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Lucian Manu, Renaissance School of Medicine at Stony Brook University, 100 Nicolls Road, Putnam Hall, Stony Brook, NY, 11794, USA, Tel +1 631-601-5139, Fax +1 631-350-0286, Email Lucian.Manu@stonybrookmedicine.edu

Background/Objectives: Quantitative assessments of facial muscle function and cognitive responses can enhance the clinic evaluations in neuromuscular disorders such as Bell’s palsy and psychiatric conditions including anxiety and depression. This study explored the application of Digital Image Speckle Correlation (DISC) in detecting enervation of facial musculature and assessing reaction times in response to visual stimuli. Methods: A consistent video recording setup was used to capture facial movements of human subjects in response to visual stimuli from a calibrated database. The DISC method utilizes the displacement of naturally occurring skin pores to map the specific locus of underlying muscular movement. The technique was applied to two distinct case studies: Patient 1 had unilateral Bell’s palsy and was monitored for 1 month of recovery. Patient 2 had a comorbidity of refractory depression and anxiety disorders with ketamine treatment and was assessed over 3 consecutive weekly visits. For patient 1, facial asymmetry was calculated by comparing left-to-right displacement signals. For patient 2, visual reaction time was measured, and facial motion intensity and response rate were compared with self-reported depression and anxiety scales. Results: DISC effectively mapped biomechanical properties of facial motions, providing detailed spatial and temporal resolution of muscle activity. In a control cohort of 10 subjects, when executing a facial expression, the degree of left/right facial asymmetry was determined to be 13.2 (8)%. And showed a robust response in an average of 275 (81) milliseconds to five out of the five images shown. For patient 1, obtained an initial asymmetry of nearly 100%, which decreased steadily to 20% in one month, demonstrating a progressive recovery. Patient 2 exhibited a prolonged reaction time of 518 (93) milliseconds and reduced response rates compared with controls of 275 (81) milliseconds and a decrease in the overall rate of response relative to the control group. The data obtained before treatment in three visits correlated strongly with selected depression and anxiety scores. Conclusions: These findings highlight the utility of DISC in enhancing clinical monitoring, complementing traditional examinations and self-reported measures.

Patients with schizophrenia have a high prevalence of cigarette smoking and respond poorly to conventional treatments, highlighting the need for new therapies. We conducted a mechanistic, proof-of-concept study using bilateral deep repetitive transcranial magnetic stimulation (dTMS) of insular and prefrontal cortices at high frequency, using the specialized H4 coil. Feasibility of dTMS was tested for disruption of tobacco self-administration, insula target engagement, and insula circuit modulation, all of which were a priori outcomes of interest. Twenty patients completed the study, consisting of weekday dTMS sessions (randomization to active dTMS or sham; double-blind; 10 patients per group), a laboratory tobacco self-administration paradigm (pre/post assessments), and multimodal imaging (three MRI total sessions). Results showed that participants assigned to active dTMS were slower to initiate smoking their first cigarette compared with sham, consistent with smoking disruption. The imaging analyses did not reveal significant Time × Group interactions, but effects were in the anticipated directions. In arterial spin labeling analyses testing for target engagement, an overall decrease in insula blood flow, measured during a post-treatment MRI versus baseline, was numerically more pronounced in the active dTMS group than sham. In fMRI analyses, resting-state connectivity between the insula and default mode network showed a numerically greater change from baseline in the active dTMS group than sham, consistent with a functional change to insula circuits. Exploratory analyses further suggested a therapeutic effect of dTMS on symptoms of psychosis. These initial observations pave the way for future confirmatory studies of dTMS in smoking patients with schizophrenia.

The variation in the expression patterns of the gap genes in the blastoderm of the fruit fly Drosophila melanogaster reduces over time as a result of cross regulation between these genes, a fact that we have demonstrated in an accompanying article in PLoS Biology (see Manu et al., doi:10.1371/journal.pbio.1000049). This biologically essential process is an example of the phenomenon known as canalization. It has been suggested that the developmental trajectory of a wild-type organism is inherently stable, and that canalization is a manifestation of this property. Although the role of gap genes in the canalization process was established by correctly predicting the response of the system to particular perturbations, the stability of the developmental trajectory remains to be investigated. For many years, it has been speculated that stability against perturbations during development can be described by dynamical systems having attracting sets that drive reductions of volume in phase space. In this paper, we show that both the reduction in variability of gap gene expression as well as shifts in the position of posterior gap gene domains are the result of the actions of attractors in the gap gene dynamical system. Two biologically distinct dynamical regions exist in the early embryo, separated by a bifurcation at 53% egg length. In the anterior region, reduction in variation occurs because of stability induced by point attractors, while in the posterior, the stability of the developmental trajectory arises from a one-dimensional attracting manifold. This manifold also controls a previously characterized anterior shift of posterior region gap domains. Our analysis shows that the complex phenomena of canalization and pattern formation in the Drosophila blastoderm can be understood in terms of the qualitative features of the dynamical system. The result confirms the idea that attractors are important for developmental stability and shows a richer variety of dynamical attractors in developmental systems than has been previously recognized.

The utility of serum glial fibrillary acidic protein (GFAP) in acute ischemic stroke (AIS) has been extensively studied in recent years. Here, we aimed to assess its potential role as a cargo protein of extracellular vesicles (EVs) secreted by astrocytes (ADEVs) in response to brain ischemia. Plasma samples from eighteen AIS patients at 24 h (D1), 7 days (D7), and one month (M1) post-symptoms onset, and nine age, sex, and cardiovascular risk factor-matched healthy controls were obtained to isolate EVs using the Exoquick ULTRA EV kit. Subsets of presumed ADEVs were identified further by the expression of the glutamate aspartate transporter (GLAST) as a specific marker of astrocytes with the Basic Exo-Flow Capture kit. Western blotting has tested the presence of GFAP in ADEV cargo. Post-stroke ADEV GFAP levels were elevated at D1 and D7 but not M1 compared to controls (p = 0.007, p = 0.019, and p = 0.344, respectively). Significant differences were highlighted in ADEV GFAP content at the three time points studied (n = 12, p = 0.027) and between D1 and M1 (z = 2.65, p = 0.023). A positive correlation was observed between the modified Rankin Scale (mRS) at D7 and ADEV GFAP at D1 (r = 0.58, p = 0.010) and D7 (r = 0.57, p = 0.013), respectively. ADEV GFAP may dynamically reflect changes during the first month post-ischemia. Profiling ADEVs from peripheral blood could provide a new way to assess the central nervous system pathology.

Glioblastoma (GBM), a primary brain tumor, exhibits intratumoral heterogeneity and dynamic spatial-temporal changes. GBM-derived extracellular vesicles (EVs), reflecting tumor characteristics, present potential as liquid-biopsy markers for early diagnosis and monitoring. This study aims to evaluate molecular signatures of plasma-derived EVs from GBM patients using a conventional flow cytometer. EVs have been isolated from glioma patients and healthy controls (HCs) plasma using density gradient ultracentrifugation (DGU). EVs were evaluated by bead-based multiplex analysis in a conventional flow cytometer. Principal component analysis (PCA), hierarchical clustering, and correlation analysis provided comprehensive insights into EV characteristics. EVs successfully isolated were visualized in transmission and scanning electron microscopy (STEM). Bead-based multiplex analysis in flow cytometer detected the level of 37 EV surface markers, including tumor-related, cancer stem cell, endothelial cell, and immune cell- specific antigens. PCA identified the EV surface markers that are most significant for differentiating the subjects, and hierarchical clustering revealed four distinct clusters based on EV surface marker levels. EV molecular signature demonstrated considerable heterogeneity across patient clusters. The presence of CD29 emerged not only as a defining factor for a cluster of patients, but also served as a marker to differentiate patients from HCs.

Extracellular vesicles (EVs) secreted by astrocytes (ADEVs) mediate numerous biological processes, providing insights into damage, repair, and protection following ischemic stroke (IS). This pilot study aimed to broaden the current knowledge on the astrocyte response to ischemia by dynamically assessing the aquaporin-4 (AQP4) and glial cell line-derived neurotrophic factor (GDNF) as cargo proteins of these vesicles in eighteen acute IS patients and nine controls. EV proteins were detected by Western blotting and followed 24 h (D1), 7 days (D7), and one month (M1) after symptoms onset. The post-ischemic ADEV AQP4 and GDNF levels were higher at D1 compared to the control group (p = 0.006 and p = 0.023). Significant differences were observed in ADEV AQP4 during the three evaluated time points (n = 12, p = 0.013) and between D1 and D7 (z = 2.858, p = 0.012), but not in EV GDNF. There was a positive relationship between the severity of stroke at D1 according to the National Institutes of Health Stroke Scale, and ADEV AQP4 at D1 (r = 0.50, p = 0.031), as well as ADEV GDNF at D1 and D7 (r = 0.49, p = 0.035 and r = 0.53, p = 0.021, respectively). The release of EVs with distinct protein profiles can be an attractive platform for the development of biomarkers in IS.

The World Health Organization reported that 80% of new HIV diagnoses in Europe in 2014 occurred in Central and Eastern Europe. Romania has a particularly high HIV incidence, AIDS prevalence, and number of related deaths. HIV incidence in Romania is largely attributed to sexual contact among gay and bisexual men. However, homophobic stigma in Romania serves as a risk factor for HIV infection for gay and bisexual men. The Comunică intervention aims to provide a much-needed HIV risk reduction strategy, and it entails the delivery of motivational interviewing and cognitive behavioral therapy skills across 8 live text-based counseling sessions on a mobile platform to gay and bisexual men at risk of HIV. The intervention is based on the information-motivation-behavior and minority stress models. There is preliminary evidence suggesting that Comunică holds promise for reducing gay and bisexual men's co-occurring sexual (eg, HIV transmission risk behavior), behavioral (eg, heavy alcohol use), and mental (eg, depression) health risks in Romania. This paper describes the protocol for a randomized controlled trial designed to test the efficacy of Comunică in a national trial. To test Comunică's efficacy, 305 gay and bisexual men were randomized to receive Comunică or a content-matched education attention control condition. The control condition consisted of 8 time-matched educational modules that present information regarding gay and bisexual men's identity development, information about HIV transmission and prevention, the importance of HIV and sexually transmitted infection testing and treatment, heavy alcohol use and its associations with HIV transmission risk behavior, sexual health communication, finding social support, and creating sexual health goals. Participants undergo rapid HIV and syphilis testing and 3-site chlamydia and gonorrhea testing at baseline and the 12-month follow-up. Outcomes are measured before the intervention (baseline) and at the 4-, 8-, and 12-month follow-ups. The study was funded in September 2018, and data collection began in May 2019. The last participant follow-up was in January 2024. Currently, the data analyst is cleaning data sets in preparation for data analyses, which are scheduled to begin in April 2024. Data analysis meetings are scheduled regularly to establish timelines and examine the results as analyses are gradually being conducted. Upon completion, a list of manuscripts will be reviewed and prioritized, and the team will begin preparing them for publication. This study is the first to test the efficacy of an intervention with the potential to simultaneously support the sexual, behavioral, and mental health of gay and bisexual men in Central and Eastern Europe using motivational interviewing support and sensitivity to the high-stigma context of the region. If efficacious, Comunică presents a scalable platform to provide support to gay and bisexual men living in Romania and similar high-stigma, low-resource countries. ClinicalTrials.gov NCT03912753; https://clinicaltrials.gov/study/NCT03912753. DERR1-10.2196/52853.

Cross-sensor comparison experimental results reported here show that the procedure defined and simulated during the Cross-Sensor Comparison Competition 2013 by our team for migrating / upgrading LG2200 based to LG4000 based biometric systems leads to better LG4000-to-LG2200 cross-sensor iris recognition results than previously reported, both in terms of user comfort and in terms of system safety. On the other hand, LG2200-to-LG400 migration/upgrade procedure defined and implemented by us is applicable to solve interoperability issues between LG2200 based and LG4000 based systems, but also to other pairs of systems having the same shift in the quality of acquired images.