Development of phase-cycling interface-specific two-dimensional electronic sum frequency generation (2D-ESFG) spectroscopy.

Two-dimensional electronic spectroscopy (2D-ES) has become an important technique for studying energy transfer, electronic coupling, and electronic-vibrational coherence in the past ten years. However, since 2D-ES is not interface specific, the electronic information at surfaces and interfaces could not be demonstrated clearly. Two-dimensional electronic sum-frequency generation (2D-ESFG) is an emerging spectroscopic technique that explores the correlations between different interfacial electronic transitions and is the extension of 2D-ES to surface and interfacial specificity. In this work, we present the detailed development and implementation of phase-cycling 2D-ESFG spectroscopy using an acousto-optic pulse shaper in a pump-probe geometry. With the pulse pair generated by a pulse shaper rather than optical devices based on birefringence or interference, this 2D-ESFG setup enables rapid scanning, phase cycling, and the separation of rephasing and nonrephasing signals. In addition, by collecting data in a rotating frame, we greatly improve experimental efficiency. We demonstrate the method for azo-derivative molecules at the air/water interface. This method could be readily extended to different interfaces and surfaces. The unique phase-cycling 2D-ESFG technique enables one to quantify the energy transfer, charge transfer, electronic coupling, and many other electronic properties and dynamics at surfaces and interfaces with precision and relative ease of use. Our goal in this article is to present the fine details of the fourth-order nonlinear optical technique in a manner that is comprehensive, succinct, and approachable such that other researchers can implement, improve, and adapt it to probe unique and innovative problems to advance the field.

Health literacy, but not memory, is associated with hippocampal connectivity in adults with low levels of formal education.

INTRODUCTION: The influence of hippocampal connectivity on memory performance is well established in individuals with high educational attainment. However, the role of hippocampal connectivity in illiterate populations remains poorly understood. METHODS: Thirty-five illiterate adults were administered a literacy assessment (Test of Functional Health Literacy in Adults [TOFHLA]), structural and resting state functional magnetic resonance imaging, and an episodic memory test (Free and Cued Selective Reminding Test). Illiteracy was defined as a TOFHLA score < 53. We evaluated the correlation between hippocampal connectivity at rest and both free recall and literacy scores. RESULTS: Participants were mostly female (57.1%) and self-declared as being Black individuals (84.8%), with a median age of 50 years. The median TOFHLA literacy score was 28.0 [21.0; 42.5] out of 100 points and the median free recall score was 30.0 [26.2; 35] out of 48 points. The median gray matter volume of both the left and right hippocampi was 2.3 [2.1; 2.4] cm3. We observed a significant connectivity between both hippocampi and the precuneus and the ventral medial prefrontal cortex. The right hippocampal connectivity positively correlated with the literacy scores (ß = 0.58, P = 0.008). There was no significant association between episodic memory and hippocampal connectivity. Neither memory nor literacy scores correlated with hippocampal gray matter volume. DISCUSSION: Low literacy levels correlated with hippocampal connectivity in illiterate adults. The lack of association with memory scores might be associated with low brain reserve in this sample. Highlights: A significant link was found between health literacy and hippocampal connectivity.Enhanced hippocampus- ventromedial prefrontal cortex connectivity suggests potential cognitive reserve improvement.Higher cognitive reserve may protect against hippocampal atrophy and neurodegeneration.Health literacy improvements could help prevent cognitive impairment in illiterate populations.Study highlights importance of considering structural racism in brain connectivity research.

Quantitative Signal Analysis of Sum-Frequency Scattering Experiments from Aerosol Surfaces.

Droplet interfaces are instrumental in processes of biology, engineering, production, and environmental systems. The chemical and physical properties of heterogeneous interfaces are known to be different from those of their underlying bulk phases, and different again when considering the curved surface of submicron aerosol droplets. The recently developed technique of vibrational sum-frequency scattering (VSFS) spectroscopy from airborne particles has emerged as an interface-specific method for the in situ analysis of this unique system. While the technique has shown promise in debut works, a quantitative analysis of the VSFS system has not yet been performed. Here we provide a comprehensive analysis of a VSFS spectrometer with reference to the well-documented planar analog. We decompose the VSFS signal into coherent and incoherent as well as resonant and nonresonant components as a function of incident pulse delay time. We then quantify and compare resonant and nonresonant VSFS and VSFG experimental data using the same laser and detection systems. Using the air/water interface as a guide, we show that the resonant and nonresonant contributions to the SF responses are comparable for the two systems by extracting second-order susceptibilities and hyperpolarizabilities, and using them to estimate single-particle susceptibilities. A quantitative analysis of the signal detection systems for the scattering and planar geometries is made, and conversion efficiencies for VSFG, VSFS, and other nonlinear scattering experiments are compared. Lastly, the possibility of a low-repetition (1 kHz) VSFS spectrometer is considered, determining that it may be possible with modern laser technology but is inevitably less efficient than a high-repetition (100 kHz) system. Though this multistep analysis we obtain a better understanding of the components of the VSFS signal from aerosol particles, further validate the feasibility of the experiments, and provide insight to those wishing to conduct similar experiments and how they may be improved.

Conical Intersections at Interfaces Revealed by Phase-Cycling Interface-Specific Two-Dimensional Electronic Spectroscopy (i2D-ES).

Conical intersections (CIs) hold significant stake in manipulating and controlling photochemical reaction pathways of molecules at interfaces and surfaces by affecting molecular dynamics therein. Currently, there is no tool for characterizing CIs at interfaces and surfaces. To this end, we have developed phase-cycling interface-specific two-dimensional electronic spectroscopy (i2D-ES) and combined it with advanced computational modeling to explore nonadiabatic CI dynamics of molecules at the air/water interface. Specifically, we integrated the phase locked pump pulse pair with an interface-specific electronic probe to obtain the two-dimensional interface-specific responses. We demonstrate that the nonadiabatic transitions of an interface-active azo dye molecule that occur through the CIs at the interface have different kinetic pathways from those in the bulk water. Upon photoexcitation, two CIs are present: one from an intersection of an optically active S2 state with a dark S1 state and the other from the intersection of the progressed S1 with the ground state S0. We find that the molecular conformations in the ground state are different for interfacial molecules. The interfacial molecules are intimately correlated with the locally populated excited state S2 being farther away from the CI region. This leads to slower nonadiabatic dynamics at the interface than in bulk water. Moreover, we show that the nonadiabatic transition from the S1 dark state to the ground state is significantly longer at the interface than that in the bulk, which is likely due to the orientationally restricted configuration of the excited state at the interface. Our findings suggest that orientational configurations of molecules manipulate reaction pathways at interfaces and surfaces.

Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes.

Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds.

Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.

Functional network collapse in neurodegenerative disease.

Cognitive and behavioral deficits in Alzheimer's disease (AD) and frontotemporal dementia (FTD) result from brain atrophy and altered functional connectivity. However, it is unclear how atrophy relates to functional connectivity disruptions across dementia subtypes and stages. We addressed this question using structural and functional MRI from 221 patients with AD (n=82), behavioral variant FTD (n=41), corticobasal syndrome (n=27), nonfluent (n=34) and semantic (n=37) variant primary progressive aphasia, and 100 cognitively normal individuals. Using partial least squares regression, we identified three principal structure-function components. The first component showed overall atrophy correlating with primary cortical hypo-connectivity and subcortical/association cortical hyper-connectivity. Components two and three linked focal syndrome-specific atrophy to peri-lesional hypo-connectivity and distal hyper-connectivity. Structural and functional component scores predicted global and domain-specific cognitive deficits. Anatomically, functional connectivity changes reflected alterations in specific brain activity gradients. Eigenmode analysis identified temporal phase and amplitude collapse as an explanation for atrophy-driven functional connectivity changes.

FTLD targets brain regions expressing recently evolved genes.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation is associated with a decline in human-specialized social-emotional and language functions. Most disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD targets brain regions that express genes containing human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and normative human regional transcriptomic data to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions expressing recently evolved genes. In addition, we asked whether genes expressed in FTLD-targeted brain regions are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions that express overlapping and distinct genes, including many linked to neuromodulatory functions. Genes whose normative brain regional expression pattern correlated with FTLD cortical atrophy were strongly associated with HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes.

Connectome-based modelling of neurodegenerative diseases: towards precision medicine and mechanistic insight.

Neurodegenerative diseases are the most common cause of dementia. Although their underlying molecular pathologies have been identified, there is substantial heterogeneity in the patterns of progressive brain alterations across and within these diseases. Recent advances in neuroimaging methods have revealed that pathological proteins accumulate along specific macroscale brain networks, implicating the network architecture of the brain in the system-level pathophysiology of neurodegenerative diseases. However, the extent to which 'network-based neurodegeneration' applies across the wide range of neurodegenerative disorders remains unclear. Here, we discuss the state-of-the-art of neuroimaging-based connectomics for the mapping and prediction of neurodegenerative processes. We review findings supporting brain networks as passive conduits through which pathological proteins spread. As an alternative view, we also discuss complementary work suggesting that network alterations actively modulate the spreading of pathological proteins between connected brain regions. We conclude this Perspective by proposing an integrative framework in which connectome-based models can be advanced along three dimensions of innovation: incorporating parameters that modulate propagation behaviour on the basis of measurable biological features; building patient-tailored models that use individual-level information and allowing model parameters to interact dynamically over time. We discuss promises and pitfalls of these strategies for improving disease insights and moving towards precision medicine.

In Situ Probing of the Surface Properties of Droplets in the Air.

Surface properties of nanodroplets and microdroplets are intertwined with their immense applicability in biology, medicine, production, catalysis, the environment, and the atmosphere. However, many means for analyzing droplets and their surfaces are destructive, non-interface-specific, not conducted under ambient conditions, require sample substrates, conducted ex situ, or a combination thereof. For these reasons, a technique for surface-selective in situ analyses under any condition is necessary. This feature article presents recent developments in second-order nonlinear optical scattering techniques for the in situ interfacial analysis of aerosol droplets in the air. First, we describe the abundant utilization of such droplets across industries and how their unique surface properties lead to their ubiquitous usage. Then, we describe the fundamental properties of droplets and their surfaces followed by common methods for their study. We next describe the fundamental principles of sum-frequency generation (SFG) spectroscopy, the Langmuir adsorption model, and how they are used together to describe adsorption processes at planar liquid and droplet surfaces. We also discuss the history of developments of second-order scattering from droplets suspended in dispersive media and introduce second-harmonic scattering (SHS) and sum-frequency scattering (SFS) spectroscopies. We then go on to outline the developments of SHS, electronic sum-frequency scattering (ESFS), and vibrational sum-frequency scattering (VSFS) from droplets in the air and discuss the fundamental insights about droplet surfaces that the techniques have provided. Finally, we describe some of the areas of nonlinear scattering from airborne droplets which need improvement as well as potential future directions and utilizations of SHS, ESFS, and VSFS throughout environmental systems, interfacial chemistry, and fundamental physics. The goal of this feature article is to spread knowledge about droplets and their unique surface properties as well as introduce second-order nonlinear scattering to a broad audience who may be unaware of recent progress and advancements in their applicability.

Neuropsychiatric symptoms and imbalance of atrophy in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia is characterized by heterogeneous frontal, insular, and anterior temporal atrophy patterns that vary along left-right and dorso-ventral axes. Little is known about how these structural imbalances impact clinical symptomatology. The goal of this study was to assess the frequency of frontotemporal asymmetry (right- or left-lateralization) and dorsality (ventral or dorsal predominance of atrophy) and to investigate their clinical correlates. Neuropsychiatric symptoms and structural images were analyzed for 250 patients with behavioral variant frontotemporal dementia. Frontotemporal atrophy was most often symmetric while left-lateralized (9%) and right-lateralized (17%) atrophy were present in a minority of patients. Atrophy was more often ventral (32%) than dorsal (3%) predominant. Patients with right-lateralized atrophy were characterized by higher severity of abnormal eating behavior and hallucinations compared to those with left-lateralized atrophy. Subsequent analyses clarified that eating behavior was associated with right atrophy to a greater extent than a lack of left atrophy, and hallucinations were driven mainly by right atrophy. Dorsality analyses showed that anxiety, euphoria, and disinhibition correlated with ventral-predominant atrophy. Agitation, irritability, and depression showed greater severity with a lack of regional atrophy, including in dorsal regions. Aberrant motor behavior and apathy were not explained by asymmetry or dorsality. This study provides additional insight into how anatomical heterogeneity influences the clinical presentation of patients with behavioral variant frontotemporal dementia. Behavioral symptoms can be associated not only with the presence or absence of focal atrophy, but also with right/left or dorsal/ventral imbalance of gray matter volume.

Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum.

OBJECTIVE: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers. METHODS: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles. RESULTS: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline. INTERPRETATION: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.

Development of Two-Dimensional Electronic-Vibrational Sum Frequency Generation (2D-EVSFG) for Vibronic and Solvent Couplings of Molecules at Interfaces and Surfaces.

Many photoinduced excited states' relaxation processes and chemical reactions occur at interfaces and surfaces, including charge transfer, energy transfer, proton transfer, proton-coupled electron transfer, configurational dynamics, conical intersections, etc. Of them, interactions of electronic and vibrational motions, namely, vibronic couplings, are the main determining factors for the relaxation processes or reaction pathways. However, time-resolved electronic-vibrational spectroscopy for interfaces and surfaces is lacking. Here we develop interface/surface-specific two-dimensional electronic-vibrational sum frequency generation spectroscopy (2D-EVSFG) for time-dependent vibronic coupling of excited states at interfaces and surfaces. We further demonstrate the fourth-order technique by investigating vibronic coupling, solvent correlation, and time evolution of the coupling for photoexcited interface-active molecules, crystal violet (CV), at the air/water interface as an example. The two vibronic absorption peaks for CV molecules at the interface from the 2D-EVSFG experiments were found to be more prominent than their counterparts in bulk from 2D-EV. Quantitative analysis of the vibronic peaks in 2D-EVSFG suggested that a non-Condon process participates in the photoexcitation of CV at the interface. We further reveal vibrational solvent coupling for the zeroth level on the electronic state with respect to that on the ground state, which is directly related to the magnitude of its change in solvent reorganization energy. The change in the solvent reorganization energy at the interface is much smaller than that in bulk methanol. Time-dependent center line slopes (CLSs) of 2D-EVSFG also showed that kinetic behaviors of CV at the air/water interface are significantly different from those in bulk methanol. Our ultrafast 2D-EVSFG experiments not only offer vibrational information on both excited states and the ground state as compared with the traditional doubly resonant sum frequency generation and electronic-vibrational coupling but also provide vibronic coupling, dynamical solvent effects, and time evolution of vibronic coupling at interfaces.

Literacy, but not memory, is associated with hippocampal connectivity in illiterate adults.

Background: The influence of hippocampal connectivity on memory performance is well established in individuals with high educational attainment. However, the role of hippocampal connectivity in illiterate populations remains poorly understood. Methods: Thirty-five illiterate adults were administered a literacy assessment (Test of Functional Health Literacy in Adults - TOFHLA), structural and resting state functional MRI and an episodic memory test (Free and Cued Selective Reminding Test). Illiteracy was defined as a TOFHLA score below 53. We evaluated the correlation between hippocampal connectivity at rest and both free recall and literacy scores. Results: Participants were mostly female (57.1%) and Black (84.8%), with a median age of 50 years. The median TOFHLA literacy score was 28.0 [21.0;42.5] out of 100 points and the median free recall score was 30.0 [26.2;35] out of 48 points. The median gray matter volume of both the left and right hippocampi was 2.3 [2.1; 2.4] cm3. We observed a significant connectivity between both hippocampi and the precuneus and the ventral medial prefrontal cortex. Interestingly, the right hippocampal connectivity positively correlated with the literacy scores (ß = 0.58, p = 0.008). There was no significant association between episodic memory and hippocampal connectivity. Neither memory nor literacy scores correlated with hippocampal gray matter volume. Conclusions: Low literacy levels correlate with hippocampal connectivity in illiterate adults. The lack of association with memory scores might be associated with low brain reserve in illiterate adults.

Interface Catalysts of Ni3Fe1 Layered Double Hydroxide and Titanium Carbide for High-Performance Water Oxidation in Alkaline and Natural Conditions.

The electrocatalytic oxygen evolution reaction (OER) is important for many renewable energy technologies. Developing cost-effective electrocatalysts with high performance remains a great challenge. Here, we successfully demonstrate our novel interface catalyst comprised of Ni3Fe1-based layered double hydroxides (Ni3Fe1-LDH) vertically immobilized on a two-dimensional MXene (Ti3C2Tx) surface. The Ni3Fe1-LDH/Ti3C2Tx yielded an anodic OER current of 100 mA cm-2 at 0.28 V versus reversible hydrogen electrode (RHE), nearly 74 times lower than that of the pristine Ni3Fe1-LDH. Furthermore, the Ni3Fe1-LDH/Ti3C2Tx catalyst requires an overpotential of only 0.31 V versus RHE to deliver an industrial-level current density as high as 1000 mA cm-2. Such excellent OER activity was attributed to the synergistic interface effect between Ni3Fe1-LDH and Ti3C2Tx. Density functional theory (DFT) results further reveal that the Ti3C2Tx support can efficiently accelerate the electron extraction from Ni3Fe1-LDH and tailor the electronic structure of catalytic sites, resulting in enhanced OER performance.

Orientational Coupling of Molecules at Interfaces Revealed by Two-Dimensional Electronic-Vibrational Sum Frequency Generation (2D-EVSFG).

Photoinduced relaxation processes at interfaces are intimately related to many fields such as solar energy conversion, photocatalysis, and photosynthesis. Vibronic coupling plays a key role in the fundamental steps of the interface-related photoinduced relaxation processes. Vibronic coupling at interfaces is expected to be different from that in bulk due to the unique environment. However, vibronic coupling at interfaces has not been well understood due to the lack of experimental tools. We have recently developed a two-dimensional electronic-vibrational sum frequency generation (2D-EVSFG) for vibronic coupling at interfaces. In this work, we present orientational correlations in vibronic couplings of electronic and vibrational transition dipoles as well as the structural evolution of photoinduced excited states of molecules at interfaces with the 2D-EVSFG technique. We used malachite green molecules at the air/water interface as an example, to be compared with those in bulk revealed by 2D-EV. Together with polarized VSFG and ESHG experiments, polarized 2D-EVSFG spectra were used to extract relative orientations of an electronic transition dipole and vibrational transition dipoles at the interface. Combined with molecular dynamics calculations, time-dependent 2D-EVSFG data have demonstrated that structural evolutions of photoinduced excited states at the interface have different behaviors than those in bulk. Our results showed that photoexcitation leads to intramolecular charge transfer but no conical interactions in 25 ps. Restricted environment and orientational orderings of molecules at the interface are responsible for the unique features of vibronic coupling.

Readily Accessible High-Throughput Experimentation: A General Protocol for the Preparation of ChemBeads and EnzyBeads.

Chemical- and enzyme-coated beads (ChemBeads and EnzyBeads) were introduced recently as a universal strategy for the accurate dispensing of various solids in submilligram quantities using automated instrumentation or manual dispensing. The coated beads are prepared using a resonant acoustic mixer (RAM)-an instrument that may be available only to well-established facilities. In this study, we evaluated alternative coating methods for preparing ChemBeads and EnzyBeads without the use of a RAM. We also evaluated the effects of bead sizes on loading accuracy using 4 coating methods and 12 solids (9 chemicals and 3 enzymes) as test subjects. While our original RAM coating method is the most versatile for the broadest range of solids, high-quality ChemBeads and EnzyBeads that are suitable for high-throughput experimentation can be prepared using alternative methods. These results should make ChemBeads and EnzyBeads readily accessible as the core technology for setting up high-throughput experimentation platforms.

Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia.

Importance: The neurological substrates of visual artistic creativity (VAC) are unknown. VAC is demonstrated here to occur early in frontotemporal dementia (FTD), and multimodal neuroimaging is used to generate a novel mechanistic hypothesis involving dorsomedial occipital cortex enhancement. These findings may illuminate a novel mechanism underlying human visual creativity. Objective: To determine the anatomical and physiological underpinnings of VAC in FTD. Design, Setting, and Participants: This case-control study analyzed records of 689 patients who met research criteria for an FTD spectrum disorder between 2002 and 2019. Individuals with FTD and emergence of visual artistic creativity (VAC-FTD) were matched to 2 control groups based on demographic and clinical parameters: (1) not visually artistic FTD (NVA-FTD) and (2) healthy controls (HC). Analysis took place between September 2019 to December 2021. Main Outcomes and Measures: Clinical, neuropsychological, genetic, and neuroimaging data were analyzed to characterize VAC-FTD and compare VAC-FTD with control groups. Results: Of 689 patients with FTD, 17 (2.5%) met VAC-FTD inclusion criteria (mean [SD] age, 65 [9.7] years; 10 [58.8%] female). NVA-FTD (n = 51; mean [SD] age, 64.8 [7] years; 25 [49.0%] female) and HC (n = 51; mean [SD] age, 64.5 [7.2] years; 25 [49%] female) groups were well matched to VAC-FTD demographically. Emergence of VAC occurred around the time of onset of symptoms and was disproportionately seen in patients with temporal lobe predominant degeneration (8 of 17 [47.1%]). Atrophy network mapping identified a dorsomedial occipital region whose activity inversely correlated, in healthy brains, with activity in regions found within the patient-specific atrophy patterns in VAC-FTD (17 of 17) and NVA-FTD (45 of 51 [88.2%]). Structural covariance analysis revealed that the volume of this dorsal occipital region was strongly correlated in VAC-FTD, but not in NVA-FTD or HC, with a volume in the primary motor cortex corresponding to the right-hand representation. Conclusions and Relevance: This study generated a novel hypothesis about the mechanisms underlying the emergence of VAC in FTD. These findings suggest that early lesion-induced activation of dorsal visual association areas may predispose some patients to the emergence of VAC under certain environmental or genetic conditions. This work sets the stage for further exploration of enhanced capacities arising early in the course of neurodegeneration.

Dysfunctional Cortical Gradient Topography in Treatment-Resistant Major Depressive Disorder.

BACKGROUND: Treatment-resistant depression (TRD) refers to patients with major depressive disorder who do not remit after 2 or more antidepressant trials. TRD is common and highly debilitating, but its neurobiological basis remains poorly understood. Recent neuroimaging studies have revealed cortical connectivity gradients that dissociate primary sensorimotor areas from higher-order associative cortices. This fundamental topography determines cortical information flow and is affected by psychiatric disorders. We examined how TRD impacts gradient-based hierarchical cortical organization. METHODS: In this secondary study, we analyzed resting-state functional magnetic resonance imaging data from a mindfulness-based intervention enrolling 56 patients with TRD and 28 healthy control subjects. Using gradient extraction tools, baseline measures of cortical gradient dispersion within and between functional brain networks were derived, compared across groups, and associated with graph theoretical measures of network topology. In patients, correlation analyses were used to associate measures of cortical gradient dispersion with clinical measures of anxiety, depression, and mindfulness at baseline and following the intervention. RESULTS: Cortical gradient dispersion was reduced within major intrinsic brain networks in patients with TRD. Reduced cortical gradient dispersion correlated with increased network degree assessed through graph theory-based measures of network topology. Lower dispersion among default mode, control, and limbic network nodes related to baseline levels of trait anxiety, depression, and mindfulness. Patients' baseline limbic network dispersion predicted trait anxiety scores 24 weeks after the intervention. CONCLUSIONS: Our findings provide preliminary support for widespread alterations in cortical gradient architecture in TRD, implicating a significant role for transmodal and limbic networks in mediating depression, anxiety, and lower mindfulness in patients with TRD.