First Report on Chronic Granulomatous Disease from Nepal and a Review of CYBC1 Deficiency.

Chronic granulomatous disease (CGD) primarily results from inherited defects in components of the nicotinamide adenine dinucleotide phosphate oxidase enzyme complex. These include gene defects in cytochrome B-245/558 subunit α/ß and neutrophil cytosolic factors 1, 2, and 4. Recently, homozygous loss-of-function variants in cytochrome B-245 chaperone 1 gene (CYBC1) have been discovered to cause CGD (CYBC1-CGD). Data on variant-proven CGD from low-income countries, the most underprivileged regions of the world, remain sparse due to numerous constraints. Herein, we report the first cohort of patients with CGD from Nepal, a low-income country in the Himalayas' challenging terrain. Our report includes a description of a new case of CYBC1 deficiency who was first diagnosed with CGD at our center. Only a dozen cases of CYBC1-CGD have been described in the literature thus far which have been reviewed comprehensively herein. Most of these patients have had significant infections and autoimmune/inflammatory manifestations. Pulmonary and invasive/disseminated bacterial/fungal infections were the most common followed by skin and soft-tissue infections. Inflammatory bowel disease (IBD) was the most common inflammatory manifestation (median age at diagnosis: 9 years) followed by episodes of recurrent/prolonged fever. Other autoimmune/inflammatory manifestations reported in CYBC1-CGD include acute pancreatitis, hemophagocytic lymphohistiocytosis, systemic granulomatosis, interstitial lung disease, arthritis, autoimmune hemolytic anemia, uveitis, nephritis, and eczema. Our analysis shows that patients with CYBC1-CGD are at a significantly higher risk of IBD-like illness as compared to other forms of CGD which merits further confirmatory studies in the future.

An essential role for EROS in redox-dependent endothelial signal transduction.

The chaperone protein EROS ("Essential for Reactive Oxygen Species") was recently discovered in phagocytes. EROS was shown to regulate the abundance of the ROS-producing enzyme NADPH oxidase isoform 2 (NOX2) and to control ROS-mediated cell killing. Reactive oxygen species are important not only in immune surveillance, but also modulate physiological signaling responses in multiple tissues. The roles of EROS have not been previously explored in the context of oxidant-modulated cell signaling. Here we show that EROS plays a key role in ROS-dependent signal transduction in vascular endothelial cells. We used siRNA-mediated knockdown and developed CRISPR/Cas9 knockout of EROS in human umbilical vein endothelial cells (HUVEC), both of which cause a significant decrease in the abundance of NOX2 protein, associated with a marked decrease in RAC1, a small G protein that activates NOX2. Loss of EROS also attenuates receptor-mediated hydrogen peroxide (H2O2) and Ca2+ signaling, disrupts cytoskeleton organization, decreases cell migration, and promotes cellular senescence. EROS knockdown blocks agonist-modulated eNOS phosphorylation and nitric oxide (NO●) generation. These effects of EROS knockdown are strikingly similar to the alterations in endothelial cell responses that we previously observed following RAC1 knockdown. Proteomic analyses following EROS or RAC1 knockdown in endothelial cells showed that reduced abundance of these two distinct proteins led to largely overlapping effects on endothelial biological processes, including oxidoreductase, protein phosphorylation, and endothelial nitric oxide synthase (eNOS) pathways. These studies demonstrate that EROS plays a central role in oxidant-modulated endothelial cell signaling by modulating NOX2 and RAC1.

Structural basis for EROS binding to human phagocyte NADPH oxidase NOX2.

Essential for reactive oxygen species (EROS) protein is a recently identified molecular chaperone of NOX2 (gp91phox), the catalytic subunit of phagocyte NADPH oxidase. Deficiency in EROS is a recently identified cause for chronic granulomatous disease, a genetic disorder with recurrent bacterial and fungal infections. Here, we report a cryo-EM structure of the EROS-NOX2-p22phox heterotrimeric complex at an overall resolution of 3.56Å. EROS and p22phox are situated on the opposite sides of NOX2, and there is no direct contact between them. EROS associates with NOX2 through two antiparallel transmembrane (TM) α-helices and multiple ß-strands that form hydrogen bonds with the cytoplasmic domain of NOX2. EROS binding induces a 79° upward bend of TM2 and a 48° backward rotation of the lower part of TM6 in NOX2, resulting in an increase in the distance between the two hemes and a shift of the binding site for flavin adenine dinucleotide (FAD). These conformational changes are expected to compromise superoxide production by NOX2, suggesting that the EROS-bound NOX2 is in a protected state against activation. Phorbol myristate acetate, an activator of NOX2 in vitro, is able to induce dissociation of NOX2 from EROS with concurrent increase in FAD binding and superoxide production in a transfected COS-7 model. In differentiated neutrophil-like HL-60, the majority of NOX2 on the cell surface is dissociated with EROS. Further studies are required to delineate how EROS dissociates from NOX2 during its transport to cell surface, which may be a potential mechanism for regulation of NOX2 activation.

Inhibition.

This article explores the notion of inhibition at a theoretical and clinical level in psychoanalysis. The first part follows the development of the notion in Freud's work, from the "Project" (1950a [1895]) to Inhibitions, Symptoms and Anxiety (1926d). It identifies the two approaches to inhibition, the first from an energetic point of view, the second from the angle of its relations to anxiety. The second part of the article is devoted to the links between inhibition and Freud's thoughts about death, in particular in Inhibitions, Symptoms and Anxiety and the links to the death drive. It draws on some of Jones' notes and presents a brief clinical illustration. The third part focuses more particularly on general inhibition, especially in depression and melancholia. Based on the treatment of one patient, the author shows how the slow process of overcoming general inhibition is achieved through the gradual use of negation. From an economic point of view, it is suggested that psychoanalytic treatment, through the transference and associative speech, has an effect on the depletion of energy by diverting the "suction" of stimuli, paving the way for the formation of drive representatives, or inhibitions as symptoms, which will need to be dissected.

Lower oddball event-related EEG delta and theta responses in patients with dementia due to Parkinson's and Lewy body than Alzheimer's disease.

Oddball task-related EEG delta and theta responses are associated with frontal executive functions, which are significantly impaired in patients with dementia due to Parkinson's disease (PDD) and Lewy bodies (DLB). The present study investigated the oddball task-related EEG delta and theta responses in patients with PDD, DLB, and Alzheimer's disease dementia (ADD). During visual and auditory oddball paradigms, EEG activity was recorded in 20 ADD, 17 DLB, 20 PDD, and 20 healthy (HC) older adults. Event-related EEG power spectrum and phase-locking analysis were performed at the delta (1-4 Hz) and theta (4-7 Hz) frequency bands for target and nontarget stimuli. Compared to the HC persons, dementia groups showed lower frontal and central delta and theta power and phase-locking associated with task performance and neuropsychological test scores. Notably, this effect was more significant in the PDD and DLB than in the ADD. In conclusion, oddball task-related frontal and central EEG delta and theta responses may reflect frontal supramodal executive dysfunctions in PDD and DLB patients.

Bypassing input to V1 in visual awareness: A TMS-EROS investigation.

Early visual cortex (V1-V3) is believed to be critical for normal visual awareness by providing the necessary feedforward input. However, it remains unclear whether visual awareness can occur without further involvement of early visual cortex, such as re-entrant feedback. It has been challenging to determine the importance of feedback activity to these areas because of the difficulties in dissociating this activity from the initial feedforward activity. Here, we applied single-pulse transcranial magnetic stimulation (TMS) over the left posterior parietal cortex to elicit phosphenes in the absence of direct visual input to early visual cortex. Immediate neural activity after the TMS pulse was assessed using the event-related optical signal (EROS), which can measure activity under the TMS coil without artifacts. Our results show that: 1) The activity in posterior parietal cortex 50 ms after TMS was related to phosphene awareness, and 2) Activity related to awareness was observed in a small portion of V1 140 ms after TMS, but in contrast (3) Activity in V2 was a more robust correlate of awareness. Together, these results are consistent with interactive models proposing that sustained and recurrent loops of activity between cortical areas are necessary for visual awareness to emerge. In addition, we observed phosphene-related activations of the anteromedial cuneus and lateral occipital cortex, suggesting a functional network subserving awareness comprising these regions, the parietal cortex and early visual cortex.

There's Something about Uvalde: American Patriarchy and the Slaughter of Innocents.

After every school shooting in the United States both a wish and a fear arise: Will this be the one? Will this be the tipping point for change in a nation so deeply divided over the meaning of "the right to bear arms?" Sandy Hook, Connecticut? No. Parkland, Florida? No. So, why might the killing of 19 children and 2 teachers in Uvalde, Texas, prove different? The American epidemic of mass school shootings betrays a country's willingness to let its children disappear, to sacrifice them on the altar of an archetypally violent ethos. While the internal experiences of alienation, resentment and contempt are often at play in the individuals who carry out such violence, the author suggests that the uniquely American glorification of "the lone wolf", the "rugged individual" and the "misunderstood hero" fuels a supportive background for mass shooters in a nation that appears to be enamoured of ancient patriarchal attitudes as it doubles down on its valuing of weaponry. Such patriarchal attitudes, underscored by capitalism and the profits of the gun industry, are implicated in the territorial adhesion to American gun rights and in the high cost paid by the blood of innocents. Drawing on Vestergaard & Odde's (2021) concepts of socio-analysis and sociality, this paper explores the dynamic process of "mass-character" marked by "contagion, imitation, attraction and repulsion" that convolute cultural values of heritage and freedom into the perverse expression of mass violence.

Aux États­Unis, après chaque fusillade dans une école, un souhait et une crainte surgissent à la fois : est­ce que celle­ci fera une différence? Marquera­t­elle le point de basculement d'un changement dans une nation si profondément divisée sur la signification du « droit de porter des armes ¼? Sandy Hook, dans le Connecticut? Non. Santa Fe, au Texas? Non. Alors, pourquoi l'assassinat de 19 enfants et de 2 enseignants à Uvalde, au Texas, pourrait­il s'avérer différent? L'épidémie américaine de fusillades de masse dans les écoles trahit la volonté d'un pays de laisser ses enfants disparaître, de les sacrifier sur l'autel d'une philosophe archétypale de la violence. Alors que les expériences internes d'aliénation, de ressentiment et de mépris sont souvent en jeu chez les individus qui commettent de telles violences, l'auteur suggère que la glorification typiquement américaine du « loup solitaire ¼, de « l'individu robuste ¼ et du « héros incompris ¼ alimente un arrière­plan favorable aux tireurs de masse. Ceci dans une nation qui semble éprise d'anciennes attitudes patriarcales et qui persiste et signe concernant son attachement pour les armes. De telles attitudes patriarcales, soulignées par le capitalisme et les profits de l'industrie des armes à feu, sont impliquées dans l'adhésion territoriale aux droits américains sur les armes à feu et dans le coût élevé payé par le sang d'innocents. S'appuyant sur les concepts de socioanalyse et de socialité de Vestergaard et Odde (2021), cet article explore le processus dynamique du « caractère de masse ¼ marqué par « la contagion, l'imitation, l'attrait et la répulsion ¼ qui tournent les valeurs culturelles liées au patrimoine et à la liberté en une expression perverse de violence de masse.

Después de cada tiroteo en un colegio de Estados Unidos surge un deseo y un temor: ¿será éste? ¿Será éste el punto de inflexión para el cambio en una nación tan profundamente dividida sobre el significado del "derecho a portar armas"? ¿Sandy Hook, Connecticut? No. ¿Santa Fe, Texas? No. Entonces, ¿por qué la matanza de 19 niños y 2 profesores en Uvalde, Texas, podría ser diferente? La epidemia estadounidense de tiroteos masivos en escuelas revela la voluntad de un país de dejar desaparecer a sus niños, de sacrificarlos en el altar de un ethos arquetípicamente violento. Aunque las experiencias internas de alienación, resentimiento y desprecio suelen ponerse en juego en los individuos que llevan a cabo este tipo de violencia, la autora sugiere que la glorificación exclusivamente estadounidense del "lobo solitario", el "individuo rudo" y el "héroe incomprendido" alimenta un trasfondo de sostén para los autores de tiroteos masivos, en una nación que parece estar enamorada de antiguas actitudes patriarcales mientras redobla su valoración del armamento. Dichas actitudes patriarcales, acentuadas por el capitalismo y los beneficios de la industria armamentística, están implicadas en la adhesión territorial al derecho estadounidense a las armas y en el alto costo pagado por la sangre de inocentes. Basándose en los conceptos de socioanálisis y socialidad de Vestergaard y Odde (2021), este artículo explora el proceso dinámico del "carácter de masas", marcado por el "contagio, la imitación, la atracción y la repulsión", que convierte los valores culturales del patrimonio y la libertad en la expresión perversa de la violencia de masas.

Jung's Erotic Phenomenology: I. A New Translation.

In the introduction to The Psychology of the Transference (1946), Carl Jung sketched out a theory of "erotic phenomenology" which condenses his teaching about sexuality and romantic love into a very concise summary. But the meaning of this passage is obscured in the English translation given in the Collected Works of C. G. Jung. I propose here a new translation which makes Jung's meaning clearer, along with a commentary which explains it in the context of Freudian drive theory and German 19th century philosophy. Invoking the concepts of instinct, mind, and Eros (both the passion and the divine figure), Jung's theory says that male sexual desire can be cultivated or repressed in four distinct ways, each associated with a female symbolic figure or anima image: Eve, Helen, Mary and Sophia.

Dans son introduction à La Psychologie du Transfert (1946), Carl Jung esquisse une « phénoménologie érotique ¼ qui condense ses enseignements sur la sexualité et le désir en un résumé très concis. Mais le sens de ce passage est brouillé dans la traduction anglaise des Collected Works of C.G. Jung. Je propose ici une nouvelle traduction qui rend l'argument de Jung plus clair, suivie d'un commentaire qui l'explique dans le contexte de la théorie freudienne des pulsions et de la philosophie allemande du XIXe siècle. Invoquant les concepts d'instinct, d'esprit et d'Eros (en tant que passion ainsi que figure divine), la théorie de Jung dit que le désir sexuel masculin peut être cultivé ou réprimé de quatre manières distinctes, chacune associée à une figure symbolique féminine ou image de l'anima: Eve, Hélène, Marie et Sophia.

En la introducción a La Psicología de la Transferencia (1946), Carl Jung esbozó una "fenomenología erótica" que condensa sus enseñanzas sobre la sexualidad y el amor romántico en un resumen muy conciso. Pero el significado de este pasaje queda opacado en la traducción inglesa de las Obras Completas de C.G. Jung. Propongo aquí una nueva traducción que aclara el significado de Jung, junto con un comentario que lo explica en el contexto de la teoría freudiana de la pulsión y la filosofía alemana del siglo XIX. Invocando los conceptos de instinto, mente y Eros (tanto la pasión como la figura divina), la teoría de Jung expresa que el deseo sexual masculino puede cultivarse o reprimirse de cuatro maneras distintas, cada una asociada a una figura simbólica femenina o imagen del ánima: Eva, Helena, María y Sofía.

Study on the influence mechanism of perceived benefits on unsafe behavioral decision-making based on ERPs and EROs.

Introduction: Perceived benefits are considered one of the significant factors affecting an individual's decision-making process. Our study aimed to explore the influence mechanism of perceived benefits in the decision-making process of unsafe behaviors. Methods: Our study used the "One Stimulus-Two Key Choice (S-K1/K2)" paradigm to conduct an EEG experiment. Participants (N = 18) made decisions in risky scenarios under high perceived benefits (HPB), low perceived benefits (LPB), and control conditions (CC). Time domain analysis and time-frequency analysis were applied to the recorded EEG data to extract ERPs (event-related potentials) and EROs (event-related oscillations), which include the P3 component, theta oscillations, alpha oscillations, and beta oscillations. Results: Under the HPB condition, the theta power in the central (p = 0.016*) and occipital regions (p = 0.006**) was significantly decreased compared to the CC. Similarly, the alpha power in the frontal (p = 0.022*), central (p = 0.037*), and occipital regions (p = 0.014*) was significantly reduced compared to the CC. Under the LPB condition, theta power in the frontal (p = 0.026*), central (p = 0.028*), and occipital regions (p = 0.010*) was significantly reduced compared to the CC. Conversely, alpha power in the frontal (p = 0.009**), central (p = 0.012*), and occipital regions (p = 0.040*) was significantly increased compared to the HPB condition. Discussion: The high perceived benefits may reduce individuals' internal attention and evoke individuals' positive emotions and motivation, leading individuals to underestimate risks. Consequently, they exhibited a greater inclination toward unsafe behaviors. However, the low perceived benefits may reduce individuals' memory review, resulting in a simple decision-making process, and they are more inclined to make fast decisions to avoid loss. The research results can help to provide targeted intervention measures, which are beneficial to reducing workers' unsafe behaviors.

Effects of Water Deficit on Growth and Productivity in Tomato Crops Irrigated with Water Treated with Very Low-Frequency Electromagnetic Resonance Fields.

The tomato crop is very sensitive to stress conditions. A water deficit is defined as when precipitation is less than the evapotranspiration (ETc) of the crop in a given period, and in this scenario of climate change, it is identified as responsible for global productivity losses. The use of potential technologies for better irrigation management, such as electromagnetically treated water, remains controversial. Thus, the objective of the present work was to investigate the effects of very low-frequency electromagnetic resonance field treatment on water for tomato crops submitted to different irrigation rates. For this, an experiment was carried out under controlled conditions with different types of water: electromagnetically treated water (WTVLF) and untreated water (UNW), as well as four water replacement rates: 40, 60, 80, and 100% ETc. The electromagnetic treatment of the water was carried out using the commercial equipment AQUA4D®. The experiment was carried out in pots with five replications per treatment. Lower activity of SOD, POD, CAT, and APX enzymes was observed in plants irrigated with water treated with very low-frequency electromagnetic resonance fields (WTVLF), indicating less oxidative stress caused by water deficit. Water deficit reduced chlorophyll content, but the effects were less harmful with WTVLF water. The water deficit resulted in less accumulation of dry matter and less productivity in a linear relationship. However, plants irrigated with WTVLF showed increments of about 20% in dry matter accumulation and 20% in fruit production concerning plants irrigated with untreated water, independent of the irrigation rates. We can conclude that irrigation with WTVLF can be a solution to reduce the damage caused by water deficits and increase the productivity of tomato crops.

A novel mutation in EROS (CYBC1) causes chronic granulomatous disease.

Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterised by opportunistic infection and sterile granulomatous inflammation. CGD is caused by a failure of reactive oxygen species (ROS) production by the phagocyte NADPH oxidase. Mutations in the genes encoding phagocyte NADPH oxidase subunits cause CGD. We and others have described a novel form of CGD (CGD5) secondary to lack of EROS (CYBC1), a highly selective chaperone for gp91phox. EROS-deficient cells express minimal levels of gp91phox and its binding partner p22phox, but EROS also controls the expression of other proteins such as P2X7. The full nature of CGD5 is currently unknown. We describe a homozygous frameshift mutation in CYBC1 leading to CGD. Individuals who are heterozygous for this mutation are found in South Asian populations (allele frequency = 0.00006545), thus it is not a private mutation. Therefore, it is likely to be the underlying cause of other cases of CGD.

"No one can hate you more than I do": The perverse interplay of life and death drives in Roman Polanski's film Bitter Moon.

In this paper, the authors explore the depiction of perversion and the associated interplay of life and death drives in Roman Polanski's 1992 film Bitter Moon. To begin with, a theoretical discussion is presented regarding perverse organizations of mastery and sadomasochism. Perversion is viewed as an expression of the death drive under erotic disguise, in which the destructive fingerprint of the death drive is revealed at every stage, having as its ultimate purpose the destruction of the other. Based on these theoretical insights a dialogue is developed with Polanski's film, which brings to life the theory of sadomasochistic relations through the multidimensional aesthetic medium of cinema. It is shown how Polanski's cinematic oeuvre conveys the essence of the difficult and complex experience of perverse relations, where the life and death drives and their transformations are manifested. The portrayal of the sadomasochistic relations in this film contributes to the experiential knowledge with which the authors promote insight that would potentially enrich the clinical work with patients with perverse organizations.

Escala de Percepción de Reforzamiento Medioambiental (EROS): evidencias de validez en una muestra colombiana

Introducción: El objetivo de esta investigación fue confirmar la estructura interna de la Environmental Reward Observation Scale (EROS) y recoger evidencias de su relación con otros constructos en una muestra colombiana de 902 adultos que consintieron participar voluntariamente. Método: Se realizaron análisis psicométricos con Teoría Clásica de los Test y el modelo de Rasch. Se recolectaron evidencias de validez de la estructura interna y de la relación de las puntuaciones con otras variables. Resultados: Se obtuvieron buenos índices en los coeficientes alfa y omega de McDonald, nueve de los 10 ítems tuvieron buenos ajustes en los índices infit y outfit, y el ítem ocho presentó DIF en el nivel educativo. Se confirmó la estructura unidimensional de la EROS y fue invariante respecto al sexo y nivel educativo. Los puntajes tuvieron correlaciones de magnitud alta con sintomatología emocional y variables afines a la Activación Conductual. Conclusiones: La EROS presentó altas calidades psicométricas para su uso en población colombiana; sin embargo, se recomienda su uso solo para evaluación de tamizaje, porque los niveles de información están centrados en un área reducida a lo largo de la métrica logit.

Introduction: The aim of this research was to confirm the internal structure of the Environmental Reward Observation Scale (EROS) and to collect evidence of its relationship with other constructs in a Colombian sample of 902 adults who voluntarily consented to participate. Method: Psychometric analyses were performed using Classical Test Theory and the Rasch model. Evidence of validity based on internal structure and relations of scores with other variables was collected. Results: Good indexes were obtained in McDonald's Alpha and Omega coefficients, 9 of the 10 items had good adjustments in the Infit and Outfit indexes, and item 8 presented DIF in the educational level. The unidimensional structure of the EROS was confirmed and was invariant with respect to sex and educational level. Scores had high magnitude correlations with emotional symptomatology and variables related to Behavioral Activation. Conclusions: The EROS presented high psychometric qualities for its use in the Colombian population; however, its use is recommended only for screening assessment because the levels of information are centered in a reduced area along the Logit scaling.

Fast Optical Signals for Real-Time Retinotopy and Brain Computer Interface.

A brain-computer interface (BCI) allows users to control external devices through brain activity. Portable neuroimaging techniques, such as near-infrared (NIR) imaging, are suitable for this goal. NIR imaging has been used to measure rapid changes in brain optical properties associated with neuronal activation, namely fast optical signals (FOS) with good spatiotemporal resolution. However, FOS have a low signal-to-noise ratio, limiting their BCI application. Here FOS were acquired with a frequency-domain optical system from the visual cortex during visual stimulation consisting of a rotating checkerboard wedge, flickering at 5 Hz. We used measures of photon count (Direct Current, DC light intensity) and time of flight (phase) at two NIR wavelengths (690 nm and 830 nm) combined with a machine learning approach for fast estimation of visual-field quadrant stimulation. The input features of a cross-validated support vector machine classifier were computed as the average modulus of the wavelet coherence between each channel and the average response among all channels in 512 ms time windows. An above chance performance was obtained when differentiating visual stimulation quadrants (left vs. right or top vs. bottom) with the best classification accuracy of ~63% (information transfer rate of ~6 bits/min) when classifying the superior and inferior stimulation quadrants using DC at 830 nm. The method is the first attempt to provide generalizable retinotopy classification relying on FOS, paving the way for the use of FOS in real-time BCI.

Characterization of AR-CGD female patient with a novel homozygous deletion in CYBC1 gene presenting with unusual clinical phenotype.

Chronic granulomatous disease (CGD) is a human IEI caused by mutations in genes encoding the NADPH oxidase subunits, the enzyme responsible for the respiratory burst. CGD patients have severe life-threatening infections, hyperinflammation and immune dysregulation. Recently, an additional autosomal recessive AR-CGD (type 5) caused by mutations in CYBC1/EROS gene was identified. We report a AR-CGD5 patient with a novel loss of function (LOF) homozygous deletion c.8_7del in the CYBC1 gene including the initiation ATG codon that leads to failure of CYBC1/EROS protein expression and presenting with an unusual clinical manifestation of childhood-onset sarcoidosis-like disease requiring multiple immunosuppressive therapies. We described an abnormal gp91phox protein expression/function in the patient's neutrophils and monocytes (about 50%) and a severely compromised B cell subset (gp91phox < 15%; DHR+ < 4%). Our case-report emphasized the importance of considering a diagnosis of AR-CGD5 deficiency even in absence of typical clinical and laboratory findings.

Clitoral Therapy Device for Alleviating Sexual Dysfunction After Female Genital Mutilation: Randomized Controlled Trial.

BACKGROUND: Female genital mutilation is considered a crime but is still practiced today in Africa and the Middle East, despite all the laws that make this procedure illegal due to the long-term physical and psychological harm it causes to women. Millions of girls and women living today have undergone genital mutilation, which involves removing the external female genitalia either partially or totally, based on the belief that it restricts feminine sexuality, thereby "saving" a girl for marriage. For girls and women, the surgery offers no health advantages. Girls' right to control critical decisions regarding their sexual and reproductive health is violated because genital mutilation is frequently done against their will and frequently without their consent, leading to lifelong psychic trauma in addition to sexual dysfunction and lack of satisfaction due to distortion of the genitalia that threatens marital stability. OBJECTIVE: To determine the effect of a clitoral therapy device on improving sexual domains in women suffering from sexual dysfunction after female genital mutilation. METHODS: This study examined 80 married women aged from 20 to 45 years who were referred from the gynecology outpatient clinic of the Faculty of Medicine, Suez University, for sexual dysfunction resulting from female genital mutilation. The women were divided into 2 equal groups: the study group received a clitoral therapy device and traditional psychosexual education and were closely followed for 3 months, while the control group received only traditional psychosexual education for 3 months. The Arabic version of the Female Sexual Function Index (FSFI) questionnaire was used to assess sexual outcomes pre- and posttreatment in the 2 groups. RESULTS: Our findings revealed a significant increase in the 6 domains of the FSFI pretreatment in both groups compared to posttreatment (P>.001), except the orgasm domain in the control group, which showed only a nonsignificant increase (P=.16). CONCLUSIONS: Clitoral therapy devices may be an effective, safe, noninvasive rehabilitation method for sexual dysfunction following female genital mutilation. TRIAL REGISTRATION: ClinicalTrials.gov NCT05039775; https://clinicaltrials.gov/ct2/show/NCT05039775.

Abnormal Cross Frequency Coupling of Brain Electroencephalographic Oscillations Related to Visual Oddball Task in Parkinson's Disease with Mild Cognitive Impairment.

Parkinson's disease (PD) is a movement disorder caused by degeneration in dopaminergic neurons. During the disease course, most of PD patients develop mild cognitive impairment (PDMCI) and dementia, especially affecting frontal executive functions. In this study, we tested the hypothesis that PDMCI patients may be characterized by abnormal neurophysiological oscillatory mechanisms coupling frontal and posterior cortical areas during cognitive information processing. To test this hypothesis, event-related EEG oscillations (EROs) during counting visual target (rare) stimuli in an oddball task were recorded in healthy controls (HC; N = 51), cognitively unimpaired PD patients (N = 48), and PDMCI patients (N = 53). Hilbert transform served to estimate instantaneous phase and amplitude of EROs from delta to gamma frequency bands, while modulation index computed ERO phase-amplitude coupling (PAC) at electrode pairs. As compared to the HC and PD groups, the PDMCI group was characterized by (1) more posterior topography of the delta-theta PAC and (2) reversed delta-low frequency alpha PAC direction, ie, posterior-to-anterior rather than anterior-to-posterior. These results suggest that during cognitive demands, PDMCI patients are characterized by abnormal neurophysiological oscillatory mechanisms mainly led by delta frequencies underpinning functional connectivity from frontal to parietal cortical areas.

Reward-based decision-making in mesial temporal lobe epilepsy patients with unilateral hippocampal sclerosis pre- and post-surgery.

BACKGROUND: Correct functioning of the reward processing system is critical for optimizing decision-making as well as preventing the development of addictions and/or neuropsychiatric symptoms such as depression, apathy, and anhedonia. Consequently, patients with mesial temporal lobe epilepsy due to unilateral hippocampal sclerosis (mTLE-UHS) represent an excellent opportunity to study the brain networks involved in this system. OBJECTIVE: The aim of the current study was to evaluate decision-making and the electrophysiological correlates of feedback processing in a sample of mTLE-UHS patients, compared to healthy controls. In addition, we assessed the impact of mesial temporal lobe surgical resection on these processes, as well as general, neuropsychological functioning. METHOD: 17 mTLE-UHS patients and 17 matched healthy controls completed: [1] a computerized version of the Game of Dice Task, [2] a Standard Iowa Gambling Task, and [3] a modified ERP version of a probabilistic gambling task coupled with multichannel electroencephalography. Neuropsychological scores were also obtained both pre- and post-surgery. RESULTS: Behavioral analyses showed a pattern of increased risk for the mTLE-UHS group in decision-making under ambiguity compared to the control group. A decrease in the amplitude of the Feedback Related Negativity (FRN), a weaker effect of valence on delta power, and a general reduction of delta and theta power in the mTLE-UHS group, as compared to the control group, were also found. The beta-gamma activity associated with the delivery of positive reward was similar in both groups. Behavioral performance and electrophysiological measures did not worsen post-surgery. CONCLUSIONS: Patients with mTLE-UHS showed impairments in decision-making under ambiguity, particularly when they had to make decisions based on the outcomes of their choices, but not in decision-making under risk. No group differences were observed in decision-making when feedbacks were random. These results might be explained by the abnormal feedback processing seen in the EEG activity of patients with mTLE-UHS, and by concomitant impairments in working memory, and memory. These impairments may be linked to the disruption of mesial temporal lobe networks. Finally, feedback processing and decision-making under ambiguity were already affected in mTLE-UHS patients pre-surgery and did not show evidence of clear worsening post-surgery.

Identification of novel proteins involved in P2X7-mediated signaling cascades.

High concentration of extracellular ATP acts as a danger signal that is sensed by the P2X7 receptor (P2X7R). This ATP-gated ion channel has been shown to induce multiple metabotropic events such as changes in plasma membrane composition and morphology, ectodomain shedding, activation of lipases, kinases, and transcription factors as well as cytokine release. The specific signaling pathways and molecular mechanisms remain largely obscure. Using an unbiased genome-scale CRISPR/Cas9 screening approach in a murine T cell line, Ryoden et al. (2022, 2020) identified three proteins involved in P2X7 regulation and signaling: Essential for Reactive Oxygen Species (EROS) is essential for P2X7 folding and maturation, and Xk and Vsp13a are required for P2X7-mediated phosphatidyl serine exposure and cell lysis. They further provide evidence for an interaction of Xk and Vsp13a at the plasma membrane and confirm the role of Xk in ATP-induced cytolysis in primary CD25+CD4+ T cells from Xk-/- mice.

Conformational ensemble of the full-length SARS-CoV-2 nucleocapsid (N) protein based on molecular simulations and SAXS data.

The nucleocapsid protein of the SARS-CoV-2 virus comprises two RNA-binding domains and three regions that are intrinsically disordered. While the structures of the RNA-binding domains have been solved using protein crystallography and NMR, current knowledge of the conformations of the full-length nucleocapsid protein is rather limited. To fill in this knowledge gap, we combined coarse-grained molecular simulations with data from small-angle X-ray scattering (SAXS) experiments using the ensemble refinement of SAXS (EROS) method. Our results show that the dimer of the full-length nucleocapsid protein exhibits large conformational fluctuations with its radius of gyration ranging from about 4 to 8 nm. The RNA-binding domains do not make direct contacts. The disordered region that links these two domains comprises a hydrophobic α-helix which makes frequent and nonspecific contacts with the RNA-binding domains. Each of the intrinsically disordered regions adopts conformations that are locally compact, yet on average, much more extended than Gaussian chains of equivalent lengths. We offer a detailed picture of the conformational ensemble of the nucleocapsid protein dimer under near-physiological conditions, which will be important for understanding the nucleocapsid assembly process.