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Key Points Extracellular vesicle (EV) research in Gram-positive bacteria, mycobacteria and fungi was neglected until recently, owing to the presumption that vesicles could not traverse the thick cell walls found in these organisms. EVs are now understood to be produced by all types of microorganism, including those with thick cell walls, and are biologically active. EVs from bacteria, mycobacteria and fungi contain virulence factors, such as toxins, that are involved in pathogenesis and elicit strong host immune responses. For example, Cryptococcus neoformans EVs carry the capsular polysaccharide glucuronoxylomannan, which is an important virulence factor. Interaction of EVs with the host is specific to the microorganism from which the EVs were produced and is based on the lipid content and cargo of the EVs. Research into EVs produced by microorganisms with thick cell walls is a very young field. By learning how these microorganisms use EVs, we hope that researchers will gain insight into pathogenesis, therapeutics and vaccines. How extracellular vesicles traverse the thick cell walls of Gram-positive bacteria, mycobacteria and fungi has perplexed researchers. In this Review, Prados-Rosales and colleagues consider possible solutions to this conundrum and describe the diverse functions of the extracellular vesicles produced by these organisms. Extracellular vesicles (EVs) are produced by all domains of life. In Gram-negative bacteria, EVs are produced by the pinching off of the outer membrane; however, how EVs escape the thick cell walls of Gram-positive bacteria, mycobacteria and fungi is still unknown. Nonetheless, EVs have been described in a variety of cell-walled organisms, including Staphylococcus aureus , Mycobacterium tuberculosis and Cryptococcus neoformans . These EVs contain varied cargo, including nucleic acids, toxins, lipoproteins and enzymes, and have important roles in microbial physiology and pathogenesis. In this Review, we describe the current status of vesiculogenesis research in thick-walled microorganisms and discuss the cargo and functions associated with EVs in these species.

Reluctance to make eye contact during natural interactions is a central diagnostic criterion for autism spectrum disorder (ASD). However, the underlying neural correlates for eye contacts in ASD are unknown, and diagnostic biomarkers are active areas of investigation. Here, neuroimaging, eye-tracking, and pupillometry data were acquired simultaneously using two-person functional near-infrared spectroscopy (fNIRS) during live “in-person” eye-to-eye contact and eye-gaze at a video face for typically-developed (TD) and participants with ASD to identify the neural correlates of live eye-to-eye contact in both groups. Comparisons between ASD and TD showed decreased right dorsal-parietal activity and increased right ventral temporal-parietal activity for ASD during live eye-to-eye contact (p≤0.05, FDR-corrected) and reduced cross-brain coherence consistent with atypical neural systems for live eye contact. Hypoactivity of right dorsal-parietal regions during eye contact in ASD was further associated with gold standard measures of social performance by the correlation of neural responses and individual measures of: ADOS-2, Autism Diagnostic Observation Schedule, 2 nd Edition (r = -0.76, -0.92 and -0.77); and SRS-2, Social Responsiveness Scale, Second Edition (r = -0.58). The findings indicate that as categorized social ability decreases, neural responses to real eye-contact in the right dorsal parietal region also decrease consistent with a neural correlate for social characteristics in ASD.

Functional magnetic resonance imaging of brain responses to biological motion in children with autism spectrum disorder (ASD), unaffected siblings (US) of children with ASD, and typically developing (TD) children has revealed three types of neural signatures: (i) state activity, related to the state of having ASD that characterizes the nature of disruption in brain circuitry; (ii) trait activity, reflecting shared areas of dysfunction in US and children with ASD, thereby providing a promising neuroendophenotype to facilitate efforts to bridge genomic complexity and disorder heterogeneity; and (iii) compensatory activity, unique to US, suggesting a neural system—level mechanism by which US might compensate for an increased genetic risk for developing ASD. The distinct brain responses to biological motion exhibited by TD children and US are striking given the identical behavioral profile of these two groups. These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

Cryptococcus neoformans is an encapsulated fungal pathogen that causes cryptococcosis, which is a major opportunistic infection in immunosuppressed individuals. Mammalian β-galactoside-binding protein Galectin-3 (Gal-3) modulates the host innate and adaptive immunity, and plays significant roles during microbial infections including some fungal diseases. Here we show that this protein plays a role also in C . neoformans infection. We find augmented Gal-3 serum levels in human and experimental infections, as well as in spleen, lung, and brain tissues of infected mice. Gal-3-deficient mice are more susceptible to cryptococcosis than WT animals, as demonstrated by the higher fungal burden and lower animal survival. In vitro experiments show that Gal-3 inhibits fungal growth and exerts a direct lytic effect on C . neoformans extracellular vesicles (EVs). Our results indicate a direct role for Gal-3 in antifungal immunity whereby this molecule affects the outcome of C . neoformans infection by inhibiting fungal growth and reducing EV stability, which in turn could benefit the host. The protein Galectin-3 modulates host immunity and plays roles during infections. Here, Almeida et al. show that this protein contributes to host defence against infection with the fungal pathogen Cryptococcus neoformans by inhibiting fungal growth and inducing lysis of fungal extracellular vesicles.

Background Deficits in establishing and maintaining eye-contact are early and persistent vulnerabilities of autism spectrum disorder (ASD), and the neural bases of these deficits remain elusive. A promising hypothesis is that social features of autism may reflect difficulties in making predictions about the social world under conditions of uncertainty. However, no research in ASD has examined how predictability impacts the neural processing of eye-contact in naturalistic interpersonal interactions. Method We used eye tracking to facilitate an interactive social simulation wherein onscreen faces would establish eye-contact when the participant looked at them. In Experiment One, receipt of eye-contact was unpredictable; in Experiment Two, receipt of eye-contact was predictable. Neural response to eye-contact was measured via the N170 and P300 event-related potentials (ERPs). Experiment One included 23 ASD and 46 typically developing (TD) adult participants. Experiment Two included 25 ASD and 43 TD adult participants. Results When receipt of eye-contact was unpredictable, individuals with ASD showed increased N170 and increased, but non-specific, P300 responses. The magnitude of the N170 responses correlated with measures of sensory and anxiety symptomology, such that increased response to eye-contact was associated with increased symptomology. However, when receipt of eye-contact was predictable, individuals with ASD, relative to controls, exhibited slower N170s and no differences in the amplitude of N170 or P300. Limitations Our ASD sample was composed of adults with IQ > 70 and included only four autistic women. Thus, further research is needed to evaluate how these results generalize across the spectrum of age, sex, and cognitive ability. Additionally, as analyses were exploratory, some findings failed to survive false-discovery rate adjustment. Conclusions Neural response to eye-contact in ASD ranged from attenuated to hypersensitive depending on the predictability of the social context. These findings suggest that the vulnerabilities in eye-contact during social interactions in ASD may arise from differences in anticipation and expectation of eye-contact in addition to the perception of gaze alone.

Pivotal Response Treatment (PRT) is an empirically validated behavioral treatment for individuals with autism spectrum disorders (ASD). The purpose of the current study was to assess the efficacy of PRT for ten cognitively-able preschool-aged children with ASD in the context of a short-duration (4-month) treatment model. Most research on PRT used individual behavioral goals as outcome measures, but the current study utilized standardized assessments of broader-based social communication and adaptive skills. The children made substantial gains; however, magnitude and consistency of response across measures were variable. The results provide additional support for the efficacy of PRT as well as evidence for improvements in higher-order social communication and adaptive skill development within the context of a short-duration PRT model.

Research on the experiences of siblings of individuals with ASD and the quality of their sibling relationships has yielded mixed results. The present study examined the significance of parent- versus child-report of both positive and negative behaviors exhibited by siblings and their brothers and sisters with ASD within sibling dyads. Findings indicated that siblings were more positive in their assessment of the sibling relationship than were their parents. Siblings exhibited more positive behaviors within the sibling relationship than did their brothers and sisters with ASD, and were recipients of aggression. These findings are consistent with prior research suggesting that siblings tend to take on a caretaking role, and point to important targets for intervention.

The neural bases of autism are poorly understood at the molecular level, but evidence from animal models, genetics, post-mortem studies, and single-gene disorders implicate synaptopathology. Here, we use positron emission tomography (PET) to assess the density of synapses with synaptic vesicle glycoprotein 2A (SV2A) in autistic adults using 11 C-UCB-J. Twelve autistic (mean (SD) age 25 (4) years; six males), and twenty demographically matched non-autistic individuals (26 (3) years; eleven males) participated in a 11 C-UCB-J PET scan. Binding potential, BP ND , was the primary outcome measure and computed with the centrum semiovale as the reference region. Partial volume correction with Iterative Yang was applied to control for possible volumetric differences. Mixed-model statistics were calculated for between-group differences. Relationships to clinical characteristics were evaluated based on clinician ratings of autistic features. Whole cortex synaptic density was 17% lower in the autism group ( p  = 0.01). All brain regions in autism had lower 11 C-UCB-J BP ND compared to non-autistic participants. This effect was evident in all brain regions implicated in autism. Significant differences were observed across multiple individual regions, including the prefrontal cortex (−15%, p  = 0.02), with differences most pronounced in gray matter ( p  < 0.0001). Synaptic density was significantly associated with clinical measures across the whole cortex ( r  = 0.67, p  = 0.02) and multiple regions ( r s = −0.58 to −0.82, p s = 0.05 to <0.01). The first in vivo investigation of synaptic density in autism with PET reveals pervasive and large-scale lower density in the cortex and across multiple brain areas. Synaptic density also correlated with clinical features, such that a greater number of autistic features were associated with lower synaptic density. These results indicate that brain-wide synaptic density may represent an as-yet-undiscovered molecular basis for the clinical phenotype of autism and associated pervasive alterations across a diversity of neural processes.

The opportunistic pathogen Candida albicans can grow over a wide pH range, which is associated with its ability to colonize and infect distinct host niches. C. albicans growth in neutral-alkaline environments requires proteolytic activation of the transcription factor Rim101. Rim101 activation requires Snf7, a member of the endosomal sorting complex required for transport (ESCRT) pathway. We hypothesized that Snf7 has distinct functions in the Rim101 and ESCRT pathways, which we tested by alanine-scanning mutagenesis. While some snf7 alleles conferred no defects, we identified alleles with solely ESCRT-dependent, solely Rim101-dependent, or both Rim101- and ESCRT-dependent defects. Thus, Snf7 function in these two pathways is at least partially separable. Both Rim101- and ESCRT-dependent functions require Snf7 recruitment to the endosomal membrane and alleles that disrupted both pathways were found to localize normally, suggesting a downstream defect. Most alleles that conferred solely Rim101-dependent defects were still able to process Rim101 normally under steady-state conditions. However, these same strains did display a kinetic defect in Rim101 processing. Several alleles with solely Rim101-dependent defects mapped to the C-terminal end of Snf7. Further analyses suggested that these mutations disrupted interactions with bro-domain proteins, Rim20 and Bro1, in overlapping but slightly divergent Snf7 domains.

TRAIL preferentially induces apoptosis in tumor cells and virus-infected cells. Unlike other tumor necrosis factor family members, TRAIL does not kill cells from most normal tissues and has thus been proposed as a promising new cancer treatment. Our study demonstrated that IFN γ combined with TRAIL can trigger apoptosis in vitro in several resistant thyroid tumor cell lines, such as thyroid anaplastic carcinoma cells (ARO cells), while either agent alone exerts only a minimal effect. We further tested this effect on a mouse thyroid tumor model, when in vivo tumor growth was also significantly inhibited by this combination. The mechanism of how IFN γ sensitized thyroid carcinoma cells to TRAIL-induced apoptosis was investigated by screening global gene alterations in ARO cells treated with IFN γ . Microarray data revealed that a proapoptotic gene, Bak, is markedly upregulated by IFN γ , and this was confirmed by RNase protection assay. Western blot analysis also showed a significant increase in Bak at the protein level. Upregulation of Bak and sensitization for apoptosis by IFN γ was blocked by overexpression of antisense Bak in ARO cells. Furthermore, overexpression of Bak sensitized ARO cell to TRAIL-induced apoptosis without the need for IFN γ pretreatment. This suggests that Bak is a regulatory molecule involved in IFN γ -facilitated TRAIL-mediated apoptosis in thyroid cancer cells.