Divergent Substrates Research Articles

Chromosomal evolution, environmental heterogeneity, and migration drive spatial patterns of species richness in Calochortus (Liliaceae)

We used nuclear genomic data and statistical models to evaluate the ecological and evolutionary processes shaping spatial variation in species richness in Calochortus (Liliaceae, 74 spp.). Calochortus occupies diverse habitats in the western United States and Mexico and has a center of diversity in the California Floristic Province, marked by multiple orogenies, winter rainfall, and highly divergent climates and substrates (including serpentine). We used sequences of 294 low-copy nuclear loci to produce a time-calibrated phylogeny, estimate historical biogeography, and test hypotheses regarding drivers of present-day spatial patterns in species number. Speciation and species coexistence require reproductive isolation and ecological divergence, so we examined the roles of chromosome number, environmental heterogeneity, and migration in shaping local species richness. Six major clades-inhabiting different geographic/climatic areas, and often marked by different base chromosome numbers (n = 6 to 10)-began diverging from each other ~10.3 Mya. As predicted, local species number increased significantly with local heterogeneity in chromosome number, elevation, soil characteristics, and serpentine presence. Species richness is greatest in the Transverse/Peninsular Ranges where clades with different chromosome numbers overlap, topographic complexity provides diverse conditions over short distances, and several physiographic provinces meet allowing immigration by several clades. Recently diverged sister-species pairs generally have peri-patric distributions, and maximum geographic overlap between species increases over the first million years since divergence, suggesting that chromosomal evolution, genetic divergence leading to gametic isolation or hybrid inviability/sterility, and/or ecological divergence over small spatial scales may permit species co-occurrence.

The neural correlates of memory integration in value-based decision-making during human spatial navigation

In daily life, we often make decisions based on relative value of the options, and we often derive these values from segmenting or integrating the outcomes of past episodes in memory. The neural correlates involved in value-based decision-making have been extensively studied in the literature, but few studies have investigated this topic in decisions that require segmenting or integrating episodic memory from related sources, and even fewer studies examine it in the context of spatial navigation. Building on the computational models from our previous studies, the current study investigates the neural substrates involved in decisions that require people either segment or integrate wayfinding outcomes involving different goals, across virtual spatial navigation tasks with differing demands. We find that when decisions require computation of spatial distances for navigation options, but also evaluation of one's prior spatial navigation ability with the task, the estimated value of navigational choices (EV) modulates neural activity in the dorsomedial prefrontal (dmPFC) cortex and ventrolateral prefrontal (vlFPC) cortex. However, superior parietal cortex tracked EV when decision-making tasks only require spatial distance memory but not evaluation of spatial navigation ability. Our findings reveal divergent neural substrates of memory integration in value-based decision-making under different spatial processing demands.

Pseudophomins A–D Produced from Pseudomonas sp. HN8-3 Using an OSMAC Approach and Their Roles in Biocontrol of Phytophthora capsici in Cucumbers

In this study, two new cyclic lipopeptides (CLPs) pseudophomins C (3) and D (4) and two known CLPs pseudophomins A (1) and B (2) were produced and characterized from the bacterial supernatant of Pseudomonas sp. HN8-3 by an OSMAC (one strain-many compounds) approach. OSMAC is a strategy that involves feeding of a single microorganism with divergent substrates to stimulate the production of new secondary metabolites. These pseudophomins were purified and identified via chromatographic methods, droplet collapse assay, genome mining, spectroscopic and spectrometric analyses, and single-crystal X-ray diffraction (XRD). Moreover, bioactivity tests showed that pseudophomins could lyse the zoospores of Phytophthora capsici in vitro, and coapplication of pseudophomins with zoospores of P. capsici further reduced the incidence of P. capsici on cucumber leaves. Collectively, these results indicated that pseudophomins have the potential to be developed as biopesticides for controlling P. capsici in cucumber.

Gray matter asymmetry atypical patterns in subgrouping minors with autism based on core symptoms.

Abnormal gray matter (GM) asymmetry has been verified in autism spectrum disorder (ASD), which is characterized by high heterogeneity. ASD is distinguished by three core symptom domains. Previous neuroimaging studies have offered support for divergent neural substrates of different core symptom domains in ASD. However, no previous study has explored GM asymmetry alterations underlying different core symptom domains. This study sought to clarify atypical GM asymmetry patterns underlying three core symptom domains in ASD with a large sample of 230 minors with ASD (ages 7-18 years) and 274 matched TD controls from the Autism Brain Imaging Data Exchange I (ABIDE I) repository. To this end, the scores of the revised autism diagnostic interview (ADI-R) subscales were normalized for grouping ASD into three core-symptom-defined subgroups: social interaction (SI), verbal communication (VA), and restricted repetitive behaviors (RRB). We investigated core-symptom-related GM asymmetry alterations in ASD resulting from advanced voxel-based morphometry (VBM) by general linear models. We also examined the relationship between GM asymmetry and age and between GM asymmetry and symptom severity assessed by the Autism Diagnostic Observation Schedule (ADOS). We found unique GM asymmetry alterations underlying three core-symptom-defined subgroups in ASD: more rightward asymmetry in the thalamus for SI, less rightward asymmetry in the superior temporal gyrus, anterior cingulate and caudate for VA, and less rightward asymmetry in the middle and inferior frontal gyrus for RRB. Furthermore, the asymmetry indexes in the thalamus were negatively associated with ADOS_SOCIAL scores in the general ASD group. We also showed significant correlations between GM asymmetry and age in ASD and TD individuals. Our results support the theory that each core symptom domain of ASD may have independent etiological and neurobiological underpinnings, which is essential for the interpretation of heterogeneity and the future diagnosis and treatment of ASD.

The CLP and PREP protease systems coordinate maturation and degradation of the chloroplast proteome in Arabidopsis thaliana.

A network of peptidases governs proteostasis in plant chloroplasts and mitochondria. This study reveals strong genetic and functional interactions in Arabidopsis between the chloroplast stromal CLP chaperone-protease system and the PREP1,2 peptidases, which are dually localized to chloroplast stroma and the mitochondrial matrix. Higher order mutants defective in CLP or PREP proteins were generated and analyzed by quantitative proteomics and N-terminal proteomics (terminal amine isotopic labeling of substrates (TAILS)). Strong synergistic interactions were observed between the CLP protease system (clpr1-2, clpr2-1, clpc1-1, clpt1, clpt2) and both PREP homologs (prep1, prep2) resulting in embryo lethality or growth and developmental phenotypes. Synergistic interactions were observed even when only one of the PREP proteins was lacking, suggesting that PREP1 and PREP2 have divergent substrates. Proteome phenotypes were driven by the loss of CLP protease capacity, with little impact from the PREP peptidases. Chloroplast N-terminal proteomes showed that many nuclear encoded chloroplast proteins have alternatively processed N-termini in prep1prep2, clpt1clpt2 and prep1prep2clpt1clpt2. Loss of chloroplast protease capacity interferes with stromal processing peptidase (SPP) activity due to folding stress and low levels of accumulated cleaved cTP fragments. PREP1,2 proteolysis of cleaved cTPs is complemented by unknown proteases. A model for CLP and PREP activity within a hierarchical chloroplast proteolysis network is proposed.

Divergent and Convergent Imaging Markers Between Bipolar and Unipolar Depression Based on Machine Learning.

Distinguishing bipolar depression (BD) from unipolar depression (UD) based on symptoms only is challenging. Brain functional connectivity (FC), especially dynamic FC, has emerged as a promising approach to identify possible imaging markers for differentiating BD from UD. However, most of such studies utilized conventional FC and group-level statistical comparisons, which may not be sensitive enough to quantify subtle changes in the FC dynamics between BD and UD. In this paper, we present a more effective individualized differentiation model based on machine learning and the whole-brain "high-order functional connectivity (HOFC)" network. The HOFC, capturing temporal synchronization among the dynamic FC time series, a more complex "chronnectome" metric compared to the conventional FC, was used to classify 52 BD, 73 UD, and 76 healthycontrols (HC). We achieved a satisfactory accuracy (70.40%) in BD vs. UD differentiation. The resultant contributing features revealed the involvement of the coordinated flexible interactions among sensory (e.g., olfaction, vision, and audition), motor, and cognitive systems. Despite sharing common chronnectome of cognitive and affective impairments, BD and UD also demonstrated unique dynamic FC synchronization patterns. UD is more associated with abnormal visual-somatomotor inter-network connections, while BD is more related to impaired ventral attention-frontoparietal inter-network connections. Moreover, we found that the illness duration modulated the BD vs. UD separation, with the differentiation performance hampered by the secondary disease effects. Our findings suggest that BD and UD may have divergent and convergent neural substrates, which further expand our knowledge of the two different mental disorders.

Rational design of fatty acid photodecarboxylase enables the efficient decarboxylation of medium- and short-chain fatty acids for the production of gasoline bio-alkanes

Fatty acid photodecarboxylase (CvFAP) from Chlorella variabilis NC64A can convert efficiently long-chain fatty acids to hydrocarbons via decarboxylation, and offer a new opportunity for bio-alkanes production. However, the catalytic activity of CvFAP towards medium- and short- fatty acids significantly decreased, leading to a great limitation for the application of CvFAP into the production of gasoline bio-alkanes, which are one of the most important fuels in our modern society. To improve the catalytic efficiency of CvFAP toward these specific fatty acids, a rational design based on the strategy of ‘Focused Rational Iterative Site-specific Mutagenesis’ (FRISM) was performed, where only dozens of mutants needed to be screened. Two mutants (I398L and P460A/G462A) with 29 to 552-fold increasement in decarboxylation catalytic efficiency (kcat/Km) toward different fatty acids (C3-C14) were achieved. The substrate scope of the best mutants is quite broad. Gram-scale reactions were also tested successfully. MD simulations explained the results of improved catalytic activity of mutants for divergent substrates. Based on our experimental results, the best mutants in this study exhibited great potential to generate high value-added gasoline alkanes.

Recognition of Divergent Viral Substrates by the SARS-CoV-2 Main Protease.

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), is an ideal target for pharmaceutical inhibition. Mpro is conserved among coronaviruses and distinct from human proteases. Viral replication depends on the cleavage of the viral polyprotein at multiple sites. We present crystal structures of SARS-CoV-2 Mpro bound to two viral substrate peptides. The structures show how Mpro recognizes distinct substrates and how subtle changes in substrate accommodation can drive large changes in catalytic efficiency. One peptide, constituting the junction between viral nonstructural proteins 8 and 9 (nsp8/9), has P1′ and P2′ residues that are unique among the SARS-CoV-2 Mpro cleavage sites but conserved among homologous junctions in coronaviruses. Mpro cleaves nsp8/9 inefficiently, and amino acid substitutions at P1′ or P2′ can enhance catalysis. Visualization of Mpro with intact substrates provides new templates for antiviral drug design and suggests that the coronavirus lifecycle selects for finely tuned substrate-dependent catalytic parameters.

Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis.

The co‐catabolism of multiple host‐derived carbon substrates is required by Mycobacterium tuberculosis (Mtb) to successfully sustain a tuberculosis infection. However, the metabolic plasticity of this pathogen and the complexity of the metabolic networks present a major obstacle in identifying those nodes most amenable to therapeutic interventions. It is therefore critical that we define the metabolic phenotypes of Mtb in different conditions. We applied metabolic flux analysis using stable isotopes and lipid fingerprinting to investigate the metabolic network of Mtb growing slowly in our steady‐state chemostat system. We demonstrate that Mtb efficiently co‐metabolises either cholesterol or glycerol, in combination with two‐carbon generating substrates without any compartmentalisation of metabolism. We discovered that partitioning of flux between the TCA cycle and the glyoxylate shunt combined with a reversible methyl citrate cycle is the critical metabolic nodes which underlie the nutritional flexibility of Mtb. These findings provide novel insights into the metabolic architecture that affords adaptability of bacteria to divergent carbon substrates and expand our fundamental knowledge about the methyl citrate cycle and the glyoxylate shunt.

Structural basis for recognition of distinct deaminated DNA lesions by endonuclease Q

Significance Deamination of cytosine and adenine bases in DNA is one of the most common sources of genetic mutation in biology and a major driver of virus and tumor evolution. Recent studies have identified a novel class of DNA-repair enzyme from archaea and bacteria, designated endonuclease Q (EndoQ), which has unique activity to initiate the repair of both these deaminated lesions. Our X-ray crystallographic and biochemical analyses presented here reveal how EndoQ achieves high selectivity toward these chemically divergent substrates without cleaving undamaged DNA. We also demonstrate that EndoQ, as the only known nuclease that cleaves DNA at deoxyuridine nucleotide, is useful for studying DNA deamination and repair in mammalian systems.

Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex

Membrane protein biogenesis faces the challenge of chaperoning hydrophobic transmembrane helices for faithful membrane insertion. The guided entry of tail-anchored proteins (GET) pathway targets and inserts tail-anchored (TA) proteins into the endoplasmic reticulum (ER) membrane with an insertase (yeast Get1/Get2 or mammalian WRB/CAML) that captures the TA from a cytoplasmic chaperone (Get3 or TRC40, respectively). Here, we present cryo-electron microscopy reconstructions, native mass spectrometry, and structure-based mutagenesis of human WRB/CAML/TRC40 and yeast Get1/Get2/Get3 complexes. Get3 binding to the membrane insertase supports heterotetramer formation, and phosphatidylinositol binding at the heterotetramer interface stabilizes the insertase for efficient TA insertion invivo. We identify a Get2/CAML cytoplasmic helix that forms a "gating" interaction with Get3/TRC40 important for TA insertion. Structural homology with YidC and the ER membrane protein complex (EMC) implicates an evolutionarily conserved insertion mechanism for divergent substrates utilizing a hydrophilic groove. Thus, we provide a detailed structural and mechanistic framework to understand TA membrane insertion.

Development of Magnesium Oxide-Silver Hybrid Nanocatalysts for Synergistic Carbon Dioxide Activation to Afford Esters and Heterocycles at Ambient Pressure.

Multi-metallic hybrid nancatalysts consisting of a porous metal oxide host and metal satellite guests serve as a scaffold for multi-step transformations of divergent and energy-challenging substrates. Here we have developed a 3D porous MgO framework (Lewis basic host) with Ag0 nanoparticles (noble metal guest) for ambient pressure activation and insertion of CO2 into unsaturated alkyne substrates. The hybrid MgO@Ag-x (x = 2, 5, 7, 8 at % Ag) catalysts are synthesized by impregnating Ag+ ions in porous MgO cubes followed by reduction using NaBH4. Morphological (SEM, TEM, EDX mapping) and structural (PXRD, XPS) characterization reveal that the micron-sized hybrid cubes derive from self-assembly of ~100 nm (edge length) MgO cubes decorated with ~ 5 to 25 nm Ag0 NPs. Detailed XPS analysis illustrates Ag0 is present in two forms, <10 nm NPs and ~25 nm aggregates. The MgO@Ag-7 catalyst is effective for inserting CO2 into aryl alkynes followed by SN2 coupling with allylic chlorides to afford a wide range of ester and lactone heterocycles in excellent yields (61-93%) and with low E-factor (2.8). The proposed mechanism suggests a CO2 capture and substrate assembly role for 3D porous MgO while Ag0 performs the key activation of alkyne and CO2 insertion steps. The catalyst is recyclable (5x) with no significant loss of product yield. Overall, these results demonstrate viable approaches to hybrid catalyst development for challenging conversions such as CO2 utilization in a green and sustainable manner.

Scene construction impairments in frontotemporal dementia: Evidence for a primary hippocampal contribution

The capacity to generate naturalistic three-dimensional and spatially coherent representations of the world, i.e., scene construction, is posited to lie at the heart of a wide range of complex cognitive endeavours. Clinical populations with selective damage to key nodes of a putative scene construction network of the brain have provided important insights regarding the contribution of medial temporal and prefrontal regions in this regard. Here, we explored the capacity for atemporal scene construction, and its associated neural substrates, in the behavioural-variant of frontotemporal dementia (bvFTD); a neurodegenerative brain disorder in which atrophy systematically erodes medial and lateral prefrontal cortices with variable medial temporal lobe involvement. Nineteen bvFTD patients were compared to 18 typical Alzheimer's Disease (AD), and 25 healthy older Control participants on a scene construction task. Relative to Controls, both patient groups displayed marked impairments in generating contextually detailed and spatially coherent scenes, with bvFTD indistinguishable from AD patients across the majority of task metrics. Voxel-based morphometry, based on structural brain MRI, revealed divergent neural substrates of scene construction performance in each patient group. Despite widespread medial and lateral prefrontal atrophy, the capacity to generate richly detailed and spatially coherent scenes in bvFTD was found to rely predominantly upon the integrity of right medial temporal structures, including the hippocampus and parahippocampal gyrus. Scene construction impairments in AD, by contrast, hinged upon the integrity of posterior parietal brain regions. Our findings in bvFTD resonate with a large body of work implicating the right hippocampus in the construction of spatially integrated scene imagery. How these impairments relate to changes in autobiographical memory and prospection in bvFTD will be an important question for future studies to address.

Chromatin Modifiers Alter Recombination Between Divergent DNA Sequences.

Recombination between divergent DNA sequences is actively prevented by heteroduplex rejection mechanisms. In baker's yeast, such antirecombination mechanisms can be initiated by the recognition of DNA mismatches in heteroduplex DNA by MSH proteins, followed by recruitment of the Sgs1-Top3-Rmi1 helicase-topoisomerase complex to unwind the recombination intermediate. We previously showed that the repair/rejection decision during single-strand annealing recombination is temporally regulated by MSH (MutShomolog) protein levels and by factors that excise nonhomologous single-stranded tails. These observations, coupled with recent studies indicating that mismatch repair (MMR) factors interact with components of the histone chaperone machinery, encouraged us to explore roles for epigenetic factors and chromatin conformation in regulating the decision to reject vs. repair recombination between divergent DNA substrates. This work involved the use of an inverted repeat recombination assay thought to measure sister chromatid repair during DNA replication. Our observations are consistent with the histone chaperones CAF-1 and Rtt106, and the histone deacetylase Sir2, acting to suppress heteroduplex rejection and the Rpd3, Hst3, and Hst4 deacetylases acting to promote heteroduplex rejection. These observations, and double-mutant analysis, have led to a model in which nucleosomes located at DNA lesions stabilize recombination intermediates and compete with MMR factors that mediate heteroduplex rejection.

Multi-omics analysis unravels a segregated metabolic flux network that tunes co-utilization of sugar and aromatic carbons in Pseudomonas putida

Pseudomonas species thrive in different nutritional environments and can catabolize divergent carbon substrates. These capabilities have important implications for the role of these species in natural and engineered carbon processing. However, the metabolic phenotypes enabling Pseudomonas to utilize mixed substrates remain poorly understood. Here, we employed a multi-omics approach involving stable isotope tracers, metabolomics, fluxomics, and proteomics in Pseudomonas putida KT2440 to investigate the constitutive metabolic network that achieves co-utilization of glucose and benzoate, respectively a monomer of carbohydrate polymers and a derivative of lignin monomers. Despite nearly equal consumption of both substrates, metabolite isotopologues revealed nonuniform assimilation throughout the metabolic network. Gluconeogenic flux of benzoate-derived carbons from the tricarboxylic acid cycle did not reach the upper Embden-Meyerhof-Parnas pathway nor the pentose-phosphate pathway. These latter two pathways were populated exclusively by glucose-derived carbons through a cyclic connection with the Entner-Doudoroff pathway. We integrated the 13C-metabolomics data with physiological parameters for quantitative flux analysis, demonstrating that the metabolic segregation of the substrate carbons optimally sustained biosynthetic flux demands and redox balance. Changes in protein abundance partially predicted the metabolic flux changes in cells grown on the glucose:benzoate mixture versus on glucose alone. Notably, flux magnitude and directionality were also maintained by metabolite levels and regulation of phosphorylation of key metabolic enzymes. These findings provide new insights into the metabolic architecture that affords adaptability of P. putida to divergent carbon substrates and highlight regulatory points at different metabolic nodes that may underlie the high nutritional flexibility of Pseudomonas species.

The Amygdala in Schizophrenia and Bipolar Disorder: A Synthesis of Structural MRI, Diffusion Tensor Imaging, and Resting-State Functional Connectivity Findings.

Frequently implicated in psychotic spectrum disorders, the amygdala serves as an important hub for elucidating the convergent and divergent neural substrates in schizophrenia and bipolar disorder, the two most studied groups of psychotic spectrum conditions. A systematic search of electronic databases through December 2017 was conducted to identify neuroimaging studies of the amygdala in schizophrenia and bipolar disorder, focusing on structural MRI, diffusion tensor imaging (DTI), and resting-state functional connectivity studies, with an emphasis on cross-diagnostic studies. Ninety-four independent studies were selected for the present review (49 structural MRI, 27 DTI, and 18 resting-state functional MRI studies). Also selected, and analyzed in a separate meta-analysis, were 33 volumetric studies with the amygdala as the region-of-interest. Reduced left, right, and total amygdala volumes were found in schizophrenia, relative to both healthy controls and bipolar subjects, even when restricted to cohorts in the early stages of illness. No volume abnormalities were observed in bipolar subjects relative to healthy controls. Shape morphometry studies showed either amygdala deformity or no differences in schizophrenia, and no abnormalities in bipolar disorder. In contrast to the volumetric findings, DTI studies of the uncinate fasciculus tract (connecting the amygdala with the medial- and orbitofrontal cortices) largely showed reduced fractional anisotropy (a marker of white matter microstructure abnormality) in both schizophrenia and bipolar patients, with no cross-diagnostic differences. While decreased amygdalar-orbitofrontal functional connectivity was generally observed in schizophrenia, varying patterns of amygdalar-orbitofrontal connectivity in bipolar disorder were found. Future studies can consider adopting longitudinal approaches with multimodal imaging and more extensive clinical subtyping to probe amygdalar subregional changes and their relationship to the sequelae of psychotic disorders.

Rad51-mediated double-strand break repair and mismatch correction of divergent substrates.

The Rad51 (also known as RecA) family of recombinases executes the critical step in homologous recombination: the search for homologous DNA to serve as a template during the repair of DNA double-strand breaks (DSBs). Although budding yeast Rad51 has been extensively characterized in vitro, the stringency of its search and sensitivity to mismatched sequences in vivo remain poorly defined. Here, in Saccharomyces cerevisiae, we analysed Rad51-dependent break-induced replication in which the invading DSB end and its donor template share a 108-base-pair homology region and the donor carries different densities of single-base-pair mismatches. With every eighth base pair mismatched, repair was about 14% of that of completely homologous sequences. With every sixth base pair mismatched, repair was still more than 5%. Thus, completing break-induced replication in vivo overcomes the apparent requirement for at least 6-8 consecutive paired bases that has been inferred from in vitro studies. When recombination occurs without a protruding nonhomologous 3' tail, the mismatch repair protein Msh2 does not discourage homeologous recombination. However, when the DSB end contains a 3' protruding nonhomologous tail, Msh2 promotes the rejection of mismatched substrates. Mismatch correction of strand invasion heteroduplex DNA is strongly polar, favouring correction close to the DSB end. Nearly all mismatch correction depends on the proofreading activity of DNA polymerase-δ, although the repair proteins Msh2, Mlh1 and Exo1 influence the extent of correction.

Crystal structure and biochemical features of dye-decolorizing peroxidase YfeX from Escherichia coli O157 Asp143 and Arg232 play divergent roles toward different substrates

YfeX from Escherichia coli O157 is a bacterial dye-decolorizing peroxidase that represents both dye-decoloring activity and typical peroxidase activity. We reported the crystal structure of YfeX bound to heme at 2.09 Å resolution. The YfeX monomer resembles a ferredoxin-like fold and contains two domains. The three conserved residues surrounding the heme group are His215, Asp143 and Arg232. His215 functions as the proximal axial ligand of the heme iron atom. Biochemical data show that the catalytic significance of the conserved Asp143 and Arg232 depends on the substrate types and that YfeX may adopt various catalytic mechanisms toward divergent substrates. In addition, it is observed that an access tunnel spans from the protein molecular surface to the heme distal region, it serves as the passageway for the entrance and binding of the H2O2.

Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits inAlzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia.

Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information.

Socio-Cognitive Phenotypes Differentially Modulate Large-Scale Structural Covariance Networks.

Functional neuroimaging studies have suggested the existence of 2 largely distinct social cognition networks, one for theory of mind (taking others' cognitive perspective) and another for empathy (sharing others' affective states). To address whether these networks can also be dissociated at the level of brain structure, we combined behavioral phenotyping across multiple socio-cognitive tasks with 3-Tesla MRI cortical thickness and structural covariance analysis in 270 healthy adults, recruited across 2 sites. Regional thickness mapping only provided partial support for divergent substrates, highlighting that individual differences in empathy relate to left insular-opercular thickness while no correlation between thickness and mentalizing scores was found. Conversely, structural covariance analysis showed clearly divergent network modulations by socio-cognitive and -affective phenotypes. Specifically, individual differences in theory of mind related to structural integration between temporo-parietal and dorsomedial prefrontal regions while empathy modulated the strength of dorsal anterior insula networks. Findings were robust across both recruitment sites, suggesting generalizability. At the level of structural network embedding, our study provides a double dissociation between empathy and mentalizing. Moreover, our findings suggest that structural substrates of higher-order social cognition are reflected rather in interregional networks than in the the local anatomical markup of specific regions per se.