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.

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.

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.

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.

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.

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.

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.

Increasing empathic concern relates to salience network hyperconnectivity in cognitively healthy older adults with elevated amyloid-ß burden.

Enhanced emotional empathy, the ability to share others' affective experiences, can be a feature of Alzheimer's disease (AD), but whether emotional empathy increases in the preclinical phase of the disease is unknown. We measured emotional empathy over time (range = 0 - 7.3 years, mean = 2.4 years) in 86 older adults during a period in which they were cognitively healthy, functionally normal, and free of dementia symptoms. For each participant, we computed longitudinal trajectories for empathic concern (i.e., an other-oriented form of emotional empathy that promotes prosocial actions) and emotional contagion (i.e., a self-focused form of emotional empathy often accompanied by feelings of distress) from informant ratings of participants' empathy on the Interpersonal Reactivity Index. Amyloid-ß (Aß) positron emission tomography (PET) scans were used to classify participants as either Aß positive (Aß+, n = 23) or negative (Aß-, n = 63) based on Aß-PET cortical binding. Participants also underwent structural and task-free functional magnetic resonance imaging approximately two years on average after their last empathy assessment, at which time most participants remained cognitively healthy. Results indicated that empathic concern, but not emotional contagion, increased more over time in Aß+ participants than in Aß- participants despite no initial group difference at the first measurement. Higher connectivity between certain salience network node-pairs (i.e., pregenual anterior cingulate cortex and periaqueductal gray) predicted longitudinal increases in empathic concern in the Aß+ group but not in the Aß- group. The Aß+ participants also had higher overall salience network connectivity than Aß- participants despite no differences in gray matter volume. These results suggest gains in empathic concern may be a very early feature of AD pathophysiology that relates to hyperconnectivity in the salience network, a system that supports emotion generation and interoception. A better understanding of emotional empathy trajectories in the early stages of AD pathophysiology will broaden the lens on preclinical AD changes and help clinicians to identify older adults who should be screened for AD biomarkers.

Dynamic autonomic nervous system states arise during emotions and manifest in basal physiology.

The outflow of the autonomic nervous system (ANS) is continuous and dynamic, but its functional organization is not well understood. Whether ANS patterns accompany emotions, or arise in basal physiology, remain unsettled questions in the field. Here, we searched for brief ANS patterns amidst continuous, multichannel physiological recordings in 45 healthy older adults. Participants completed an emotional reactivity task in which they viewed video clips that elicited a target emotion (awe, sadness, amusement, disgust, or nurturant love); each video clip was preceded by a pre-trial baseline period and followed by a post-trial recovery period. Participants also sat quietly for a separate 2-min resting period to assess basal physiology. Using principal components analysis and unsupervised clustering algorithms to reduce the second-by-second physiological data during the emotional reactivity task, we uncovered five ANS states. Each ANS state was characterized by a unique constellation of patterned physiological changes that differentiated among the trials of the emotional reactivity task. These ANS states emerged and dissipated over time, with each instance lasting several seconds on average. ANS states with similar structures were also detectable in the resting period but were intermittent and of smaller magnitude. Our results offer new insights into the functional organization of the ANS. By assembling short-lived, patterned changes, the ANS is equipped to generate a wide range of physiological states that accompany emotions and that contribute to the architecture of basal physiology.

A dynamic gradient architecture generates brain activity states.

The human brain exhibits a diverse yet constrained range of activity states. While these states can be faithfully represented in a low-dimensional latent space, our understanding of the constitutive functional anatomy is still evolving. Here we applied dimensionality reduction to task-free and task fMRI data to address whether latent dimensions reflect intrinsic systems and if so, how these systems may interact to generate different activity states. We find that each dimension represents a dynamic activity gradient, including a primary unipolar sensory-association gradient underlying the global signal. The gradients appear stable across individuals and cognitive states, while recapitulating key functional connectivity properties including anticorrelation, modularity, and regional hubness. We then use dynamical systems modeling to show that gradients causally interact via state-specific coupling parameters to create distinct brain activity patterns. Together, these findings indicate that a set of dynamic, intrinsic spatial gradients interact to determine the repertoire of possible brain activity states.

Default Mode Network quantitative diffusion and resting-state functional magnetic resonance imaging correlates in sporadic Creutzfeldt-Jakob disease.

Grey matter involvement is a well-known feature in sporadic Creutzfeldt-Jakob disease (sCJD), yet precise anatomy-based quantification of reduced diffusivity is still not fully understood. Default Mode Network (DMN) areas have been recently demonstrated as selectively involved in sCJD, and functional connectivity has never been investigated in prion diseases. We analyzed the grey matter involvement using a quantitatively multi-parametric MRI approach. Specifically, grey matter mean diffusivity of 37 subjects with sCJD was compared with that of 30 age-matched healthy controls with a group-wise approach. Differences in mean diffusivity were also examined between the cortical (MM(V)1, MM(V)2C, and VV1) and subcortical (VV2 and MV2K) subgroups of sCJD for those with autopsy data available (n = 27, 73%). We also assessed resting-state functional connectivity of both ventral and dorsal components of DMN in a subset of subject with a rs-fMRI dataset available (n = 17). Decreased diffusivity was predominantly present in posterior cortical regions of the DMN, but also outside of the DMN in temporal areas and in a few limbic and frontal areas, in addition to extensive deep nuclei involvement. Both subcortical and cortical sCJD subgroups showed decreased diffusivity subcortically, whereas only the cortical type expressed significantly decreased diffusivity cortically, mainly in parietal, occipital, and medial-inferior temporal cortices bilaterally. Interestingly, we found abnormally increased connectivity in both dorsal and ventral components of the DMN in sCJD subjects compared with healthy controls. The significance and possible utility of functional imaging as a biomarker for tracking disease progression in prion disease needs to be explored further.

In Situ Detection of Chemical Compositions at Nanodroplet Surfaces and In-Nanodroplet Phases.

Small-volume nanodroplets play an increasingly common role in chemistry and biology. Such nanodroplets are believed to have unique chemical and physical properties at the interface between a droplet and its surrounding medium, however, they are underexamined. In this study, we present the novel technique of vibrational sum frequency scattering (VSFS) spectroscopy as an interface-specific, high-performance method for the in situ investigation of nanodroplets with sub-micron radii; as well as the droplet bulk through simultaneous hyper-Raman scattering (HRS) spectroscopy. We use laboratory-generated nanodroplets from aqueous alcohol solutions to demonstrate this technique's ability to separate the vibrational phenomena which take place at droplet surfaces from the underlying bulk phase. In addition, we systemically examine interfacial spectra of nanodroplets containing methanol, ethanol, 1-propanol, and 1-butanol through VSFS. Furthermore, we demonstrate interfacial differences between such nanodroplets and their analogous planar surfaces. The sensitivity of this technique to probe droplet surfaces with few-particle density at standard conditions validates VSFS as an analytical technique for the in situ investigation of small nanodroplets, providing breakthrough information about these species of ever-increasing relevance.