coded pyrosequencing of the V3–V5 hypervariable region of the 16S rRNA gene, defining 662 operational taxonomic units (OTUs) from >633,000 sequences. Bacterial community diversity decreased significantly over time in patients with typically progressive lung disease but remained relatively stable in patients with a mild lung disease phenotype. Antibiotic use, rather than patient age or lung function, was the primary driver of decreasing diversity. Interpatient variability in community structure exceeded intrapatient variability in serial samples. Antibiotic treatment was associated with pronounced shifts in community structure, but communities showed both short- and long-term resilience after antibiotic perturbation. There was a positive correlation between OTU occurrence and relative abundance, with a small number of persistent OTUs accounting for the greatest abundance. Significant changes in community structure, diversity, or total bacterial density at the time of pulmonary exacerbation were not observed. Despite decreasing community diversity in patients with progressive disease, total bacterial density remained relatively stable over time. These findings show the critical relationship between airway bacterial community structure, disease stage, and clinical state at the time of sample collection. These features are the key parameters with which to assess the complex ecology of the CF airway.
Many image segmentation algorithms first generate an affinity graph and then partition it. We present a machine learning approach to computing an affinity graph using a convolutional network (CN) ...trained using ground truth provided by human experts. The CN affinity graph can be paired with any standard partitioning algorithm and improves segmentation accuracy significantly compared to standard hand-designed affinity functions.
We apply our algorithm to the challenging 3D segmentation problem of reconstructing neuronal processes from volumetric electron microscopy (EM) and show that we are able to learn a good affinity graph directly from the raw EM images. Further, we show that our affinity graph improves the segmentation accuracy of both simple and sophisticated graph partitioning algorithms.
In contrast to previous work, we do not rely on prior knowledge in the form of hand-designed image features or image preprocessing. Thus, we expect our algorithm to generalize effectively to arbitrary image types.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
New approaches to electrospray ionization mass spectrometry (ESI-MS)with exact compositional assignmentsof small (Au25) nanoparticles with uniform and mixed protecting organothiolate monolayers are ...described. The results expand the scope of analysis and reveal a rich chemistry of ionization behavior. ESI-MS of solutions of phenylethanethiolate monolayer-protected gold clusters (MPCs), Au25(SC2Ph)18, containing alkali metal acetate salts (MOAc) produce spectra in which, for Na+, K+, Rb+, and Cs+ acetates, the dominant species are MAu25(SC2Ph)18 2+ and M2Au25(SC2Ph)18 2+. Li+ acetates caused ligand loss. This method was extended to the analysis of Au25 MPCs with mixed monolayers, where thiophenolate (−SPh), hexanethiolate (−SC6), or biotinylated (−S−PEG−biotin) ligands had been introduced by ligand exchange. In negative-mode ESI-MS, no added reagents were needed in order to observe Au25(SC2Ph)18 - and to analyze mixed monolayer Au25 MPCs prepared by ligand exchange with 4-mercaptobenzoic acid, HSPhCOOH, which gave spectra through deprotonation of the carboxylic acids. Adducts of tetraoctylammonium (Oct4N+) with −SPhCOO- sites were also observed. Mass spectrometry is the only method that has demonstrated capacity for measuring the exact distribution of ligand-exchange products. The possible origins of the different Au25 core charges (1−, 0, 1+, 2+) observed during electrospray ionization are discussed.
The introduction of plasmids into Agrobacterium cells is one of the key steps in the Agrobacterium-mediated transformation of plants for gene editing applications. Depending on chromosomal ...background, some Agrobacterium strains exhibit a very low transformation efficiency, which results in a low number of colonies for subsequent screening and thus limits the potential for automated high-throughput transformation processes, especially with low copy or large plasmids. This study demonstrates improvements of transformation frequency by modifying the competent cell preparation process and optimizing electroporation parameters for two Agrobacterium strains. The competent cell preparation process was modified by prolonging bacterial growth in the log phase and optimizing the endpoint cell density for cell harvest which resulted in a significant cell yield increase and transformation frequency improvement. Optimization of electroporation by fine-tuning the parameters not only resulted in a 30-fold transformation frequency increase but also revealed a strain-dependent requirement for field strength and electric pulse length. To further improve transformation of a recalcitrant strain, different concentrations of dimethyl sulfoxide (DMSO) in recovery medium were examined. The study revealed an important role of DMSO in transformed cell recovery, with 5% DMSO resulting in the highest transformation frequency. The significant improvements in Agrobacterium transformation frequency addressed a critical bottleneck towards establishing a high throughput process.
Algorithms for data-driven learning of domain-specific overcomplete dictionaries are developed to obtain maximum likelihood and maximum a posteriori dictionary estimates based on the use of Bayesian ...models with concave/Schur-concave (CSC) negative log priors. Such priors are appropriate for obtaining sparse representations of environmental signals within an appropriately chosen (environmentally matched) dictionary. The elements of the dictionary can be interpreted as concepts, features, or words capable of succinct expression of events encountered in the environment (the source of the measured signals). This is a generalization of vector quantization in that one is interested in a description involving a few dictionary entries (the proverbial “25 words or less”), but not necessarily as succinct as one entry. To learn an environmentally adapted dictionary capable of concise expression of signals generated by the environment, we develop algorithms that iterate between a representative set of sparse representations found by variants of FOCUSS and an update of the dictionary using these sparse representations.
Experiments were performed using synthetic data and natural images. For complete dictionaries, we demonstrate that our algorithms have improved performance over other independent component analysis (ICA) methods, measured in terms of signal-to-noise ratios of separated sources. In the overcomplete case, we show that the true underlying dictionary and sparse sources can be accurately recovered. In tests with natural images, learned overcomplete dictionaries are shown to have higher coding efficiency than complete dictionaries; that is, images encoded with an overcomplete dictionary have both higher compression (fewer bits per pixel) and higher accuracy (lower mean square error).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Excited-state relaxation dynamics of a gold cluster, the anion Au25(SCH2CH2Ph)18 −, with a known crystal structure are measured with femtosecond laser spectroscopies. The cluster consists of an ...icosahedral Au13 core bonded to six Au2(SCH2CH2Ph)3 semirings. Pump−probe experiments excite Au13 core electronic transitions and then monitor relaxation of the system as it reaches quasi-equilibrium in lower-energy fluorescing state(s) localized on the semiring moieties. The measurements show that an extremely rapid (<200 fs) internal conversion process takes place within the multilevel electronic structure of the Au13 core, whereas core to semiring relaxation requires 1.2 ps. Photoinduced optical anisotropy persists for up to 1 ps after excitation of the lowest-energy Au13 core-localized transition, which, as suggested by the “superatom” model, distinguishes the optical response from that of a system with spherical symmetry (i.e., jellium sphere). Detection of an 80 cm−1 vibration localized to the Au13 core reflects the strong vibronic coupling of a delocalized Au−Au bond-stretching vibration analogous to the radial breathing modes of larger Au nanoparticles. Overall, the results give strong support to the superatom model for electronic structure of the cluster. Observation of the 80 cm−1 vibration highlights the contrast in mechanical properties between small clusters and larger nanoparticles.
Lesion studies in macaques suggest dissociable functions of the orbitofrontal cortex (OFC) and medial frontal cortex (MFC), with OFC being essential for goal-directed decision-making and MFC ...supporting social cognition. Bilateral amygdala damage results in impairments in both of these domains. There are extensive reciprocal connections between these prefrontal areas and the amygdala; however, it is not known whether the dissociable roles of OFC and MFC depend on functional interactions with the amygdala. To test this possibility, we compared the performance of male rhesus macaques (
) with crossed surgical disconnection of the amygdala and either MFC (MFC × AMY,
= 4) or OFC (OFC × AMY,
= 4) to a group of unoperated controls (CON,
= 5). All monkeys were assessed for their performance on two tasks to measure the following: (1) food-retrieval latencies while viewing videos of social and nonsocial stimuli in a test of social interest and (2) object choices based on current food value using reinforcer devaluation in a test of goal-directed decision-making. Compared with the CON group, the MFC × AMY group, but not the OFC × AMY group, showed significantly reduced food-retrieval latencies while viewing videos of conspecifics, indicating reduced social valuation and/or interest. By contrast, on the devaluation task, group OFC × AMY, but not group MFC × AMY, displayed deficits on object choices following changes in food value. These data indicate that the MFC and OFC must functionally interact with the amygdala to support normative social and nonsocial valuation, respectively.
Ascribing value to conspecifics (social) versus objects (nonsocial) may be supported by distinct but overlapping brain networks. Here, we test whether two nonoverlapping regions of the prefrontal cortex, the medial frontal cortex and the orbitofrontal cortex, must causally interact with the amygdala to sustain social valuation and goal-directed decision-making, respectively. We found that these prefrontal-amygdala circuits are functionally dissociable, lending support for the idea that medial frontal and orbital frontal cortex make independent contributions to cognitive appraisals of the environment. These data provide a neural framework for distinct value assignment processes and may enhance our understanding of the cognitive deficits observed following brain injury or in the development of mental health disorders.
In persons with cystic fibrosis (CF), repeated exacerbations of pulmonary symptoms are associated with a progressive decline in lung function. Changes in the airway microbiota around the time of ...exacerbations are not well understood.
To characterize changes in airway bacterial communities around the time of exacerbations and to identify predictors for these changes.
DNA prepared from 68 paired baseline and exacerbation sputum samples collected from 28 patients with CF were subjected to barcoded 16S rRNA gene pyrosequencing. Bacterial density was calculated by quantitative PCR.
Overall, significant differences in bacterial community diversity and bacterial density between baseline and exacerbation samples were not observed. However, considerable changes in community structures were observed in a subset of patients. In these patients, the dominant taxa and initial level of community diversity were significant predictors of the magnitude of community structure changes at exacerbation. Pseudomonas-dominant communities became more diverse at exacerbation compared with communities with other or no dominant species. The relative abundance of Gemella increased in 24 (83%) of 29 samples at exacerbation and was found to be the most discriminative genus between baseline and exacerbation samples.
The magnitude of changes in the CF lung microbiota around the time of exacerbation was found to be largely dependent on community diversity and composition at baseline. Certain genera appear to play important roles in driving change in airway bacterial community composition at exacerbation. Gemella might play a direct role in and/or be a biomarker for pulmonary exacerbation.
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