Effect of Adding Integrated Core and Graduated Upper Limb Exercises to Inpatient Cardiac Rehabilitation on Sternal Instability After Coronary Artery Bypass Grafting: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect of adding integrated core and graduated resistance upper limb exercises to an inpatient cardiac rehabilitation program in patients with acute sternal instability after coronary artery bypass grafting (CABG). DESIGN: This was a single-center, randomized, controlled, parallel-group intervention study. SETTING: This study was conducted at the National Heart Institute. PARTICIPANTS: Forty patients with post-CABG with sternal instability aged 50-60 years completed this study and were randomized into 2 groups: an intervention group (n=20) and an active control group (n=20). INTERVENTION: The intervention group (A) received a routine inpatient rehabilitation program from the first postoperative day plus integrated core and graduated resistance upper limb exercises, which started from the seventh postoperative day for approximately 4 weeks, whereas the control group (B) received only the routine inpatient rehabilitation program. MAIN OUTCOME MEASURES: Sternal separation measured by ultrasonography, visual analog scale for measuring pain, and activities of daily living (ADL) index were main outcome measures. RESULTS: Patients in the intervention group (A) showed a significant reduction in sternal separation from the supine and long sitting positions, whereas those in the control group (B) showed a significant increase in sternal separation (P=.0001). Both groups showed a reduction in pain, and an increase in the ADL score was observed in group A. There was a significant interaction between the time and group effects (P=.0001). CONCLUSION: Adding integrated core and graduated upper limb exercises to inpatient cardiac rehabilitation for patients with sternal instability after coronary artery bypass grafting significantly improved sternal healing, pain, and ADL.

Effect of Buerger-Allen exercise on wound healing in patients with diabetic foot ulcers: a randomised controlled trial.

OBJECTIVE: A diabetic foot ulcer (DFU) is a complication of type 2 diabetes that is difficult to treat. Buerger-Allen exercise has shown effectiveness in improving foot circulation and neuropathy in several studies; however, to the best of our knowledge, no randomised controlled study has investigated its effectiveness for DFU healing. Therefore, this study aimed to assess the effects of Buerger-Allen exercise on the healing of DFUs in patients with type 2 diabetes. METHOD: This is a parallel-group randomised controlled trial (RCT). Of 50 patients with neuropathic DFUs, 41 completed the study. They were assigned randomly to a study group (n=21) and a control group (n=20). Patients in the study group received the standard medical treatment and semi-supervised Buerger-Allen exercise for three sessions per week for four weeks, while patients in the control group only received the standard medical treatment. The outcome measures were: ankle-brachial pressure index (ABPI); ulcer size; ulcer depth; SINBAD score; and ulcer risk for poor outcomes (based on the SINBAD score). RESULTS: The study group's mean age was 49.48±6.45 years and the control group's mean age was 49.15±5.85. The study group's ABPI increased significantly compared to the baseline (1.17±0.04 versus 1.11±0.05, respectively; p<0.001) and the control group (1.17±0.04 versus 1.14±0.05, respectively; p=0.04) post-intervention. Ulcer size also reduced significantly in the study group compared to the baseline (2.63±2.0 versus 7.48±5.55cm2, respectively; p<0.001) and the control group (2.63±2.0 versus 6.43±4.45cm2, respectively; p<0.001) post-intervention. Ulcer depth decreased significantly in the study group compared to the baseline (1.71±1.05 versus 4.19±1.74mm, respectively; p<0.001) and the control group (1.71±1.05 versus 2.80±1.57mm, respectively; p=0.01) post-intervention. Furthermore, the SINBAD score in the study group decreased significantly compared to the baseline (1.38±0.86 versus 2.14±1.06, respectively; p<0.001) and the control group (1.38±0.86 versus 2.0±0.79, respectively; p=0.02) post-intervention. Moreover, the ulcer risk for poor outcomes, based on the SINBAD score, reduced significantly only in the study group, compared to the baseline (p=0.041). The control group showed non-significant changes compared to the baseline in all outcome measures (p>0.05). CONCLUSION: From the findings of this RCT, Buerger-Allen exercise, in combination with standard wound care, may help accelerate the healing of neuropathic DFUs in patients with type 2 diabetes, and could be suggested as part of the management plan for such conditions as an easy-to-perform offloading exercise intervention.

Psychosocial and mental profile of children with sickle cell disease and their caregivers.

Sickle cell disease (SCD), a chronic debilitating disorder that may negatively affect health-related quality-of-life (HRQoL). In this observational, case-control study, we aim to assess the prevalence of impaired psychosocial profile and poor HRQoL among SCD patients and their caregivers as well as to determine the association of such impairment with parameters of disease severity. Sixty-five children and adolescents with SCD and 65 age- and sex-matched healthy controls and their caregivers were recruited. Demographic and clinical characteristics were collected, and a thorough clinical and psychiatric assessments and HR QoL were conducted. Recruited children and adolescents with SCD were 34 (52.3%) boys and 31 (47.7%) girls, and their mean age was 11.40 ± 3.55. Most of them (n = 44, 67.7%) had sickle HbSß+, and vaso-occlusive crises were the most common causes for hospital admission (n = 24, 36.9%). Children with SCD and their caregivers had depression and anxiety symptoms scores higher than reported in the control group. Children with SCD had significantly less self-esteem and less QoL scores with the least scores were in the communication domain. This adverse psychological profile was significantly negatively correlated with the age of the child, duration of illness, number and duration of hospitalizations, disease severity score, and occurrence of complications. We conclude that HRQoL of children suffering from SCD, and their caregivers are adversely affected necessitating implementation of interventions which focus on reducing depressive symptoms, enhancing self-esteem and QoL.

Exploring the association between internet addiction and time management among undergraduate nursing students.

BACKGROUND: Modern undergraduate nursing students face unique challenges as digital natives balancing internet activities with the substantial academic demands of nursing studies. Given the detrimental effects of internet addiction on students' academic performance and well-being, having time management skills is crucial. AIMS: To assess the prevalence and levels of internet addiction and time management and their association among undergraduate nursing students. DESIGN: A cross-sectional, survey-based research design was used. SETTING: The Faculty of Nursing at Alexandria University in Egypt. SUBJECTS: A stratified random sample consisting of 825 undergraduate nursing students. TOOLS: The internet addiction test and time management questionnaire were utilized to collect data. FINDINGS: Internet addiction was prevalent among 98.8% of students, with 56.0% exhibiting mild levels, 40.0% showing moderate levels, and 2.8% having severe levels. A statistically significant negative correlation was found between students' internet addiction and overall time management (r= - 0.387, p < 0.001). CONCLUSION: A considerable level of internet addiction was revealed among the great majority of undergraduate nursing students; however, many students also demonstrated strong time management skills. Furthermore, internet addiction and overall time management were negatively associated, indicating that students with higher levels of internet addiction tend to have poorer time management abilities. RECOMMENDATIONS: Individual counseling and educational training programs should be developed to teach nursing students how to manage time and effectively plan internet usage.

Deciphering the influence: academic stress and its role in shaping learning approaches among nursing students: a cross-sectional study.

BACKGROUND: Nursing education presents unique challenges, including high levels of academic stress and varied learning approaches among students. Understanding the relationship between academic stress and learning approaches is crucial for enhancing nursing education effectiveness and student well-being. AIM: This study aimed to investigate the prevalence of academic stress and its correlation with learning approaches among nursing students. DESIGN AND METHOD: A cross-sectional descriptive correlation research design was employed. A convenient sample of 1010 nursing students participated, completing socio-demographic data, the Perceived Stress Scale (PSS), and the Revised Study Process Questionnaire (R-SPQ-2 F). RESULTS: Most nursing students experienced moderate academic stress (56.3%) and exhibited moderate levels of deep learning approaches (55.0%). Stress from a lack of professional knowledge and skills negatively correlates with deep learning approaches (r = -0.392) and positively correlates with surface learning approaches (r = 0.365). Female students showed higher deep learning approach scores, while male students exhibited higher surface learning approach scores. Age, gender, educational level, and academic stress significantly influenced learning approaches. CONCLUSION: Academic stress significantly impacts learning approaches among nursing students. Strategies addressing stressors and promoting healthy learning approaches are essential for enhancing nursing education and student well-being. NURSING IMPLICATION: Understanding academic stress's impact on nursing students' learning approaches enables tailored interventions. Recognizing stressors informs strategies for promoting adaptive coping, fostering deep learning, and creating supportive environments. Integrating stress management, mentorship, and counseling enhances student well-being and nursing education quality.

Study the association of microRNA polymorphisms (miR-146a, miR-4513) with the risk of coronary heart diseases in Egyptian population.

Coronary heart disease (CHD) is the most prevalent cause of cardiovascular mortality in the world. It is well established that microRNAs (miRNAs) and their variants have an essential role in regulating the development of cardiovascular physiology, thus impacting the pathophysiology of heart diseases. This study was designed to determine the possible association of miRNA polymorphisms (miRNA-146a rs2910164C/G and miR-4513 rs2168518G/A) with susceptibility to CHD in Egyptian patients and their correlation with different biochemical parameters. The study comprised 300 participants, including 200 unrelated patients with CHD and 100 healthy controls. Anthropometric and blood biochemical parameters were measured as well genetic analysis for rs2910164C/G and rs2168518G/A polymorphisms were performed for all subjects using TaqMan real-time PCR assay. Our results revealed that the biomedical parameters have a significant correlation between CHD patients and healthy controls with a p < 0.05. Analyses of genotype distribution for (rs2910164 and rs2168518) revealed a significant association with CHD [odd ratio = 4.54, confidence interval (CI 95%) = (2.41-8.53)] and [odd ratio = 0.88, (CI 95%) = (0.83-0.92)], respectively. Furthermore, a statistically significant difference was detected between lipid profile levels and both rs2910164 and rs2168518 polymorphisms. The present study's findings indicated that the selected polymorphisms, miR-146a rs2910164 and miR-4513 rs2168518 could represent a useful biomarker for susceptibility to CHD in the Egyptian population. These genetic characteristics and personal habits and environmental factors may contribute to the development of CHD.

Altered theta and beta oscillatory synchrony in a genetic mouse model of pathological anxiety.

While the neural circuits mediating normal, adaptive defensive behaviors have been extensively studied, substantially less is currently known about the network mechanisms by which aberrant, pathological anxiety is encoded in the brain. Here we investigate in mice how deletion of Neuroligin-2 (Nlgn2), an inhibitory synapse-specific adhesion protein that has been associated with pathological anxiety and other psychiatric disorders, alters the communication between key brain regions involved in mediating defensive behaviors. To this end, we performed multi-site simultaneous local field potential (LFP) recordings from the basolateral amygdala (BLA), centromedial amygdala (CeM), bed nucleus of the stria terminalis (BNST), prefrontal cortex (mPFC) and ventral hippocampus (vHPC) in an open field paradigm. We found that LFP power in the vHPC was profoundly increased and was accompanied by an abnormal modulation of the synchrony of theta frequency oscillations particularly in the vHPC-mPFC-BLA circuit. Moreover, deletion of Nlgn2 increased beta and gamma frequency synchrony across the network, and this increase was associated with increased center avoidance. Local deletion of Nlgn2 in the vHPC and BLA revealed that they encode distinct aspects of this avoidance phenotype, with vHPC linked to immobility and BLA linked to a reduction in exploratory activity. Together, our data demonstrate that alterations in long-range functional connectivity link synaptic inhibition to abnormal defensive behaviors, and that both exaggerated activation of normal defensive circuits and recruitment of fundamentally distinct mechanisms contribute to this phenotype. Nlgn2 knockout mice therefore represent a highly relevant model to study the role of inhibitory synaptic transmission in the circuits underlying anxiety disorders.

Substance Use and Overdose in Public Libraries: Results from a Five-State Survey in the US.

In the U.S., overdoses have become a health crisis in both public and private places. We describe the impact of the overdose crisis in public libraries across five U.S. states, and the front-line response of public library workers. We conducted a cross-sectional survey, inviting one worker to respond at each public library in five randomly selected states (CO, CT, FL, MI, and VA), querying participants regarding substance use and overdose in their communities and institutions, and their preparedness to respond. We describe substance use and overdose patterns, as well as correlates of naloxone uptake, in public libraries. Participating library staff (N = 356) reported witnessing alcohol use (45%) and injection drug use (14%) in their libraries in the previous month. Across states surveyed, 12% of respondents reported at least one on-site overdose in the prior year, ranging from a low of 10% in MI to a high of 17% in FL. There was wide variation across states in naloxone uptake at libraries, ranging from 0% of represented libraries in FL to 33% in CO. Prior on-site overdose was associated with higher odds of naloxone uptake by the library (OR 2.5, 95% CI 1.1-5.7). Although 24% of respondents had attended a training regarding substance use in the prior year, over 90% of respondents wanted to receive additional training on the topic. Public health professionals should partner with public libraries to expand and strengthen substance use outreach and overdose prevention efforts.

New quantification method for monitoring 18 l-amino acids levels in schizophrenic patients by high-performance liquid chromatography coupled to tandem quadrupole mass spectrometer.

A fast, uncomplicated, sensitive and fully validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method has been developed for estimating l-amino acids in the plasma of schizophrenic patients. The gradient-elution chromatographic method was implemented with the Luna® PFP column (50 × 2.0 mm, 5 µm), and a mobile phase of 0.1% formic acid in water and methanol was used. The intra- and interday variability of the l-amino acids was <13.11%, their accuracy ranged from 85.14 to 116.75% at the quality control levels and the lower limit of quantification ranged from 2.5 to 15 nm. The extraction efficiency (apparent recovery) of amino acids from healthy plasma was employed by spiking the plasma with standard amino acids at the quality control levels. Their percentage recoveries ranged from 80.4 to 119.94%. Our method has a short run time and fast sample preparation compared with existing methods, which suffer from long preparative steps and/or time-consuming analysis, restricted reagents and the suboptimal performance characteristics of presently available technologies. Therefore, the proposed HPLC-MS/MS method was effectively applied for monitoring the l-amino acids in the plasma of schizophrenic patients and healthy volunteers.

Corporate dividend policy in the time of COVID-19: Evidence from the G-12 countries.

This paper examines how the COVID-19 pandemic affects corporate dividend policy. Utilizing a sample of 8889 firms listed in the G-12 countries, the findings show that although the proportion of dividend cuts and omissions is significantly higher during the pandemic, yet the majority of firms could either maintain or increase dividends. By doing so, firms might aim to purse more stable dividend policies and signal their financial prospects during the crisis, as posited by dividend signaling theory. Logit regression findings reveal that firm profitability, earnings prospects, size and leverage appear to be important determinants of dividend policy decisions during the pandemic.

Therapeutic Assessment of Combination Therapy with a Neprilysin Inhibitor and Angiotensin Type 1 Receptor Antagonist on Angiotensin II-Induced Atherosclerosis, Abdominal Aortic Aneurysms, and Hypertension.

Combined neprilysin (NEP) inhibition (sacubitril) and angiotensin type 1 receptor (AT1R) antagonism (valsartan) is used in the treatment of congestive heart failure and is gaining interest for other angiotensin II (AngII)-related cardiovascular diseases. In addition to heart failure, AngII promotes hypertension, atherosclerosis, and abdominal aortic aneurysms (AAAs). Similarly, NEP substrates or products have broad effects on the cardiovascular system. In this study, we examined NEP inhibition (with sacubitril) and AT1R antagonism (with valsartan) alone or in combination on AngII-induced hypertension, atherosclerosis, or AAAs in male low-density lipoprotein receptor-deficient mice. Preliminary studies assessed drug delivery via osmotic minipumps for simultaneous release of sacubitril and/or valsartan with AngII over 28 days. Mice were infused with AngII (1000 ng/kg per minute) in the absence (vehicle) or presence of sacubitril (1, 6, or 9 mg/kg per day), valsartan (0.3, 0.5, 1, 6, or 20 mg/kg per day), or the combination thereof (1 and 0.3, or 9 or 0.5 mg/kg per day of sacubitril and valsartan, respectively). Plasma AngII and renin concentrations increased 4-fold at higher valsartan doses, indicative of removal of AngII negative feedback on renin. Sacubitril doubled plasma AngII concentrations at lower doses (1 mg/kg per day). Valsartan dose-dependently decreased systolic blood pressure, aortic atherosclerosis, and AAAs of AngII-infused mice, whereas sacubitril had no effect on atherosclerosis or AAAs but reduced blood pressure of AngII-infused mice. Combination therapy with sacubitril and valsartan did not provide additive benefits. These results suggest limited effects of combination therapy with NEP inhibition and AT1R antagonism against AngII-induced hypertension, atherosclerosis, or AAAs. SIGNIFICANCE STATEMENT: The combination of valsartan (angiotensin type 1 receptor antagonist) and sacubitril (neprilysin inhibitor) did not provide benefit above valsartan alone on AngII-induced hypertension, atherosclerosis, or abdominal aortic aneurysms in low-density lipoprotein receptor-deficient male mice. These results do not support this drug combination in therapy of these AngII-induced cardiovascular diseases.

Disturbance calls of five migratory Characiformes species and advertisement choruses in Amazon spawning sites.

Species-specific disturbance calls of five commercially-important characiform species are described, the Curimatidae commonly called branquinhas: Potamorhina latior, Potamorhina altamazonica and Psectrogaster amazonica; Prochilodontidae: jaraquí Semaprochilodus insignis and curimatã Prochilodus nigricans. All species have a two-chambered swimbladder and the sonic mechanism, present exclusively in males, utilises hypertrophied red muscles between ribs that adhere to the anterior chamber. The number of muscles is unusually plastic across species and varies from 1 to 4 pairs suggesting considerable evolution in an otherwise conservative system. Advertisement calls are produced in river confluences in the Madeira Basin during the high-water mating season (January-February). Disturbance calls and sampling allowed recognition of underwater advertisement choruses from P. latior, S. insignis and P. nigricans. The advertisement calls of the first two species have largely similar characteristics and they mate in partially overlapping areas in the Guaporé River. However, P. latior sounds have a lower dominant frequency and it prefers to call from river confluences whereas S. insignis shoals occur mostly in the main river channel adjacent to the confluence. These results help identify and differentiate underwater sounds and evaluate breeding areas during the courtship of commercially important characids likely to be affected by two hydroelectric dams.

Wall structure and material properties cause viscous damping of swimbladder sounds in the oyster toadfish Opsanus tau.

Despite rapid damping, fish swimbladders have been modelled as underwater resonant bubbles. Recent data suggest that swimbladders of sound-producing fishes use a forced rather than a resonant response to produce sound. The reason for this discrepancy has not been formally addressed, and we demonstrate, for the first time, that the structure of the swimbladder wall will affect vibratory behaviour. Using the oyster toadfish Opsanus tau, we find regional differences in bladder thickness, directionality of collagen layers (anisotropic bladder wall structure), material properties that differ between circular and longitudinal directions (stress, strain and Young's modulus), high water content (80%) of the bladder wall and a 300-fold increase in the modulus of dried tissue. Therefore, the swimbladder wall is a viscoelastic structure that serves to damp vibrations and impart directionality, preventing the expression of resonance.

Efficacy of different modes of fractional CO2 laser in the treatment of primary cutaneous amyloidosis: A randomized clinical trial.

BACKGROUND: Primary cutaneous amyloidosis (PCA) comprises three main forms: macular, lichen, and nodular amyloidosis. The current available treatments are quite disappointing. OBJECTIVES: Assess and compare the clinical and histological changes induced by different modes of Fractional CO2 laser in treatment of PCA. PATIENTS AND METHODS: Twenty five patients with PCA (16 macular and 9 lichen amyloidosis) were treated by fractional CO2 using; superficial ablation (area A) and deep rejuvenation (area B). Each patient received 4 sessions with 4 weeks intervals. Skin biopsies were obtained from all patients at baseline and one month after the last session. Patients were assessed clinically and histologically (Congo red staining, polarized light). Patients were followed-up for 3 months after treatment. RESULTS: Both modes yielded significant reduction of pigmentation, thickness, itching, and amyloid deposits (P-value < 0.001). However, the percentage of reduction of pigmentation was significantly higher in area A (P-value = 0.003). Pain was significantly higher in area B. Significant reduction in dermal amyloid deposits denotes their trans-epidermal elimination induced by fractional photothermolysis. CONCLUSION: Both superficial and deep modes of fractional CO2 laser showed comparable efficacy in treatment of PCA. Superficial mode being better tolerated by patients, is recommended as a valid therapeutic option.

Corpus callosum changes in euthymic bipolar affective disorder.

BACKGROUND: Changes in corpus callosum area and thickness have been reported in bipolar disorder. Imaging and limited neuropathological data suggest possible abnormalities in myelination and/or glial function. AIMS: To compare corpus callosum area, thickness and magnetic resonance imaging (MRI) T1 signal intensity in patients with bipolar disorder and healthy controls. METHOD: A total of 48 patients with euthymic bipolar disorder and 46 healthy controls underwent MRI analysis of callosal midsagittal area, callosal thickness and T1 signal intensity. RESULTS: The bipolar group had smaller overall and subregional callosal areas and correspondingly reduced callosal width than the control group. Age correlated negatively with callosal area in the control group but not in the bipolar group. Signal intensity was higher in women than in men in both groups. Signal intensity was reduced in women, but not in men, in the bipolar group. CONCLUSIONS: Observed differences probably relate to diagnosis rather than mood state and bipolar disorder appears to result in morphometric change that overrides changes seen in normal ageing. Intensity changes are consistent with possible altered myelination or glial function. A gender-dependent factor appears to operate and to interact with diagnosis.

Epigenetic regulation of tumor-immune symbiosis in glioma.

Glioma is a type of aggressive and incurable brain tumor. Patients with glioma are highly resistant to all types of therapies, including immunotherapies. Epigenetic reprogramming is a key molecular hallmark in tumors across cancer types, including glioma. Mounting evidence highlights a pivotal role of epigenetic regulation in shaping tumor biology and therapeutic responses through mechanisms involving both glioma cells and immune cells, as well as their symbiotic interactions in the tumor microenvironment (TME). In this review, we discuss the molecular mechanisms of epigenetic regulation that impacts glioma cell biology and tumor immunity in both a cell-autonomous and non-cell-autonomous manner. Moreover, we provide an overview of potential therapeutic approaches that can disrupt epigenetic-regulated tumor-immune symbiosis in the glioma TME.

Epigenetic regulation of tumor immunity.

Although cancer has long been considered a genetic disease, increasing evidence shows that epigenetic aberrations play a crucial role in affecting tumor biology and therapeutic response. The dysregulated epigenome in cancer cells reprograms the immune landscape within the tumor microenvironment, thereby hindering antitumor immunity, promoting tumor progression, and inducing immunotherapy resistance. Targeting epigenetically mediated tumor-immune crosstalk is an emerging strategy to inhibit tumor progression and circumvent the limitations of current immunotherapies, including immune checkpoint inhibitors. In this Review, we discuss the mechanisms by which epigenetic aberrations regulate tumor-immune interactions and how epigenetically targeted therapies inhibit tumor progression and synergize with immunotherapy.

Dual targeting macrophages and microglia is a therapeutic vulnerability in models of PTEN-deficient glioblastoma.

Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent anti-tumor effects and offers a complete tumor regression in more than 60% of animals when combined with anti-PD1 therapy in PTEN-deficient GBM mouse models. Thus, our findings provide a translational triple therapeutic strategy for this lethal disease.

ERß mediates sex-specific protection in the App-NL-G-F mouse model of Alzheimer's disease.

Menopausal loss of neuroprotective estrogen is thought to contribute to the sex differences in Alzheimer's disease (AD). Activation of estrogen receptor beta (ERß) can be clinically relevant since it avoids the negative systemic effects of ERα activation. However, very few studies have explored ERß-mediated neuroprotection in AD, and no information on its contribution to the sex differences in AD exists. In the present study we specifically explored the role of ERß in mediating sex-specific protection against AD pathology in the clinically relevant App NL-G-F knock-in mouse model of amyloidosis, and if surgical menopause (ovariectomy) modulates pathology in this model. We treated male and female App NL-G-F mice with the selective ERß agonist LY500307 and subset of the females was ovariectomized prior to treatment. Memory performance was assessed and a battery of biochemical assays were used to evaluate amyloid pathology and neuroinflammation. Primary microglial cultures from male and female wild-type and ERß-knockout mice were used to assess ERß's effect on microglial activation and phagocytosis. We find that ERß activation protects against amyloid pathology and cognitive decline in male and female App NL-G-F mice. Ovariectomy increased soluble amyloid beta (Aß) in cortex and insoluble Aß in hippocampus, but had otherwise limited effects on pathology. We further identify that ERß does not alter APP processing, but rather exerts its protection through amyloid scavenging that at least in part is mediated via microglia in a sex-specific manner. Combined, we provide new understanding to the sex differences in AD by demonstrating that ERß protects against AD pathology differently in males and females, warranting reassessment of ERß in combating AD.

Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation.

Neuroligin-2 (Nlgn2) is a key synaptic adhesion protein at virtually all GABAergic synapses, which recruits GABAARs by promoting assembly of the postsynaptic gephyrin scaffold. Intriguingly, loss of Nlgn2 differentially affects subsets of GABAergic synapses, indicating that synapse-specific interactors and redundancies define its function, but the nature of these interactions remain poorly understood. Here we investigated how Nlgn2 function in hippocampal area CA1 is modulated by two proposed interaction partners, MDGA1 and MDGA2. We show that loss of MDGA1 expression, but not heterozygous deletion of MDGA2, ameliorates the abnormal cytosolic gephyrin aggregation, the reduction in inhibitory synaptic transmission and the exacerbated anxiety-related behaviour characterizing Nlgn2 knockout (KO) mice. Additionally, combined Nlgn2 and MDGA1 deletion causes an exacerbated layer-specific loss of gephyrin puncta. Given that both Nlgn2 and the MDGA1 have been correlated with many psychiatric disorders, our data support the notion that cytosolic gephyrin aggregation may represent an interesting target for novel therapeutic strategies.