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Abstract Background The β-adrenergic augmentation of cardiac contraction, by increasing the conductivity of L-type voltage-gated CaV1.2 channels, is of great physiological and pathophysiological importance. Stimulation of β-adrenergic receptors (βAR) activates protein kinase A (PKA) through separation of regulatory (PKAR) from catalytic (PKAC) subunits. Free PKAC phosphorylates the inhibitory protein Rad, leading to increased Ca2+ influx. In cardiomyocytes, the core subunit of CaV1.2, CaV1.2α1, exists in two forms: full-length or truncated (lacking the distal C-terminus (dCT)). Signaling efficiency is believed to emanate from protein interactions within multimolecular complexes, such as anchoring PKA (via PKAR) to CaV1.2α1 by A-kinase anchoring proteins (AKAPs). However, AKAPs are inessential for βAR regulation of CaV1.2 in heterologous models, and their role in cardiomyocytes also remains unclear. Results We show that PKAC interacts with CaV1.2α1 in heart and a heterologous model, independently of Rad, PKAR, or AKAPs. Studies with peptide array assays and purified recombinant proteins demonstrate direct binding of PKAC to two domains in CaV1.2α1-CT: the proximal and distal C-terminal regulatory domains (PCRD and DCRD), which also interact with each other. Data indicate both partial competition and possible simultaneous interaction of PCRD and DCRD with PKAC. The βAR regulation of CaV1.2α1 lacking dCT (which harbors DCRD) was preserved, but subtly altered, in a heterologous model, the Xenopus oocyte. Conclusions We discover direct interactions between PKAC and two domains in CaV1.2α1. We propose that these tripartite interactions, if present in vivo, may participate in organizing the multimolecular signaling complex and fine-tuning the βAR effect in cardiomyocytes.

Abstract ARL5 is a member of the ARF family of small GTPases that is recruited to the trans-Golgi network (TGN) by another ARF-family member, ARFRP1, in complex with the transmembrane protein SYS1. ARL5 recruits its effector, the multisubunit tethering complex GARP, to promote SNARE-dependent fusion of endosome-derived retrograde transport carriers with the TGN. To further investigate the function of ARL5, we sought to identify additional effectors. Using proximity biotinylation and protein interaction assays, we found that the armadillo-repeat protein ARMH3 (C10orf76) binds to active, but not inactive, ARL5, and that it is recruited to the TGN in a SYS1-ARFRP1-ARL5-dependent manner. Unlike GARP, ARMH3 is not required for the retrograde transport of various cargo proteins. Instead, ARMH3 functions to activate phosphatidylinositol 4-kinase IIIβ (PI4KB), accounting for the main pool of phosphatidylinositol 4-phosphate (PI4P) at the TGN. This function contributes to recruitment of the oncoprotein GOLPH3 and glycan modifications at the TGN. These studies thus identify the SYS1-ARFRP1-ARL5-ARMH3 axis as a regulator of PI4KB-dependent generation of PI4P at the TGN.

Long-term plasticity at pyramidal cell to basket cell (PC → BC) synapses is important for the functioning of cortical microcircuits. It is well known that at neocortical PC → PC synapses, dendritic calcium (Ca2+) dynamics signal coincident pre-and postsynaptic spiking which in turn triggers long-term potentiation (LTP). However, the link between dendritic Ca2+ dynamics and long-term plasticity at PC → BC synapses of primary visual cortex (V1) is not as well known. Here, we explored if PC → BC synaptic plasticity in developing V1 is sensitive to postsynaptic spiking. Two-photon (2P) Ca2+ imaging revealed that action potentials (APs) in dendrites of V1 layer-5 (L5) BCs back-propagated decrementally but actively to the location of PC → BC putative synaptic contacts. Pairing excitatory inputs with postsynaptic APs elicited dendritic Ca2+ supralinearities for pre-before-postsynaptic but not post-before-presynaptic temporal ordering, suggesting that APs could impact synaptic plasticity. In agreement, extracellular stimulation as well as high-throughput 2P optogenetic mapping of plasticity both revealed that pre-before-postsynaptic but not post-before-presynaptic pairing resulted in anti-Hebbian long-term depression (LTD). Our results demonstrate that V1 BC dendritic Ca2+ nonlinearities and synaptic plasticity at PC → BC connections are both sensitive to somatic spiking.

Abstract Differential diagnosis is a crucial aspect of medical practice, as it guides clinicians to accurate diagnoses and effective treatment plans. Traditional resources, such as medical books and services like UpToDate, are constrained by manual curation, potentially missing out on novel or less common findings. This paper introduces and analyzes two novel methods to mine etiologies from scientific literature. The first method employs a traditional Natural Language Processing (NLP) approach based on syntactic patterns. By using a novel application of human-guided pattern bootstrapping patterns are derived quickly, and symptom etiologies are extracted with significant coverage. The second method utilizes generative models, specifically GPT-4, coupled with a fact verification pipeline, marking a pioneering application of generative techniques in etiology extraction. Analyzing this second method shows that while it is highly precise, it offers lesser coverage compared to the syntactic approach. Importantly, combining both methodologies yields synergistic outcomes, enhancing the depth and reliability of etiology mining.

Abstract Background Hybrid models that integrate both in-person and remote health services are increasingly recognized as a promising approach. Nevertheless, research that defines and characterizes these models in children and young people is scarce and essential for establishing guidelines for implementation of hybrid allied health services. This scoping review evaluates four key aspects of hybrid allied health services in children and young people: 1. definitions, 2. service characteristics, 3. outcome measures, and 4. results of hybrid allied health services. Methods Six databases were searched: Medline (Ovid), Embase, CINHAL, Psycinfo, Cochrane CENTRAL, and Web of Science. Of the 9,868 studies potentially meeting the inclusion criteria, 49 studies focused on children and young people. Following full-text review, n = 21 studies were included. Results Terminology used for hybrid allied health services varied across studies which targeted diverse clinical populations and varied in study design, type and frequency of remote and in-person treatments. Over 75% of cases used custom-written software, limiting scalability. All interventions started in-person, possibly to establish a therapeutic alliance and solve technological issues. Most hybrid allied health services (67%) were in mental health, while only a minority involved physical, occupational or speech therapy. The most common outcomes were feasibility and satisfaction, but tools used to measure them were inconsistent. Although 57% of studies demonstrated effectiveness of hybrid allied health services, none measured cost-effectiveness. Discussion Despite the potential of hybrid allied health services for children and young people, the literature remains at a preliminary stage. Standardization of definitions and outcome measures, and clearer reporting of service characteristics and results would likely promote consolidation of hybrid allied health services in children and young people into clinical practice.

IntroductionMany employees perceived the move to remote work due to the COVID-19 pandemic as an abrupt organizational change. While research on work engagement has examined this construct in different contexts, it is unclear what may happen to work engagement in such an extreme context and over the course of time. In the current study, we examined the relationship between time and employees' work engagement after an abrupt change as well as the way job crafting interacts with this relationship. We hypothesized that a pre-transition high level of approach crafting strategies will have a negative effect, harming employees' ability to maintain their engagement over time, while a pre-transition high level of avoidance crafting strategies will actually have a mitigating effect, weakening the decrease in engagement.MaterialsWe used a three-wave longitudinal study design, collecting data during the first 3 months of the pandemic. The sample included employees from different organizations across the U.S randomly recruited through Amazon Mechanical Turk. We utilized a multilevel repeated measures approach to analyze the data.ResultsResults supported our first hypothesis, demonstrating a negative relationship between time and engagement such that engagement declined over time. Our second hypothesis was partially supported, showing that the job crafting strategy of increasing challenging demands moderated the relationship between time and engagement, such that for employees that job craft by increasing their challenging demands, at the onset of the transition, the decrease in work engagement over time was more substantial. We did not find support for our hypothesis regarding the positive effect of avoidance crafting strategies on the decrease in work engagement.DiscussionOur findings suggest that the tendency to job craft by pursuing more challenging demands at the onset of the pandemic, as an approach strategy of job crafting, gives employees an unnecessary added workload that requires the use of more resources. Over time, this extra load, depletes resource reservoirs and prohibits remaining engaged over time. In contrast, other types of approach crafting strategies seem to have no such harmful effect. Our findings highlight the importance of context, suggesting that under specifics conditions some job crafting strategies may be more energy draining than others.

Lentiviral vector-transduced T cells were approved by the FDA as gene therapy anti-cancer medications. Little is known about the effects of host genetic variation on the safety and efficacy of the lentiviral vector gene delivery system. To narrow this knowledge gap, we characterized hepatic gene delivery by lentiviral vectors across the Collaborative Cross (CC) mouse genetic reference population. For 24 weeks, we periodically measured hepatic luciferase expression from lentiviral vectors in 41 CC mouse strains. Hepatic and splenic vector copy numbers were determined. We report that the CC mouse strains showed highly diverse outcomes following lentiviral gene delivery. For the first time, a moderate correlation between mouse-strain-specific sleeping patterns and transduction efficiency was observed. We associated two quantitative trait loci (QTLs) with intrastrain variations in transduction phenotypes, which mechanistically relates to the phenomenon of metastable epialleles. An additional QTL was associated with the kinetics of hepatic transgene expression. Genes found in the above QTLs are potential targets for personalized gene therapy protocols. Importantly, we identified two mouse strains that open new directions for characterizing continuous viral vector silencing and HIV latency. Our findings suggest that wide-range patient-specific outcomes of viral vector-based gene therapy should be expected. Thus, novel clinical protocols should be considered for non-fatal diseases.

Abstract Traditional histochemical staining of post-mortem samples often confronts inferior staining quality due to autolysis caused by delayed fixation of cadaver tissue, and such chemical staining procedures covering large tissue areas demand substantial labor, cost and time. Here, we demonstrate virtual staining of autopsy tissue using a trained neural network to rapidly transform autofluorescence images of label-free autopsy tissue sections into brightfield equivalent images, matching hematoxylin and eosin (H&E) stained versions of the same samples. The trained model can effectively accentuate nuclear, cytoplasmic and extracellular features in new autopsy tissue samples that experienced severe autolysis, such as COVID-19 samples never seen before, where the traditional histochemical staining fails to provide consistent staining quality. This virtual autopsy staining technique provides a rapid and resource-efficient solution to generate artifact-free H&E stains despite severe autolysis and cell death, also reducing labor, cost and infrastructure requirements associated with the standard histochemical staining.

The peripheral and central auditory subsystems together form a complex sensory network that allows an organism to hear. The genetic programs of the two subsystems must therefore be tightly coordinated during development. Yet, their interactions and common expression pathways have never been systematically explored. MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression and are essential for normal development of the auditory system. We performed mRNA and small-RNA sequencing of organs from both auditory subsystems at three critical developmental timepoints (E16, P0, P16) to obtain a comprehensive and unbiased insight of their expression profiles. Our analysis reveals common and organ-specific expression patterns for differentially regulated mRNAs and miRNAs, which could be clustered with a particular selection of functions such as inner ear development, Wnt signalling, K+ transport, and axon guidance, based on gene ontology. Bioinformatics detected enrichment of predicted targets of specific miRNAs in the clusters and predicted regulatory interactions by monitoring opposite trends of expression of miRNAs and their targets. This approach identified six miRNAs as strong regulatory candidates for both subsystems. Among them was miR-96, an established critical factor for proper development in both subsystems, demonstrating the strength of our approach. We suggest that other miRNAs identified by this analysis are also common effectors of proper hearing acquirement. This first combined comprehensive analysis of the developmental program of the peripheral and central auditory systems provides important data and bioinformatics insights into the shared genetic program of the two sensory subsystems and their regulation by miRNAs.

Abstract Background Post-COVID-19 condition refers to persistent or new onset symptoms occurring three months after acute COVID-19, which are unrelated to alternative diagnoses. Symptoms include fatigue, breathlessness, palpitations, pain, concentration difficulties ("brain fog"), sleep disorders, and anxiety/depression. The prevalence of post-COVID-19 condition ranges widely across studies, affecting 10–20% of patients and reaching 50–60% in certain cohorts, while the associated risk factors remain poorly understood. Methods This multicentre cohort study, both retrospective and prospective, aims to assess the incidence and risk factors of post-COVID-19 condition in a cohort of recovered patients. Secondary objectives include evaluating the association between circulating SARS-CoV-2 variants and the risk of post-COVID-19 condition, as well as assessing long-term residual organ damage (lung, heart, central nervous system, peripheral nervous system) in relation to patient characteristics and virology (variant and viral load during the acute phase). Participants will include hospitalised and outpatient COVID-19 patients diagnosed between 01/03/2020 and 01/02/2025 from 8 participating centres. A control group will consist of hospitalised patients with respiratory infections other than COVID-19 during the same period. Patients will be followed up at the post-COVID-19 clinic of each centre at 2–3, 6–9, and 12–15 months after clinical recovery. Routine blood exams will be conducted, and patients will complete questionnaires to assess persisting symptoms, fatigue, dyspnoea, quality of life, disability, anxiety and depression, and post-traumatic stress disorders. Discussion This study aims to understand post-COVID-19 syndrome's incidence and predictors by comparing pandemic waves, utilising retrospective and prospective data. Gender association, especially the potential higher prevalence in females, will be investigated. Symptom tracking via questionnaires and scales will monitor duration and evolution. Questionnaires will also collect data on vaccination, reinfections, and new health issues. Biological samples will enable future studies on post-COVID-19 sequelae mechanisms, including inflammation, immune dysregulation, and viral reservoirs. Trial registration This study has been registered with ClinicalTrials.gov under the identifier NCT05531773.

Abstract Background Delayed cerebral ischemia is a clinical entity commonly encountered in patients presenting with acute neurological injury and is often complicated by dysnatremias, such as the cerebral salt wasting syndrome. In this case report, we described an exceptional case of polyuria attributed to an initial cerebral salt wasting phenomenon and iatrogenic-induced medullary washout. Case presentation A 53-year-old woman was admitted to our hospital for the management of a Modified Fisher scale grade 4 subarachnoid hemorrhage due to a ruptured posterior communicating aneurysm. She was initially managed with coil embolization and external ventricular drain due to secondary hydrocephalus. Throughout the course of her hospitalization, she developed severe polyuria reaching up to 40L per day. To keep up with the excessive urinary losses and maintain appropriate cerebral perfusion, fluid replacement therapy was adjusted every hour, reaching up to 1.3 L of crystalloid per hour in addition to aminergic support. An initial diagnosis of partial diabetes insipidus, followed by a cerebral salt wasting syndrome was suspected. While the urine output continued to increase, her serum urea concentration progressively decreased to a point of almost being undetectable on day 9. At that time, the presence of an interstitial medulla washout was hypothesized. Various pharmacological and non-pharmacological interventions were progressively introduced to regain normal renal homeostasis, including non-steroidal anti-inflammatory drugs, fludrocortisone, oral urea and high-protein intake. Medications were progressively weaned, and the patient was successfully discharged from the ICU. Conclusions Cerebral salt wasting should be considered in the initial differential diagnosis of a patient presenting with polyuria in the context of acute neurological injury. Early recognition of this entity is critical to quickly implement proper management. However, as shown in this case report, the concomitance of delayed cerebral ischemia may complexify that management.

The global population has been gradually aging over the past few decades, with a growing proportion of people aged 65 years or older. Simultaneously, the medical profession has shifted towards promoting the concept of “positive” gerontology, emphasizing healthy aging. In this context, we investigated the trends in pathological specimen submissions from patients aged 85 or older over ten years at a single center. We observed a nearly two-fold increase in submissions during 2015–2019 compared to 2010–2014, out of proportion to the change in the fraction of older adults in the population, suggesting a changing attitude towards medical care in these older patients. Dermatologic samples were the main driver of growth, followed by gastrointestinal and urinary tract samples. However, other samples, like breast and lung, did not significantly increase. Although further research is needed to understand the implications of increasing invasive procedures in the oldest old, a noteworthy trend has emerged towards increased and more active healthcare for this population. Healthcare providers and administrators should be prepared for a continued rise in invasive interventions in this age group.

Abstract Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. The vaginal microbiome has been associated with PTB, yet the mechanisms underlying this association are not fully understood. Understanding microbial genetic adaptations to selective pressures, especially those related to the host, may yield insights into these associations. Here, we analyze metagenomic data from 705 vaginal samples collected during pregnancy from 40 women who delivered preterm spontaneously and 135 term controls from the Multi-Omic Microbiome Study-Pregnancy Initiative. We find that the vaginal microbiome of pregnancies that ended preterm exhibited unique genetic profiles. It was more genetically diverse at the species level, a result which we validate in an additional cohort, and harbored a higher richness and diversity of antimicrobial resistance genes, likely promoted by transduction. Interestingly, we find that Gardnerella species drove this higher genetic diversity, particularly during the first half of the pregnancy. We further present evidence that Gardnerella spp. underwent more frequent recombination and stronger purifying selection in genes involved in lipid metabolism. Overall, our population genetics analyses reveal associations between the vaginal microbiome and PTB and suggest that evolutionary processes acting on vaginal microbes may play a role in adverse pregnancy outcomes such as PTB.

Objective and Impact Statement: Human epidermal growth factor receptor 2 (HER2) is a critical protein in cancer cell growth that signifies the aggressiveness of breast cancer (BC) and helps predict its prognosis. Here, we introduce a deep learning-based approach utilizing pyramid sampling for the automated classification of HER2 status in immunohistochemically (IHC) stained BC tissue images. Introduction: Accurate assessment of IHC-stained tissue slides for HER2 expression levels is essential for both treatment guidance and understanding of cancer mechanisms. Nevertheless, the traditional workflow of manual examination by board-certified pathologists encounters challenges, including inter- and intra-observer inconsistency and extended turnaround times. Methods: Our deep learning-based method analyzes morphological features at various spatial scales, efficiently managing the computational load and facilitating a detailed examination of cellular and larger-scale tissue-level details. Results: This approach addresses the tissue heterogeneity of HER2 expression by providing a comprehensive view, leading to a blind testing classification accuracy of 84.70%, on a dataset of 523 core images from tissue microarrays. Conclusion: This automated system, proving reliable as an adjunct pathology tool, has the potential to enhance diagnostic precision and evaluation speed, and might substantially impact cancer treatment planning.

Freezing of Gait (FOG) is among the most debilitating symptoms of Parkinson’s Disease (PD), characterized by a sudden inability to generate effective stepping. In preparation for the development of a real-time FOG prediction and intervention device, this work presents a novel FOG prediction algorithm based on detection of altered interlimb coordination of the legs, as measured using two inertial movement sensors and analyzed using a wavelet coherence algorithm. Methods: Fourteen participants with PD (in OFF state) were asked to walk in challenging conditions (e.g. with turning, dual-task walking, etc.) while wearing inertial motion sensors (waist, 2 shanks) and being videotaped. Occasionally, participants were asked to voluntarily stop (VOL). FOG and VOL events were identified by trained researchers based on videos. Wavelet analysis was performed on shank sagittal velocity signals and a synchronization loss threshold (SLT) was defined and compared between FOG and VOL. A proof-of-concept analysis was performed for a subset of the data to obtain preliminary classification characteristics of the novel measure. Results: 128 FOG and 42 VOL episodes were analyzed. SLT occurred earlier for FOG (MED = 1.81 sec prior to stop, IQR = 1.57) than for VOL events (MED = 0.22 sec, IQR = 0.76) (Z =−4.3, p < 0.001, ES = 1.15). These time differences were not related with measures of disease severity. Preliminary results demonstrate sensitivity of 98%, specificity of 42% (mostly due to ‘turns’ detection) and balanced accuracy of 70% for SLT-based prediction, with good differentiation between FOG and VOL. Conclusions: Wavelet analysis provides a relatively simple, promising approach for prediction of FOG in people with PD.

Charisma, the captivating attribute that endows an individual with the power to inspire and influence others, is frequently associated with possessing an attractive personality, effective communication skills, and the capacity to draw people in and lead them. The concept of the trickle-down effect in leadership theory suggests that the characteristics of a leader’s style including perceptions, emotions, attitudes, and behaviors, have the potential to be “contagious” and spread to their followers. Nevertheless, it is unclear whether and when a leader’s charisma may be transferred to followers, as charisma is predominantly a trait associated with the leader. Integrating insights from the social learning, emotional contagion, and self-concept theories, we propose that charisma can cascade downward from the leader to followers and that this effect is contingent on the individual follower’s level of self-monitoring. Measuring a sample of 127 followers and 15 leaders in a large organization at two time points, we found that throughout time the leader’s charisma indeed cascaded down to followers, i.e., followers of a charismatic leader were perceived as more charismatic throughout time. However, this effect was prominent only for low-monitoring followers. Novel insights into the flow-down effect of charisma, avenues for future research, and practical implications are discussed.

Concerns have been mounting regarding the underdiagnosis of HIV among respiratory co-infections associated with the COVID-19 pandemic. The delay in recognizing HIV/AIDS may be attributed to the similarities in clinical, laboratory (lymphopenia) and imaging presentations, which are typical for advanced AIDS but could also be indicative of a COVID-19 infection.Herein, we present a case of a 38-year-old ultraorthodox Jew with a late diagnosis of AIDS in the context of COVID-19 infection. This occurred after several months of recurrent respiratory infections compounded by SARS-COV 2 infection, during which no HIV testing was conducted. As a result, a cascade of various opportunistic infections ensued, leading to an extended hospitalization period, ultimately culminating in the patient's demise despite receiving optimal treatment.

Abstract Background Cognition and motor skills are interrelated throughout the aging process and often show simultaneous deterioration among older adults with cognitive impairment. Co-dependent training has the potential to ameliorate both domains; however, its effect on the gait and cognition of older adults with cognitive impairment has yet to be explored. The aim of this study is to compare the effects of the well-established single-modality cognitive computerized training program, CogniFit, with “Thinking in Motion (TIM),” a co-dependent group intervention, among community-dwelling older adults with cognitive impairment. Methods Employing a single-blind randomized control trial design, 47 community-dwelling older adults with cognitive impairment were randomly assigned to 8 weeks of thrice-weekly trainings of TIM or CogniFit. Pre- and post-intervention assessments included cognitive performance, evaluated by a CogniFit battery, as a primary outcome; and gait, under single- and dual-task conditions, as a secondary outcome. Results CogniFit total Z scores significantly improved from baseline to post-intervention for both groups. There was a significant main effect for time [F (1, 44) = 17.43, p

BackgroundThe drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome represents a severe hypersensitivity reaction. Up-to-date treatment is based on withdrawal of medication, supportive care, and immunosuppression using high-dose corticosteroid (CS) therapy. However, evidence-based data are lacking regarding second-line therapy for steroid-resistant or steroid-dependent patients.ObjectivesWe hypothesize that the interleukin (IL)-5 axis plays a critical role in the pathophysiology of DRESS; hence, inhibition of this signaling pathway could offer a potential therapy for steroid-dependent and/or steroid-resistant cases, and it may offer an alternative to CS therapy in certain patients more prone to CS toxicity.MethodsHerein, we collected worldwide data on DRESS cases treated with biological agents targeting the IL-5 axis. We reviewed all cases indexed in PubMed up to October 2022 and performed a total analysis including our center experience with two additional novel cases.ResultsA review of the literature yielded 14 patients with DRESS who were treated with biological agents targeting the IL-5 axis as well as our two new cases. Reported patients are characterized by a female-to-male ratio of 1:1 and a mean age of 51.8 (17–87) years. The DRESS-inducing drugs, as expected from the prospective RegiSCAR study, were mostly antibiotics (7/16), as follows: vancomycin, trimethoprim-sulfamethoxazole, ciprofloxacin, piperacillin-tazobactam, and cefepime. DRESS patients were treated with anti-IL-5 agents (mepolizumab and reslizumab) or anti-IL-5 receptor (IL-5R) biologics (benralizumab). All patients have clinically improved under anti-IL-5/IL-5R biologics. Multiple doses of mepolizumab were needed to achieve clinical resolution, whereas a single dose of benralizumab was often sufficient. Relapse was noted in one patient receiving benralizumab treatment. One patient receiving benralizumab had a fatal outcome, although mortality was probably related to massive bleeding and cardiac arrest due to coronavirus disease 2019 (COVID-19) infection.ConclusionCurrent treatment guidelines for DRESS are based on case reports and expert opinion. Understanding the central role of eosinophils in DRESS pathogenicity emphasizes the need for future implementation of IL-5 axis blockade as steroid-sparing agents, potential therapy to steroid-resistant cases, and perhaps an alternative to CS treatment in certain DRESS patients more prone to CS toxicity.

Organellar transport is carefully regulated, and endolysosome localized ARL8 is important for kinesin recruitment and anterograde movement. Here, the authors show that RUFY3 and RUFY4 promote retrograde transport of endolysosomes by mediating interaction of ARL8 with dynein-dynactin.

Summary: The transfer of endocytosed cargoes to lysosomes (LYSs) requires HOPS, a multiprotein complex that tethers late endosomes (LEs) to LYSs before fusion. Many proteins interact with HOPS on LEs/LYSs. However, it is not clear whether these HOPS interactors localize to LEs or LYSs or how they participate in tethering. Here, we biochemically characterized endosomes purified from untreated or experimentally manipulated cells to put HOPS and interacting proteins in order and to establish their functional interdependence. Our results assign Rab2a and Rab7 to LEs and Arl8 and BORC to LYSs and show that HOPS drives LE-LYS fusion by bridging late endosomal Rab2a with lysosomal BORC-anchored Arl8. We further show that Rab7 is absent from sites of HOPS-dependent tethering but promotes fusion by moving LEs toward LYSs via dynein. Thus, our study identifies the topology of the machinery for LE-LYS tethering and elucidates the role of different small GTPases in the process.

Individuals with autism spectrum disorder (ASD) commonly display speech processing abnormalities. Binding of acoustic features of speech distributed across different frequencies into coherent speech objects is fundamental in speech perception. Here, we tested the hypothesis that the cortical processing of bottom-up acoustic cues for speech binding may be anomalous in ASD. We recorded magnetoencephalography while ASD children (ages 7–17) and typically developing peers heard sentences of sine-wave speech (SWS) and modulated SWS (MSS) where binding cues were restored through increased temporal coherence of the acoustic components and the introduction of harmonicity. The ASD group showed increased long-range feedforward functional connectivity from left auditory to parietal cortex with concurrent decreased local functional connectivity within the parietal region during MSS relative to SWS. As the parietal region has been implicated in auditory object binding, our findings support our hypothesis of atypical bottom-up speech binding in ASD. Furthermore, the long-range functional connectivity correlated with behaviorally measured auditory processing abnormalities, confirming the relevance of these atypical cortical signatures to the ASD phenotype. Lastly, the group difference in the local functional connectivity was driven by the youngest participants, suggesting that impaired speech binding in ASD might be ameliorated upon entering adolescence.

Stress tests, e.g., the cardiac stress test, are standard clinical screening tools aimed to unmask clinical pathology. As such stress tests indirectly measure physiological reserves. The term reserve has been developed to account for the dis-junction, often observed, between pathology and clinical manifestation. It describes a physiological capacity that is utilized in demanding situations. However, developing a new and reliable stress test based screening tool is complex, prolonged, and relies extensively on domain knowledge. We propose a novel distributional-free machine–learning framework, the Stress Test Performance Scoring (STEPS) framework, to model expected performance in a stress test. A performance scoring function is trained with measures taken during the performance in a given task while exploiting information regarding the stress test set-up and subjects’ medical state. Multiple ways of aggregating performance scores at different stress levels are suggested and are examined with an extensive simulation study. When applied to a real-world data example, an AUC of 84.35[95%CI: 70.68 − 95.13] was obtained for the STEPS framework to distinguish subjects with neurodegeneration from controls. In summary, STEPS improved screening by exploiting existing domain knowledge and state-of-the-art clinical measures. The STEPS framework can ease and speed up the production of new stress tests.

Abstract Biomechanical and molecular processes of premature cervical remodeling preceding spontaneous preterm birth (sPTB) likely result from interactions between the cervicovaginal microbiota and host immune responses. A non-optimal cervicovaginal microbiota confers increased risk of sPTB. The cervicovaginal space is metabolically active in pregancy; microbiota can produce, modify, and degrade metabolites within this ecosystem. We establish that cervicovaginal metabolomic output clusters by microbial community in pregnancy among Black individuals, revealing increased metabolism within the amino acid and dipeptide pathways as hallmarks of a non-optimal microbiota. Few differences were detected in metabolomic profiles when stratified by birth outcome. The study raises the possibility that metabolites could distinguish women with greater risk of sPTB among those with similar cervicovaginal microbiota, and that metabolites within the amino acid and carbohydrate pathways may play a role in this distinction.

Abstract Twenty years ago, molecular biology transitioned from predominantly studying genes as isolated elements to viewing them as part of complex modules, giving rise to the field of systems biology. This transition was made possible by technological advances that allowed to simultaneously measure the expression levels of thousands of genes in a single experiment and drove a shift toward analyses identifying gene sets, modules, and pathways involved in a biological process of interest. Today we are excitingly facing a similar turning point in cell biology, where single‐cell technologies have enabled us to approach cells as cellular modules.

The coronavirus SARS-CoV-2 pandemic has affected over one hundred million people worldwide and has resulted in over two million deaths. In addition to the toll that coronavirus takes on the health of humans infected with the virus and the potential long term effects of infection, the repercussions of the pandemic on the economy as well as on the healthcare system have been enormous. The global supply of equipment necessary for dealing with the pandemic experienced extreme stress as healthcare systems around the world attempted to acquire personal protective equipment for their workers and medical devices for treating COVID-19. This review describes how 3D printing is currently being used in life saving surgeries such as heart and lung surgery and how 3D printing can address some of the worldwide shortage of personal protective equipment, by examining recent trends of the use of 3D printing and how these technologies can be applied during and after the pandemic. We review the use of 3D printed models for treating the long term effects of COVID-19. We then focus on methods for generating face shields and different types of respirators. We conclude with areas for future investigation and application of 3D printing technology.

Autism Spectrum (AS) is defined primarily by differences in social interactions, with impairments in sensory processing also characterizing the condition. In the search for neurophysiological biomarkers associated with traits relevant to the condition, focusing on sensory processing offers a path that is likely to be translatable across populations with different degrees of ability, as well as into animal models and across imaging modalities. In a prior study, a somatosensory neurophysiological signature of AS was identified using magnetoencephalography (MEG). Specifically, source estimation results showed differences between AS and neurotypically developing (NTD) subjects in the brain response to 25-Hz vibrotactile stimulation of the right fingertips, with lower inter-trial coherence (ITC) observed in the AS group. Here, we examined whether these group differences can be detected without source estimation using scalp electroencephalography (EEG), which is more commonly available in clinical settings than MEG, and therefore offers a greater potential for clinical translation. To that end, we recorded simultaneous whole-head MEG and EEG in 14 AS and 10 NTD subjects (age 15–28 years) using the same vibrotactile paradigm. Based on the scalp topographies, small sets of left hemisphere MEG and EEG sensors showing the maximum overall ITC were selected for group comparisons. Significant differences between the AS and NTD groups in ITC at 25 Hz as well as at 50 Hz were recorded in both MEG and EEG sensor data. For each measure, the mean ITC was lower in the AS than in the NTD group. EEG ITC values correlated with behaviorally assessed somatosensory sensation avoiding scores. The results show that information about ITC from MEG and EEG signals have substantial overlap, and thus EEG sensor-based ITC measures of the AS somatosensory processing biomarker previously identified using source localized MEG data have a potential to be developed into clinical use in AS, thanks to the higher accessibility to EEG in clinical settings.

Persons with Parkinson’s disease (PwP) are advised to use compensatory strategies such as external cues or cognitive movement strategies to overcome gait disturbances. It is suggested that external cues involve the processing of sensory stimulation, while cognitive-movement strategies use attention allocation. This study aimed to compare over time changes in attention allocation in PwP between prolonged walking with cognitive movement strategy and external cues; to compare the effect of cognitive movement strategies and external cues on gait parameters; and evaluate whether these changes depend on cognitive function. Eleven PwP participated in a single-group pilot study. Participants walked for 10 min under each of three conditions: natural walking, using external cuing, using a cognitive movement strategy. Attention and gait variables were extracted from a single-channel electroencephalogram and accelerometers recordings, respectively. Attention allocation was assessed by the% of Brain Engagement Index (BEI) signals within an attentive engagement range. Cognitive function was assessed using a neuropsychological battery. The walk was divided into 2-min time segments, and the results from each 2-min segment were used to determine the effects of time and condition. Associations between cognitive function and BEI signals were tested. Findings show that in the cognitive movement strategy condition, there was a reduction in the % of BEI signals within the attentive engagement range after the first 2 min of walking. Despite this reduction the BEI did not consistently differ from natural and metronome walking. Spatiotemporal gait variables were better in the cognitive movement strategy condition relative to the other conditions. Global cognitive and information processing scores were significantly associated with the BEI only when the cognitive movement strategy was applied. In conclusion, the study shows that a cognitive movement strategy has positive effects on gait variables but may impose a higher attentional load. Furthermore, when walking using a cognitive movement strategy, persons with higher cognitive function showed elevated attentive engagement. The findings support the idea that cognitive and attentional resources are required for cognitive movement strategies in PwP. Additionally, this study provides support for using single-channel EEG to explore mechanistic aspects of clinical interventions.

Abstract Background Persistent postural-perceptual dizziness (PPPD) is a condition characterized by chronic subjective dizziness and exacerbated by visual stimuli or upright movement. Typical balance tests do not replicate the environments known to increase symptoms in people with PPPD—crowded places with moving objects. Using a virtual reality system, we quantified dynamic balance in people with PPPD and healthy controls in diverse visual conditions. Methods Twenty-two individuals with PPPD and 29 controls performed a square-shaped fast walking task (Four-Square Step Test Virtual Reality—FSST-VR) using a head-mounted-display (HTC Vive) under 3 visual conditions (empty train platform; people moving; people and trains moving). Head kinematics was used to measure task duration, movement smoothness and anterior–posterior (AP) and medio-lateral (ML) ranges of movement (ROM). Heart rate (HR) was monitored using a chest-band. Participants also completed a functional mobility test (Timed-Up-and-Go; TUG) and questionnaires measuring anxiety (State-Trait Anxiety Inventory; STAI), balance confidence (Activities-Specific Balance Confidence; ABC), perceived disability (Dizziness Handicap Inventory) and simulator sickness (Simulator Sickness Questionnaire). Main effects of visual load and group and associations between performance, functional and self-reported outcomes were examined. Results State anxiety and simulator sickness did not increase following testing. AP-ROM and HR increased with high visual load in both groups (p

Abstract This article is inspired by a pseudo Oxford-style debate, which was held in Tel Aviv University, Israel at the International Conference on Virtual Rehabilitation (ICVR) 2019, which is the official conference of the International Society for Virtual Rehabilitation. The debate, between two 2-person teams with a moderator, was organized by the ICVR Program committee to address the question “Will virtual rehabilitation replace clinicians?” It brought together five academics with technical, research, and/or clinical backgrounds—Gerry Fluet, Tal Krasovsky, Anat Lubetzky, Philippe Archambault, W. Geoffrey Wright—to debate the pros and cons of using virtual reality (VR) and related technologies to help assess, diagnose, treat, and track recovery, and more specifically investigate the likelihood that advanced technology will ultimately replace human clinicians. Both teams were assigned a side to defend, whether it represented their own viewpoint or not, and to take whatever positions necessary to make a persuasive argument and win the debate. In this paper we present a recapitulation of the arguments presented by both sides, and further include an in-depth consideration of the question. We attempt to judiciously lay out a number of arguments that fall along a spectrum from moderate to extreme; the most extreme and/or indefensible positions are presented for rhetorical and demonstrative purposes. Although there may not be a clear answer today, this paper raises questions which are related to the basic nature of the rehabilitation profession, and to the current and potential role of technology within it.

Study Design A retrospective cohort study. Purpose This study aims to examine the effect of tranexamic acid (TXA) on postoperative wound healing in spine surgery. Overview of Literature TXA (Cyklokapron, Hexakapron) is a widely used anti-fibrinolytic drug that is shown to be effective in mitigating hemorrhage during and after surgery by competitively blocking plasminogen in fibrinolytic cascade. Plasminogen also plays a role in inflammatory and infectious diseases. The modulation of this role by TXA may influence the development of postoperative infectious complications. Methods We collected and reviewed the charts of 110 patients who underwent spine surgery at our academic center. We used multivariate regression analysis to assess the factors affecting surgical site infection (SSI). Results Of the 110 patients included in this study, 21 patients (19%) were categorized as having postoperative wound complications, 16 patients (14%) had deep or superficial wound infection, and five patients (4%) had wound dehiscence. Patients with a higher surgical invasiveness index score, longer surgeries, and older patients were found to be at risk for wound complications. TXA was determined not to be a direct risk factor for wound healing complications and SSIs. Conclusions We found no risk of wound healing complications and SSI directly attributable to preoperative and intraoperative treatment with TXA in spine surgeries.

Abstract Clinical differentiation between cystic lesions of endodontic and non-endodontic origin is of importance because correct diagnosis may affect treatment decision making. Most radicular cysts are treated with conservative approaches and, therefore, are not surgically removed. The objective of this study was to determine the accuracy of clinical diagnosis of periapical lesions as compared to the histological findings, and to evaluate various associated factors. All biopsy specimens submitted for histological evaluation from 2002 to 2009 were assessed. Only cases of periapical lesions with complete patient data and clinical diagnosis were included. Sensitivity, specificity and accuracy of the clinical diagnosis were calculated and various patient-related factors were evaluated. Of the 4,908 cases, 183 met inclusion criteria. Histologically, there were 171 lesions of radicular cysts and 12 cases of non-endodontic cysts, including OKC and Incisive Canal Cyst. The diagnostic accuracy for clinical diagnosis for radicular cysts was 91.84% and 91.84% for non-endodontic cysts. There was a high accuracy of clinical differentiation between cystic lesions of endodontic and non-endodontic origin. However, some non-endodontic lesions may be incorrectly diagnosed clinically as lesions of endodontic origin. Histological evaluation may be necessary for the correct diagnosis. Further clinical studies are needed to evaluate clinical examination and histological diagnosis of periapical lesions.

Cortical hubs identified within resting-state networks (RSNs), areas of the cortex that have a higher-than-average number of connections, are known to be critical to typical cognitive functioning and are often implicated in disorders leading to abnormal cognitive functioning. Functionally defined cortical hubs are also known to change with age in the developing, maturing brain, mostly based on studies carried out using fMRI. We have recently used magnetoencephalography (MEG) to study the maturation trajectories of RSNs and their hubs from age 7 to 29 in 131 healthy participants with high temporal resolution. We found that maturation trajectories diverge as a function of the underlying cortical rhythm. Specifically, we found the beta band (13–30 Hz)-mediated RSNs became more locally efficient with maturation, i.e., more organized into clusters and connected with nearby regions, while gamma (31–80 Hz)-mediated RSNs became more globally efficient with maturation, i.e., prioritizing faster signal transmission between distant cortical regions. We also found that different sets of hubs were associated with each of these networks. To better understand the functional significance of this divergence, we wanted to examine the cortical functions associated with the identified hubs that grew or shrunk with maturation within each of these networks. To that end, we analyzed the results of the prior study using Neurosynth, a platform for large-scale, automated synthesis of fMRI data that links brain coordinates with their probabilistically associated terms. By mapping the Neurosynth terms associated with each of these hubs, we found that maturing hubs identified in the gamma band RSNs were more likely to be associated with bottom-up processes while maturing hubs identified in the beta band RSNs were more likely to be associated with top-down functions. The results were consistent with the idea that beta band-mediated networks preferentially support the maturation of top-down processing, while the gamma band-mediated networks preferentially support the maturation of bottom-up processing.

The diversity of autologous cells being used and investigated for cancer therapy continues to increase. Mast cells (MCs) are tissue cells that contain a unique set of anti-cancer mediators and are found in and around tumors. We sought to exploit the anti-tumor mediators in MC granules to selectively target them to tumor cells using tumor specific immunoglobin E (IgE) and controllably trigger release of anti-tumor mediators upon tumor cell engagement. We used a human HER2/neu-specific IgE to arm human MCs through the high affinity IgE receptor (FcεRI). The ability of MCs to bind to and induce apoptosis of HER2/neu-positive cancer cells in vitro and in vivo was assessed. The interactions between MCs and cancer cells were investigated in real time using confocal microscopy. The mechanism of action using cytotoxic MCs was examined using gene array profiling. Genetically manipulating autologous MC to assess the effects of MC-specific mediators have on apoptosis of tumor cells was developed using siRNA. We found that HER2/neu tumor-specific IgE-sensitized MCs bound, penetrated, and killed HER2/neu-positive tumor masses in vitro. Tunneling nanotubes formed between MCs and tumor cells are described that parallel tumor cell apoptosis. In solid tumor, human breast cancer (BC) xenograft mouse models, infusion of HER2/neu IgE-sensitized human MCs co-localized to BC cells, decreased tumor burden, and prolonged overall survival without indications of toxicity. Gene microarray of tumor cells suggests a dependence on TNF and TGFβ signaling pathways leading to apoptosis. Knocking down MC-released tryptase did not affect apoptosis of cancer cells. These studies suggest MCs can be polarized from Type I hypersensitivity-mediating cells to cytotoxic cells that selectively target tumor cells and specifically triggered to release anti-tumor mediators. A strategy to investigate which MC mediators are responsible for the observed tumor killing is described so that rational decisions can be made in the future when selecting which mediators to target for deletion or those that could further polarize them to cytotoxic MC by adding other known anti-tumor agents. Using autologous human MC may provide further options for cancer therapeutics that offers a unique anti-cancer mechanism of action using tumor targeted IgE’s.

Abstract Background Atopic dermatitis (AD) is a remitting relapsing chronic eczematous pruritic disease. Several studies suggest that gut microbiota may influence AD by immune system regulation. Methods We performed the first in‐human efficacy and safety assessment of fecal microbiota transplantation (FMT) for AD adult patients. All patients received 2 placebo transplantations followed by 4 FMTs each 2 weeks apart. AD severity and fecal microbiome profile were evaluated by the Scoring Atopic Dermatitis Score (SCORAD), the weekly frequency of topical corticosteroids usage, and gut microbiota metagenomic analysis, at the study beginning, before every FMT, and 1–8 months after the last FMT. Results Nine patients completed the study protocol. There was no significant change in the SCORAD score following the two placebo transplants. The average SCORAD score significantly decreased from baseline at Weeks 4–12 (before and 2 weeks after 4 times of FMT) (59.2 ± 34.9%, Wilcoxon p = .011), 50% and 75% decrease was achieved by 7 (77%) and 4 (44%) patients, respectively. At Week 18 (8 weeks after the last FMT) the average SCORAD score decreased from baseline at Week 4 (85.5 ± 8.4%, Wilcoxon p = .018), 50% and 75% decrease was achieved by 7 (77%) and 6 (66.7%) patients respectively. Weekly topical corticosteroids usage was diminished during the study and follow‐up period as well. Two patients had a quick relapse and were switched to a different treatment. Two patients developed exacerbations alleviated after an additional fifth FMT. Metagenomic analysis of the fecal microbiota of patients and donors showed bacterial strains transmission from donors to patients. No adverse events were recorded during the study and follow‐up period. Conclusions FMT may be a safe and effective therapeutic intervention for AD patients, associated with transfer of specific microbial species from the donors to the patients. Further studies are required to reconfirm these results.

The emergence of cancer immunotherapies utilizing adoptive cell transfer (ACT) continues to be one of the most promising strategies for cancer treatment. Mast cells (MCs) which occur throughout vascularized tissues, are most commonly associated with Type I hypersensitivity, bind immunoglobin E (IgE) with high affinity, produce anti-cancer mediators such as tumor necrosis factor alpha (TNF-α) and granulocyte macrophage colony-stimulating factor (GM-CSF), and generally populate the tumor microenvironments. Yet, the role of MCs in cancer pathologies remains controversial with evidence for both anti-tumor and pro-tumor effects. Here, we review the studies examining the role of MCs in multiple forms of cancer, provide an alternative, MC-based hypothesis underlying the mechanism of therapeutic tumor IgE efficacy in clinical trials, and propose a novel strategy for using tumor-targeted, IgE-sensitized MCs as a platform for developing new cellular cancer immunotherapies. This autologous MC cancer immunotherapy could have several advantages over current cell-based cancer immunotherapies and provide new mechanistic strategies for cancer therapeutics alone or in combination with current approaches.

Organizing sensory information into coherent perceptual objects is fundamental to everyday perception and communication. In the visual domain, indirect evidence from cortical responses suggests that children with autism spectrum disorder (ASD) have anomalous figure-ground segregation. While auditory processing abnormalities are common in ASD, especially in environments with multiple sound sources, to date, the question of scene segregation in ASD has not been directly investigated in audition. Using magnetoencephalography, we measured cortical responses to unattended (passively experienced) auditory stimuli while parametrically manipulating the degree of temporal coherence that facilitates auditory figure-ground segregation. Results from 21 children with ASD (aged 7-17 years) and 26 age- and IQ-matched typically developing children provide evidence that children with ASD show anomalous growth of cortical neural responses with increasing temporal coherence of the auditory figure. The documented neurophysiological abnormalities did not depend on age, and were reflected both in the response evoked by changes in temporal coherence of the auditory scene and in the associated induced gamma rhythms. Furthermore, the individual neural measures were predictive of diagnosis (83% accuracy) and also correlated with behavioral measures of ASD severity and auditory processing abnormalities. These findings offer new insight into the neural mechanisms underlying auditory perceptual deficits and sensory overload in ASD, and suggest that temporal-coherence-based auditory scene analysis and suprathreshold processing of coherent auditory objects may be atypical in ASD.

Summary: Mutations in the GNB1 gene, encoding the Gβ1 subunit of heterotrimeric G proteins, cause GNB1 Encephalopathy. Patients experience seizures, pointing to abnormal activity of ion channels or neurotransmitter receptors. We studied three Gβ1 mutations (K78R, I80N and I80T) using computational and functional approaches. In heterologous expression models, these mutations did not alter the coupling between G protein-coupled receptors to Gi/o, or the Gβγ regulation of the neuronal voltage-gated Ca2+ channel CaV2.2. However, the mutations profoundly affected the Gβγ regulation of the G protein-gated inwardly rectifying potassium channels (GIRK, or Kir3). Changes were observed in Gβ1 protein expression levels, Gβγ binding to cytosolic segments of GIRK subunits, and in Gβγ function, and included gain-of-function for K78R or loss-of-function for I80T/N, which were GIRK subunit-specific. Our findings offer new insights into subunit-dependent gating of GIRKs by Gβγ, and indicate diverse etiology of GNB1 Encephalopathy cases, bearing a potential for personalized treatment.

A central paradigm in microbiome data analysis, which we term the genome-centric paradigm, is that a linear (nonbranching) DNA sequence is the ideal representation of a microbial genome. This representation is natural, as microbes indeed have nonbranching genomes.

Background:. Transgender women seeking gender-affirming breast augmentation often present with differences in preoperative chest measurements and contours in comparison with cisgender women. These include a more robust pectoralis muscle and limited glandular tissue, raising important considerations in determining the optimal anatomical plane for implantation. Abundant literature has described advantages and drawbacks of the available planes for breast augmentation in cisgender women. Certain drawbacks may be more pronounced for transgender women, given their distinct anatomy. The subfascial plane offers lower complication rates than the subglandular plane when using smooth implants, and avoids implant animation and displacement associated with the subpectoral plane. To our knowledge, existing studies have not yet addressed this discussion in the transfeminine population. The goal of this article is to highlight potential benefits of the subfascial plane for gender-affirming breast augmentation, utilizing a case series of 3 transfeminine patients, and to review the literature on surgical techniques and outcomes in this population. Methods:. A retrospective chart review of patients presenting to a single surgeon for gender-affirming breast augmentation in 2019 was performed. A narrative literature review on surgical techniques and outcomes for gender-affirming breast augmentation was conducted. Results:. Three cases of gender-affirming breast augmentation using subfascial implant placement are described. From the literature search, 12 articles inclusive of 802 transfeminine patients were identified. Conclusions:. The subfascial plane represents an option for implant placement in gender-affirming breast augmentation that merits further investigation. There is a need for more research comparing surgical techniques and outcomes in the transfeminine population.

The neurophysiology of face processing has been studied extensively in the context of social impairments associated with autism spectrum disorder (ASD), but the existing studies have concentrated mainly on univariate analyses of responses to upright faces, and, less frequently, inverted faces. The small number of existing studies on neurophysiological responses to inverted face in ASD have used univariate approaches, with divergent results. Here, we used a data-driven, classification-based, multivariate machine learning decoding approach to investigate the temporal and spatial properties of the neurophysiological evoked response for upright and inverted faces, relative to the neurophysiological evoked response for houses, a neutral stimulus. 21 (2 females) ASD and 29 (4 females) TD participants ages 7 to 19 took part in this study. Group level classification accuracies were obtained for each condition, using first the temporal domain of the evoked responses, and then the spatial distribution of the evoked responses on the cortical surface, each separately. We found that classification of responses to inverted neutral faces vs. houses was less accurate in ASD compared to TD, in both the temporal and spatial domains. In contrast, there were no group differences in the classification of evoked responses to upright neutral faces relative to houses. Using the classification in the temporal domain, lower decoding accuracies in ASD were found around 120 ms and 170 ms, corresponding the known components of the evoked responses to faces. Using the classification in the spatial domain, lower decoding accuracies in ASD were found in the right superior marginal gyrus (SMG), intra-parietal sulcus (IPS) and posterior superior temporal sulcus (pSTS), but not in core face processing areas. Importantly, individual classification accuracies from both the temporal and spatial classifiers correlated with ASD severity, confirming the relevance of the results to the ASD phenotype.