Selective Deletion of Methyl CpG Binding Protein 2 from Parvalbumin Interneurons in the Auditory Cortex Delays the Onset of Maternal Retrieval in Mice.

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome. MECP2 codes for methyl CpG binding protein 2 (MECP2), a transcriptional regulator that activates genetic programs for experience-dependent plasticity. Many neural and behavioral symptoms of Rett syndrome may result from dysregulated timing and thresholds for plasticity. As a model of adult plasticity, we examine changes to auditory cortex inhibitory circuits in female mice when they are first exposed to pups; this plasticity facilitates behavioral responses to pups emitting distress calls. Brainwide deletion of Mecp2 alters expression of markers associated with GABAergic parvalbumin interneurons (PVins) and impairs the emergence of pup retrieval. We hypothesized that loss of Mecp2 in PVins disproportionately contributes to the phenotype. Here, we find that deletion of Mecp2 from PVins delayed the onset of maternal retrieval behavior and recapitulated the major molecular and neurophysiological features of brainwide deletion of Mecp2 We observed that when PVin-selective mutants were exposed to pups, auditory cortical expression of PVin markers increased relative to that in wild-type littermates. PVin-specific mutants also failed to show the inhibitory auditory cortex plasticity seen in wild-type mice on exposure to pups and their vocalizations. Finally, using an intersectional viral genetic strategy, we demonstrate that postdevelopmental loss of Mecp2 in PVins of the auditory cortex is sufficient to delay onset of maternal retrieval. Our results support a model in which PVins play a central role in adult cortical plasticity and may be particularly impaired by loss of Mecp2 SIGNIFICANCE STATEMENT Rett syndrome is a neurodevelopmental disorder that includes deficits in both communication and the ability to update brain connections and activity during learning (plasticity). This condition is caused by mutations in the gene MECP2 We use a maternal behavioral test in mice requiring both vocal perception and neural plasticity to probe the role of Mecp2 in social and sensory learning. Mecp2 is normally active in all brain cells, but here we remove it from a specific population (parvalbumin neurons). We find that this is sufficient to delay learned behavioral responses to pups and recreates many deficits seen in whole-brain Mecp2 deletion. Our findings suggest that parvalbumin neurons specifically are central to the consequences of loss of Mecp2 activity and yield clues as to possible mechanisms by which Rett syndrome impairs brain function.

Flattening Hierarchical Structures to Empower Women Trainee Leaders on Social Media Teams.

We share our experience empowering women trainees and leadership through a flattened hierarchical social media team structure with supporting evidence from measurable outcomes.

The role of endothelial shear stress, shear stress gradient, and plaque topography in plaque erosion.

BACKGROUND AND AIMS: Plaque erosion is a common underlying cause of acute coronary syndromes. The role of endothelial shear stress (ESS) and endothelial shear stress gradient (ESSG) in plaque erosion remains unknown. We aimed to determine the role of ESS metrics and maximum plaque slope steepness in plaques with erosion versus stable plaques. METHODS: This analysis included 46 patients/plaques from TOTAL and COMPLETE trials and Brigham and Women's Hospital's database who underwent angiography and OCT. Plaques were divided into those with erosion (n = 24) and matched stable coronary plaques (n = 22). Angiographic views were used to generate a 3-D arterial reconstruction, with centerlines merged from angiography and OCT pullback. Local ESS metrics were assessed by computational fluid dynamics. Among plaque erosions, the up- and down-slope (Δ lumen area/frame) was calculated for each culprit plaque. RESULTS: Compared with stable plaque controls, plaques with an erosion were associated with higher max ESS (8.3 ± 4.8 vs. 5.0 ± 1.9 Pa, p = 0.02) and max ESSG any direction (9.2 ± 7.5 vs. 4.3 ± 3.11 Pa/mm, p = 0.005). Proximal erosion was associated with a steeper plaque upslope while distal erosion with a steeper plaque downslope. Max ESS and Max ESSG any direction were independent factors in the development of plaque erosion (OR 1.32, 95%CI 1.06-1.65, p = 0.014; OR 1.22, 95% CI 1.03-1.45, p = 0.009, respectively). CONCLUSIONS: In plaques with similar luminal stenosis, plaque erosion was strongly associated with higher ESS, ESS gradients, and plaque slope as compared with stable plaques. These data support that ESS and slope metrics play a key role in the development of plaque erosion and may help prognosticate individual plaques at risk for future erosion.

Endothelial shear stress computed from coronary computed tomography angiography: A direct comparison to intravascular ultrasound.

INTRODUCTION: Intravascular ultrasound (IVUS) studies have shown that biomechanical variables, particularly endothelial shear stress (ESS), add synergistic prognostic insight when combined with anatomic high-risk plaque features. Non-invasive risk assessment of coronary plaques with coronary computed tomography angiography (CCTA) would be helpful to enable broad population risk-screening. AIM: To compare the accuracy of ESS computation of local ESS metrics by CCTA vs IVUS imaging. METHODS: We analyzed 59 patients from a registry of patients who underwent both IVUS and CCTA for suspected CAD. CCTA images were acquired using either a 64- or 256-slice scanner. Lumen, vessel, and plaque areas were segmented from both IVUS and CCTA (59 arteries, 686 3-mm segments). Images were co-registered and used to generate a 3-D arterial reconstruction, and local ESS distribution was assessed by computational fluid dynamics (CFD) and reported in consecutive 3-mm segments. RESULTS: Anatomical plaque characteristics (vessel, lumen, plaque area and minimal luminal area [MLA] per artery) were correlated when measured with IVUS and CCTA: 12.7 â€‹± â€‹4.3 vs 10.7 â€‹± â€‹4.5 â€‹mm2, r â€‹= â€‹0.63; 6.8 â€‹± â€‹2.7 vs 5.6 â€‹± â€‹2.7 â€‹mm2, r â€‹= â€‹0.43; 5.9 â€‹± â€‹2.9 vs 5.1 â€‹± â€‹3.2 â€‹mm2, r â€‹= â€‹0.52; 4.5 â€‹± â€‹1.3 vs 4.1 â€‹± â€‹1.5 â€‹mm2, r â€‹= â€‹0.67 respectively. ESS metrics of local minimal, maximal, and average ESS were also moderately correlated when measured with IVUS and CCTA (2.0 â€‹± â€‹1.4 vs 2.5 â€‹± â€‹2.6 â€‹Pa, r â€‹= â€‹0.28; 3.3 â€‹± â€‹1.6 vs 4.2 â€‹± â€‹3.6 â€‹Pa, r â€‹= â€‹0.42; 2.6 â€‹± â€‹1.5 vs 3.3 â€‹± â€‹3.0 â€‹Pa, r â€‹= â€‹0.35, respectively). CCTA-based computation accurately identified the spatial localization of local ESS heterogeneity compared to IVUS, with Bland-Altman analyses indicating that the absolute ESS differences between the two CCTA methods were pathobiologically minor. CONCLUSION: Local ESS evaluation by CCTA is possible and similar to IVUS; and is useful for identifying local flow patterns that are relevant to plaque development, progression, and destabilization.

Selective deletion of Methyl CpG binding protein 2 from parvalbumin interneurons in the auditory cortex delays the onset of maternal retrieval in mice.

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome. MECP2 codes for methyl CpG binding protein 2 (MECP2), a transcriptional regulator that activates genetic programs for experience-dependent plasticity. Many neural and behavioral symptoms of Rett syndrome may result from dysregulated timing and threshold for plasticity. As a model of adult plasticity, we examine changes to auditory cortex inhibitory circuits in female mice when they are first exposed to pups; this plasticity facilitates behavioral responses to pups emitting distress calls. Brain-wide deletion of Mecp2 alters expression of markers associated with GABAergic parvalbumin interneurons (PVin) and impairs the emergence of pup retrieval. We hypothesized that loss of Mecp2 in PVin disproportionately contributes to the phenotype. Here we find that deletion of Mecp2 from PVin delayed the onset of maternal retrieval behavior and recapitulated the major molecular and neurophysiological features of brain-wide deletion of Mecp2 . We observed that when PVin-selective mutants were exposed to pups, auditory cortical expression of PVin markers increased relative to that in wild type littermates. PVin-specific mutants also failed to show the inhibitory auditory cortex plasticity seen in wild type mice upon exposure to pups and their vocalizations. Finally, using an intersectional viral genetic strategy, we demonstrate that post-developmental loss of Mecp2 in PVin of the auditory cortex is sufficient to delay onset of maternal retrieval. Our results support a model in which PVin play a central role in adult cortical plasticity and may be particularly impaired by loss of Mecp2 . SIGNIFICANCE STATEMENT: Rett syndrome is a neurodevelopmental disorder that includes deficits in both communication and the ability to update brain connections and activity during learning ('plasticity'). This condition is caused by mutations in the gene MECP2 . We use a maternal behavioral test in mice requiring both vocal perception and neural plasticity to probe Mecp2' s role in social and sensory learning. Mecp2 is normally active in all brain cells, but here we remove it from a specific population ('parvalbumin neurons'). We find that this is sufficient to delay learned behavioral responses to pups and recreates many deficits seen in whole brain Mecp2 deletion. Our findings suggest that parvalbumin neurons specifically are central to the consequences of loss of Mecp2 activity and yield clues as to possible mechanisms by which Rett syndrome impairs brain function.

Sex and Location Differences in Verification Status of Physician-Held Social Media Platform Accounts.

This cross-sectional study investigated the association of user sex and location with verification of physician-held social media accounts.

Parvalbumin-Positive Interneurons Regulate Cortical Sensory Plasticity in Adulthood and Development Through Shared Mechanisms.

Parvalbumin-positive neurons are the largest class of GABAergic, inhibitory neurons in the central nervous system. In the cortex, these fast-spiking cells provide feedforward and feedback synaptic inhibition onto a diverse set of cell types, including pyramidal cells, other inhibitory interneurons, and themselves. Cortical inhibitory networks broadly, and cortical parvalbumin-expressing interneurons (cPVins) specifically, are crucial for regulating sensory plasticity during both development and adulthood. Here we review the functional properties of cPVins that enable plasticity in the cortex of adult mammals and the influence of cPVins on sensory activity at four spatiotemporal scales. First, cPVins regulate developmental critical periods and adult plasticity through molecular and structural interactions with the extracellular matrix. Second, they activate in precise sequence following feedforward excitation to enforce strict temporal limits in response to the presentation of sensory stimuli. Third, they implement gain control to normalize sensory inputs and compress the dynamic range of output. Fourth, they synchronize broad network activity patterns in response to behavioral events and state changes. Much of the evidence for the contribution of cPVins to plasticity comes from classic models that rely on sensory deprivation methods to probe experience-dependent changes in the brain. We support investigating naturally occurring, adaptive cortical plasticity to study cPVin circuits in an ethologically relevant framework, and discuss recent insights from our work on maternal experience-induced auditory cortical plasticity.

Student-Run Free Clinics Stand at a Critical Junction Between Undergraduate Medical Education, Clinical Care, and Advocacy.

Student-run free clinics (SRFCs) act as primary care providers that bring health care to populations in need and are an important source of undergraduate medical education (UME), guiding trainees through the art of history taking and physical examination. However, they are also social justice and advocacy initiatives-addressing disparity in access to care and educating medical trainees with firsthand exposure to socioeconomic determinants of health as well as language and medical illiteracy barriers. Here, the authors review academic literature examining the impact of SRFCs in their 3 roles: as medical care providers, as components of medical education, and as advocacy organizations. Based on the evidence of that literature and decades of direct SRFC leadership experience, the authors make the case that SRFCs are an undersupported means by which UME institutions contribute to correcting health care disparities and to serving social justice reform.

Cardiac arrest associated with non-toxigenic corynebacterium diphtheria strain: A case report.

Here we document a rare, acute, infection caused by non-toxigenic Corynebacterium diphtheriae and the resulting unique and severe clinical sequelae. Our patient was a young man with no known pre-existing conditions that presented in cardiopulmonary arrest. We contrast this case with prior instances of non-toxigenic C. diphtheriae strain infection in the United States and summarize the literature that suggests systemic infection can result in cardiogenic toxicity. We speculate on a possible missed, pre-existing condition that could have increased this patient's susceptibility to poor clinical outcome.

Correction: Documenting Social Media Engagement as Scholarship: A New Model for Assessing Academic Accomplishment for the Health Professions.

[This corrects the article DOI: 10.2196/25070.].

Documenting Social Media Engagement as Scholarship: A New Model for Assessing Academic Accomplishment for the Health Professions.

BACKGROUND: The traditional model of promotion and tenure in the health professions relies heavily on formal scholarship through teaching, research, and service. Institutions consider how much weight to give activities in each of these areas and determine a threshold for advancement. With the emergence of social media, scholars can engage wider audiences in creative ways and have a broader impact. Conventional metrics like the h-index do not account for social media impact. Social media engagement is poorly represented in most curricula vitae (CV) and therefore is undervalued in promotion and tenure reviews. OBJECTIVE: The objective was to develop crowdsourced guidelines for documenting social media scholarship. These guidelines aimed to provide a structure for documenting a scholar's general impact on social media, as well as methods of documenting individual social media contributions exemplifying innovation, education, mentorship, advocacy, and dissemination. METHODS: To create unifying guidelines, we created a crowdsourced process that capitalized on the strengths of social media and generated a case example of successful use of the medium for academic collaboration. The primary author created a draft of the guidelines and then sought input from users on Twitter via a publicly accessible Google Document. There was no limitation on who could provide input and the work was done in a democratic, collaborative fashion. Contributors edited the draft over a period of 1 week (September 12-18, 2020). The primary and secondary authors then revised the draft to make it more concise. The guidelines and manuscript were then distributed to the contributors for edits and adopted by the group. All contributors were given the opportunity to serve as coauthors on the publication and were told upfront that authorship would depend on whether they were able to document the ways in which they met the 4 International Committee of Medical Journal Editors authorship criteria. RESULTS: We developed 2 sets of guidelines: Guidelines for Listing All Social Media Scholarship Under Public Scholarship (in Research/Scholarship Section of CV) and Guidelines for Listing Social Media Scholarship Under Research, Teaching, and Service Sections of CV. Institutions can choose which set fits their existing CV format. CONCLUSIONS: With more uniformity, scholars can better represent the full scope and impact of their work. These guidelines are not intended to dictate how individual institutions should weigh social media contributions within promotion and tenure cases. Instead, by providing an initial set of guidelines, we hope to provide scholars and their institutions with a common format and language to document social media scholarship.

Ten simple rules for running a successful women-in-STEM organization on an academic campus.

The current academic culture facing women in science, technology, engineering, and math (STEM) fields in the United States has sparked the formation of grassroots advocacy groups to empower female scientists in training. However, the impact of these initiatives often goes unmeasured and underappreciated. Our Women in Science and Engineering (WiSE) organization serves postdoctoral researchers, graduate students, and research technicians (trainees) at a private research institute for biological sciences. Here we propose the following guidelines for cultivating a successful women-in-STEM-focused group based upon survey results from our own scientific community as well as the experience of our WiSE group leaders. We hope these recommendations can provide guidance to advocacy groups at other research and academic organizations that wish to strengthen their efforts. Whereas our own group specifically focuses on the underrepresented state of women in science, we hope these guidelines may be adapted and applied to groups that advocate for any minority group within the greater scientific community (i.e., those of gender, race/ethnicity, socioeconomic background, sexual orientation, etc.).

Effective Refractive Index and Lipid Content of Extracellular Vesicles Revealed Using Optical Waveguide Scattering and Fluorescence Microscopy.

Extracellular vesicles (EVs) are generating a growing interest because of the key roles they play in various biological processes and because of their potential use as biomarkers in clinical diagnostics and as efficient carriers in drug-delivery and gene-therapy applications. Their full exploitation, however, depends critically on the possibility to classify them into different subpopulations, a task that in turn relies on efficient means to identify their unique biomolecular and physical signatures. Because of the large heterogeneity of EV samples, such information remains rather elusive, and there is accordingly a need for new and complementary characterization schemes that can help expand the library of distinct EV features. In this work, we used surface-sensitive waveguide scattering microscopy with single EV resolution to characterize two subsets of similarly sized EVs that were preseparated based on their difference in buoyant density. Unexpectedly, the scattering intensity distribution revealed that the scattering intensity of the high-density (HD) population was on an average a factor of three lower than that of the low-density (LD) population. By further labeling the EV samples with a self-inserting lipid-membrane dye, the scattering and fluorescence intensities from EVs could be simultaneously measured and correlated at the single-particle level. The labeled HD sample exhibited not only lower fluorescence and scattering intensities but also lower effective refractive index ( n ≈ 1.35) compared with the LD EVs ( n ≈ 1.38), indicating that both the lipid and protein contents were indeed lower in the HD EVs. Although separation in density gradients of similarly sized EVs is usually linked to differences in biomolecular content, we suggest based on these observations that the separation rather reflects the ability of the solute of the gradient to penetrate the lipid membrane enclosing the EVs, that is, the two gradient bands are more likely because of the differences in membrane permeability than to differences in biomolecular content of the EVs.

Pentacyclic adenine: a versatile and exceptionally bright fluorescent DNA base analogue.

Emissive base analogs are powerful tools for probing nucleic acids at the molecular level. Herein we describe the development and thorough characterization of pentacyclic adenine (pA), a versatile base analog with exceptional fluorescence properties. When incorporated into DNA, pA pairs selectively with thymine without perturbing the B-form structure and is among the brightest nucleobase analogs reported so far. Together with the recently established base analog acceptor qAnitro, pA allows accurate distance and orientation determination via Förster resonance energy transfer (FRET) measurements. The high brightness at emission wavelengths above 400 nm also makes it suitable for fluorescence microscopy, as demonstrated by imaging of single liposomal constructs coated with cholesterol-anchored pA-dsDNA, using total internal reflection fluorescence microscopy. Finally, pA is also highly promising for two-photon excitation at 780 nm, with a brightness (5.3 GM) that is unprecedented for a base analog.

Relations between cortical thickness, serotonin 1A receptor binding, and structural connectivity: A multimodal imaging study.

Serotonin 1A (5-HT1A ) receptors play a direct role in neuronal development, cell proliferation, and dendritic branching. We hypothesized that variability in 5-HT1A binding can affect cortical thickness, and may account for a subtype of major depressive disorder (MDD) in which both are altered. To evaluate this, we measured cortical thickness from structural magnetic resonance imaging (MRI) and 5-HT1A binding by positron emission tomography (PET) in an exploratory study. To examine a range of 5-HT1A binding and cortical thickness values, we recruited 25 healthy controls and 19 patients with MDD. We hypothesized increased 5-HT1A binding in the raphe nucleus (RN) would be negatively associated with cortical thickness due to reduced serotonergic transmission. Contrary to our hypothesis, raphe 5-HT1A binding was positively correlated with cortical thickness in right posterior cingulate cortex (PCC), a region implicated in the default mode network. Cortical thickness was also positively correlated with 5-HT1A in each cortical region. We further hypothesized that the strength of 5-HT1A -cortical thickness correlation depends on the number of axons between the raphe nucleus and each region. To explore this we related 5-HT1A -cortical thickness correlation coefficients to the number of tracts connecting that region and the raphe, as measured by diffusion tensor imaging (DTI) in an independent sample. The 5-HT1A -cortical thickness association correlated significantly with the number of tracts to each region, supporting our hypothesis. We posit a defect in the raphe may affect the PCC within the default mode network in MDD through serotonergic fibers, resulting in increased ruminative processing.

Artificial grammar learning in tamarins (Saguinus oedipus) in varying stimulus contexts.

The human ability to detect regularities in sound sequences is a fundamental substrate of our language faculty. However, is this an ability exclusive to human language processing, or have we usurped a more general learning mechanism for this purpose, one shared with other species? The current study is an attempt to replicate and extend Hauser, Weiss, and Marcus's (2002) retracted study (2010) of artificial grammar learning in tamarins to determine if tamarins can detect an underlying grammatical structure in a pattern of sounds. Human language consonant-vowel (CV) combinations from Hauser et al.'s original study, newly created tone sequences, and newly created monkey vocalizations made into sequences were used to familiarize tamarins to an AAB or ABB pattern. Tests of novel sounds in each condition were presented that either were consistent with the familiarized pattern or were different from it. Longer looking times toward the sound source (an audio speaker with a specific location in the auditory field) indicated recognition of novelty. Tamarins looked toward the speaker significantly longer with inconsistent human language CV sequences and with inconsistent tone sequences but not when an inconsistent monkey vocalization was presented. Moreover, tamarins showed differential rates of habituation to the different types of sound patterns, with more robust habituation to CV sequences and tone sequences than to monkey call sequences. The implications of these findings for the generality of learning mechanisms for linguistic and nonlinguistic input across species and the importance of testing across various stimuli are discussed. (PsycINFO Database Record

Methods for the physical characterization and quantification of extracellular vesicles in biological samples.

BACKGROUND: Our body fluids contain a multitude of cell-derived vesicles, secreted by most cell types, commonly referred to as extracellular vesicles. They have attracted considerable attention for their function as intercellular communication vehicles in a broad range of physiological processes and pathological conditions. Extracellular vesicles and especially the smallest type, exosomes, have also generated a lot of excitement in view of their potential as disease biomarkers or as carriers for drug delivery. In this context, state-of-the-art techniques capable of comprehensively characterizing vesicles in biological fluids are urgently needed. SCOPE OF REVIEW: This review presents the arsenal of techniques available for quantification and characterization of physical properties of extracellular vesicles, summarizes their working principles, discusses their advantages and limitations and further illustrates their implementation in extracellular vesicle research. MAJOR CONCLUSIONS: The small size and physicochemical heterogeneity of extracellular vesicles make their physical characterization and quantification an extremely challenging task. Currently, structure, size, buoyant density, optical properties and zeta potential have most commonly been studied. The concentration of vesicles in suspension can be expressed in terms of biomolecular or particle content depending on the method at hand. In addition, common quantification methods may either provide a direct quantitative measurement of vesicle concentration or solely allow for relative comparison between samples. GENERAL SIGNIFICANCE: The combination of complementary methods capable of detecting, characterizing and quantifying extracellular vesicles at a single particle level promises to provide new exciting insights into their modes of action and to reveal the existence of vesicle subpopulations fulfilling key biological tasks.

Dual-Wavelength Surface Plasmon Resonance for Determining the Size and Concentration of Sub-Populations of Extracellular Vesicles.

Accurate concentration determination of subpopulations of extracellular vesicles (EVs), such as exosomes, is of importance both in the context of understanding their fundamental biological role and of potentially using them as disease biomarkers. In principle, this can be achieved by measuring the rate of diffusion-limited mass uptake to a sensor surface modified with a receptor designed to only bind the subpopulation of interest. However, a significant error is introduced if the targeted EV subpopulation has a size, and thus hydrodynamic diffusion coefficient, that differs from the mean size and diffusion coefficient of the whole EV population and/or if the EVs become deformed upon binding to the surface. We here demonstrate a new approach to determine the mean size (or effective film thickness) of bound nanoparticles, in general, and EV subpopulation carrying a marker of interest, in particular. The method is based on operating surface plasmon resonance simultaneously at two wavelengths with different sensing depths and using the ratio of the corresponding responses to extract the particle size on the surface. By estimating in this way the degree of deformation of adsorbed EVs, we markedly improved their bulk concentration determination and showed that EVs carrying the exosomal marker CD63 correspond to not more than around 10% of the EV sample.

Effects of maternal deprivation and the duration of reunion time on rat pup ultrasonic vocalization responses to isolation: possible implications for human infant studies.

In a paradigm that may serve as a translational model for maternal separation experiences of human infants in neonatal intensive care units, we examined how the duration of reunion with the dam influenced the phenomenon of maternal potentiation of ultrasonic vocalizations, in which isolated rat pups increase rates of vocalization following brief interactions with dams. We report that maternal potentiation in 12-13 day-old rats did not occur after reunions with their anesthetized dam that lasted longer than 15-min. However, after 18 hr maternal separation, isolated pups given reunions with their anesthetized dam increased vocalization rate even with reunions as long as 3 hr. Using a split-cage apparatus that prevented physical contact, the impact of 18 hr separations on maternal potentiation was partially offset by experiencing olfactory and/or auditory stimuli of the mother. These results suggest that maintaining partial maternal sensory exposure during prolonged maternal separation can reduce responses elicited by subsequent maternal separation.