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Abstract Functional connectivity holds promise as a biomarker of schizophrenia. Yet, the high dimensionality of predictive models trained on functional connectomes, combined with small sample sizes in clinical research, increases the risk of overfitting. Recently, low-dimensional representations of the connectome such as macroscale cortical gradients and gradient dispersion have been proposed, with studies noting consistent gradient and dispersion differences in psychiatric conditions. However, it is unknown which of these derived measures has the highest predictive capacity and how they compare to raw functional connectivity specifically in the case of schizophrenia. Our study evaluates which connectome features derived from resting state functional MRI — functional connectivity, gradients, or gradient dispersion — best identify schizophrenia. To this end, we leveraged data of 936 individuals from three large open-access datasets: COBRE, LA5c, and SRPBS-1600. We developed a pipeline which allows us to aggregate over a million different features and assess their predictive potential in a single, computationally efficient experiment. We selected top 1% of features with the largest permutation feature importance and trained 13 classifiers on them using 10-fold cross-validation. Our findings indicate that functional connectivity outperforms its low-dimensional derivatives such as cortical gradients and gradient dispersion in identifying schizophrenia (Mann–Whitney test conducted on test accuracy: connectivity vs. 1st gradient: U = 142, p

Abstract Psychological states influence our happiness and productivity; however, estimates of their impact have historically been assumed to be limited by the accuracy with which introspection can quantify them. Over the last two decades, studies have shown that introspective descriptions of psychological states correlate with objective indicators of cognition, including task performance and metrics of brain function, using techniques like functional magnetic resonance imaging (fMRI). Such evidence suggests it may be possible to quantify the mapping between self-reports of experience and objective representations of those states (e.g., those inferred from measures of brain activity). Here, we used machine learning to show that self-reported descriptions of experiences across tasks can reliably map the objective landscape of task states derived from brain activity. In our study, 194 participants provided descriptions of their psychological states while performing tasks for which the contribution of different brain systems was available from prior fMRI studies. We used machine learning to combine these reports with descriptions of brain function to form a ‘state-space’ that reliably predicted patterns of brain activity based solely on unseen descriptions of experience (N = 101). Our study demonstrates that introspective reports can share information with the objective task landscape inferred from brain activity.

Infantile perianal pyramidal protrusion is characterized by a light pink to skin-colored soft tissue protrusion that is often midline and anterior [A1]to the anus. It most commonly occurs in young females and is relatively asymptomatic. Although biopsies are not routinely done, histopathology is relatively nonspecific and can appear similar to an acrochordon. The differential diagnosis is broad and clinical misdiagnosis as condyloma can lead to unnecessary accusations of child abuse. We report a case of perianal pyramidal protrusion that was originally biopsied owing to concern of condyloma acuminatum or molluscum. This case raises awareness of this diagnosis to help avoid unnecessary procedures and prevent emotional distress that could come for families with an inaccurate diagnosis of condyloma in young children.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease. We are at the nexus of creating avatars (herein defined as an extension of digital twins) of human patho/physiology to serve as paradigms for interrogation and potential intervention. Motivated by the emergence of these new capabilities, the IEEE Engineering in Medicine and Biology Society, the Departments of Biomedical Engineering at Johns Hopkins University and Bioengineering at University of California at San Diego sponsored an interdisciplinary workshop to define the grand challenges that face biomedical engineering and the mechanisms to address these challenges. The Workshop identified five grand challenges with cross-cutting themes and provided a roadmap for new technologies, identified new training needs, and defined the types of interdisciplinary teams needed for addressing these challenges. The themes presented in this paper include: 1) accumedicine through creation of avatars of cells, tissues, organs and whole human; 2) development of smart and responsive devices for human function augmentation; 3) exocortical technologies to understand brain function and treat neuropathologies; 4) the development of approaches to harness the human immune system for health and wellness; and 5) new strategies to engineer genomes and cells.

Background: The hostile immune environment created by allotransplantation can accelerate pathologic tissue remodeling. Both overt and indolent inflammatory insults propel this remodeling, but there is a paucity of tools for monitoring the speed and severity of remodeling over time. Methods: This retrospective cohort consisted of n = 2,167 digitized heart transplant biopsy slides along with records of prior inflammatory events and future allograft outcomes (cardiac death or allograft vasculopathy). Utilizing computational pathology analysis, biopsy images were analyzed to identify the pathologic stromal changes associated with future allograft loss or vasculopathy. Biopsy images were then analyzed to assess which historical inflammatory events drive progression of these pathologic stromal changes. Results: The top 5 features of pathologic stromal remodeling most associated with adverse allograft outcomes were also strongly associated with histories of both overt and indolent inflammatory events. Compared to controls, a history of high-grade or treated rejection was significantly associated with progressive pathologic remodeling and future adverse outcomes (32.9% vs 5.1%, p

Processing pathways between sensory and default mode network (DMN) regions support recognition, navigation, and memory but their organisation is not well understood. We show that functional subdivisions of visual cortex and DMN sit at opposing ends of parallel streams of information processing that support visually mediated semantic and spatial cognition, providing convergent evidence from univariate and multivariate task responses, intrinsic functional and structural connectivity. Participants learned virtual environments consisting of buildings populated with objects, drawn from either a single semantic category or multiple categories. Later, they made semantic and spatial context decisions about these objects and buildings during functional magnetic resonance imaging. A lateral ventral occipital to fronto-temporal DMN pathway was primarily engaged by semantic judgements, while a medial visual to medial temporal DMN pathway supported spatial context judgements. These pathways had distinctive locations in functional connectivity space: the semantic pathway was both further from unimodal systems and more balanced between visual and auditory-motor regions compared with the spatial pathway. When semantic and spatial context information could be integrated (in buildings containing objects from a single category), regions at the intersection of these pathways responded, suggesting that parallel processing streams interact at multiple levels of the cortical hierarchy to produce coherent memory-guided cognition.

Movie-watching is a central aspect of our lives and an important paradigm for understanding the brain mechanisms behind cognition as it occurs in daily life. Contemporary views of ongoing thought argue that the ability to make sense of events in the ‘here and now’ depend on the neural processing of incoming sensory information by auditory and visual cortex, which are kept in check by systems in association cortex. However, we currently lack an understanding of how patterns of ongoing thoughts map onto the different brain systems when we watch a film, partly because methods of sampling experience disrupt the dynamics of brain activity and the experience of movie-watching. Our study established a novel method for mapping thought patterns onto the brain activity that occurs at different moments of a film, which does not disrupt the time course of brain activity or the movie-watching experience. We found moments when experience sampling highlighted engagement with multi-sensory features of the film or highlighted thoughts with episodic features, regions of sensory cortex were more active and subsequent memory for events in the movie was better—on the other hand, periods of intrusive distraction emerged when activity in regions of association cortex within the frontoparietal system was reduced. These results highlight the critical role sensory systems play in the multi-modal experience of movie-watching and provide evidence for the role of association cortex in reducing distraction when we watch films.

AbstractThe American Institute for Medical and Biological Engineering (AIMBE) hosted a virtual symposium titled “Diversifying Paths to Academic Leadership” on January 27 and 28, 2022. The symposium sought to educate the community on the opportunities for and impact of leadership by biomedical engineering faculty, to encourage and invite women faculty, especially women of color, to consider and prepare to pursue leadership roles, to educate faculty on the expectations and duties of these roles, and to highlight experiences and paths to leadership of women engineering leaders. Here we review the main outcomes of the symposium to provide perspective on (1) personal visioning and positioning for leadership, (2) negotiating for success in leadership positions, and (3) leadership strategies for success specific to women faculty and where applicable, faculty of color.

Complex macro-scale patterns of brain activity that emerge during periods of wakeful rest provide insight into the organisation of neural function, how these differentiate individuals based on their traits, and the neural basis of different types of self-generated thoughts. Although brain activity during wakeful rest is valuable for understanding important features of human cognition, its unconstrained nature makes it difficult to disentangle neural features related to personality traits from those related to the thoughts occurring at rest. Our study builds on recent perspectives from work on ongoing conscious thought that highlight the interactions between three brain networks – ventral and dorsal attention networks, as well as the default mode network. We combined measures of personality with state-of-the-art indices of ongoing thoughts at rest and brain imaging analysis and explored whether this ‘tri-partite’ view can provide a framework within which to understand the contribution of states and traits to observed patterns of neural activity at rest. To capture macro-scale relationships between different brain systems, we calculated cortical gradients to describe brain organisation in a low-dimensional space. Our analysis established that for more introverted individuals, regions of the ventral attention network were functionally more aligned to regions of the somatomotor system and the default mode network. At the same time, a pattern of detailed self-generated thought was associated with a decoupling of regions of dorsal attention from regions in the default mode network. Our study, therefore, establishes that interactions between attention systems and the default mode network are important influences on ongoing thought at rest and highlights the value of integrating contemporary perspectives on conscious experience when understanding patterns of brain activity at rest.

Background: Short mindfulness-based interventions have gained traction in research due to their positive impact on well-being, cognition, and clinical symptoms across various settings. However, these short-term trainings are viewed as preliminary steps within a more extensive transformative path, presumably leading to long-lasting trait changes. Despite this, little is still known about the brain correlates of these meditation traits. Methods: To address this gap, we investigated the neural correlates of meditation expertise in long-term Buddhist practitioners, comparing the large-scale brain functional connectivity of 28 expert meditators with 47 matched novices. Our hypothesis posited that meditation expertise would be associated with specific and enduring patterns of functional connectivity present during both meditative (open monitoring/open presence and loving-kindness and compassion meditations) and nonmeditative resting states, as measured by connectivity gradients. Results: Applying a support vector classifier to states not included in training, we successfully decoded expertise as a trait, demonstrating its non–state-dependent nature. The signature of expertise was further characterized by an increased integration of large-scale brain networks, including the dorsal and ventral attention, limbic, frontoparietal, and somatomotor networks. The latter correlated with a higher ability to create psychological distance from thoughts and emotions. Conclusions: Such heightened integration of bodily maps with affective and attentional networks in meditation experts could point toward a signature of the embodied cognition cultivated in these contemplative practices.

This work focuses on molecules that are encoded by the major histocompatibility complex (MHC) and that bind self-, foreign- or tumor-derived peptides and display these at the cell surface for recognition by receptors on T lymphocytes (T cell receptors, TCR) and natural killer (NK) cells. The past few decades have accumulated a vast knowledge base of the structures of MHC molecules and the complexes of MHC/TCR with specificity for many different peptides. In recent years, the structures of MHC-I molecules complexed with chaperones that assist in peptide loading have been revealed by X-ray crystallography and cryogenic electron microscopy. These structures have been further studied using mutagenesis, molecular dynamics and NMR approaches. This review summarizes the current structures and dynamic principles that govern peptide exchange as these relate to the process of antigen presentation.

Background/Objectives: For several decades, protein drugs (biologics) made in cell cultures have been delivered as sterile injections, decreasing their affordability and patient preference. Angiotensin Converting Enzyme 2 (ACE2) gum is the first engineered human blood protein expressed in plant cells approved by the FDA without the need for purification and is a cold-chain and noninvasive drug delivery. This biologic is currently being evaluated in human clinical studies to debulk SARS-CoV-2 in the oral cavity to reduce coronavirus infection/transmission (NCT 0543318). Methods: Chemistry, manufacturing, and control (CMC) studies for the ACE2/Ang(1–7) drug substances (DSs) and ACE2 gum drug product (DP) were conducted following USP guidelines. GLP-compliant toxicology studies were conducted on Sprague Dawley rats (n = 120; 15/sex/group) in four groups—placebo, low (1.6/1.0 mg), medium (3.2/2.0 mg), and high (8.3/5.0 mg) doses IP/kg/day. Oral gavage was performed twice daily for 14 days (the dosing phase) followed by the recovery phase (35 days). Plasma samples (n = 216) were analyzed for the product Ang(1–7) by ELISA. Results: The ACE2 protein was stable in the gum for at least up to 78 weeks. The toxicology study revealed the dose-related drug delivery to the plasma and increases in the AUC (56.6%) and Cmax (52.9%) after 28 high-dose gavages (95% C.I.), although this quantitation excludes exogenously delivered membrane-associated ACE2/Ang(1–7). Vital biomarkers and organs were not adversely affected despite the 10-fold higher absorption in the tissues, demonstrating the safety for the first in-human clinical trials of ACE2/Ang(1–7). The NOAEL observed in the rats was 2.5–7.5-fold higher than that of the anticipated efficacious therapeutic dose in humans for the treatment of cardiopulmonary disorders, and it was 314-fold higher than the NOAEL for topical delivery via chewing gum. Conclusions: This report lays the foundation for the regulatory process approval for noninvasive and affordable human biologic drugs bioencapsulated in plant cells.

Impaired contractility after myocardial infarction (MI) causes cardiogenic shock. MARK4 activity impairs contractility post-MI by increasing α-tubulin detyrosination. We assessed the impact of naringenin, a small-molecule MARK4 inhibitor, on contractility post-MI. Naringenin (Nar) was encapsulated in PEG-PCL to augment bioavailability. Wistar rats were randomized to receive either MI + micellized naringenin (0.3 mg/kg) [MI-NarMic], MI + naringenin (0.3 mg/kg) in 1% DMSO [MI-NarDMSO], MI + empty micelle [MI-Mic], MI alone [MI-Untreated], or no MI [Sham]. MI was induced via left anterior descending artery ligation. Invasive hemodynamics with pressure–volume catheterization, cardiomyocyte contractility, and ventricular protein abundance were assessed one day post-MI. A total of 45 rats underwent hemodynamic assessment. MI-NarMic rats demonstrated decreased α-tubulin detyrosination relative to MI-Untreated rats (p < 0.05). Myocytes isolated from peri-infarct tissue had increased contraction and relaxation velocities in MI-NarMic versus MI-Untreated rats (both p < 0.0001). MI-NarMic rats had higher ejection fractions than MI-Mic and MI-Untreated rats (63 ± 3% v. 48 ± 5% vs. 39 ± 4%, p < 0.05) and similar levels to Sham (61 ± 1%, p = 0.97) and MI-NarDMSO (54 ± 5%) rats (p > 0.05). MI-Nar rats had greater stroke work and lower end-diastolic pressure and tau than MI-Untreated rats (all p < 0.05). Micellized naringenin is a translatable agent with the potential to rescue hemodynamics post-MI by inhibiting MARK4 and mitigating myocardial α-tubulin detyrosination.

Pharmacologic activation of branched-chain amino acid (BCAA) catabolism is protective in models of heart failure (HF). How protection occurs remains unclear, although a causative block in cardiac BCAA oxidation is widely assumed. Here, we use in vivo isotope infusions to show that cardiac BCAA oxidation in fact increases, rather than decreases, in HF. Moreover, cardiac-specific activation of BCAA oxidation does not protect from HF even though systemic activation does. Lowering plasma and cardiac BCAAs also fails to confer significant protection, suggesting alternative mechanisms of protection. Surprisingly, activation of BCAA catabolism lowers blood pressure (BP), a known cardioprotective mechanism. BP lowering occurred independently of nitric oxide and reflected vascular resistance to adrenergic constriction. Mendelian randomization studies revealed that elevated plasma BCAAs portend higher BP in humans. Together, these data indicate that BCAA oxidation lowers vascular resistance, perhaps in part explaining cardioprotection in HF that is not mediated directly in cardiomyocytes.

COVID-19 stay-at-home (SAH) orders were impactful on adolescence, when social interactions affect development. This has the potential to change adolescent trauma. A post-hoc multicenter retrospective analysis of adolescent (13-17 years-old) trauma patients (ATPs) at 11 trauma centers was performed. Patients were divided into 3 groups based on injury date: historical control (CONTROL:3/19/2019-6/30/2019, before SAH (PRE:1/1/2020-3/18/2020), and after SAH (POST:3/19/2020-6/30/2020). The POST group was compared to both PRE and CONTROL groups in separate analyses. 726 ATPs were identified across the 3 time periods. POST had a similar penetrating trauma rate compared to both PRE (15.8% vs 13.8%, P = .56) and CONTROL (15.8% vs 14.5%, P = .69). POST also had a similar rate of suicide attempts compared to both PRE (1.2% vs 1.5%, P = .83) and CONTROL (1.2% vs 2.1%, P = .43). However, POST had a higher rate of drug positivity compared to CONTROL (28.6% vs 20.6%, P = .032), but was similar in all other comparisons of alcohol and drugs to PRE and POST periods (all P > .05). Hence ATPs were affected differently than adults and children, as they had a similar rate of penetrating trauma, suicide attempts, and alcohol positivity after SAH orders. However, they had increased drug positivity compared to the CONTROL, but not PRE group.

Heart failure (HF) is a leading cause of mortality. Failing hearts undergo profound metabolic changes, but a comprehensive evaluation in humans is lacking. We integrate plasma and cardiac tissue metabolomics of 678 metabolites, genome-wide RNA-sequencing, and proteomic studies to examine metabolic status in 87 explanted human hearts from 39 patients with end-stage HF compared with 48 nonfailing donors. We confirm bioenergetic defects in human HF and reveal selective depletion of adenylate purines required for maintaining ATP levels. We observe substantial reductions in fatty acids and acylcarnitines in failing tissue, despite plasma elevations, suggesting defective import of fatty acids into cardiomyocytes. Glucose levels, in contrast, are elevated. Pyruvate dehydrogenase, which gates carbohydrate oxidation, is de-repressed, allowing increased lactate and pyruvate burning. Tricarboxylic acid cycle intermediates are significantly reduced. Finally, bioactive lipids are profoundly reprogrammed, with marked reductions in ceramides and elevations in lysoglycerophospholipids. These data unveil profound metabolic abnormalities in human failing hearts.