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Introduction: Diminish production of testosterone hormone could affect sperm quality; hence contribute to the infertility in man. Materials and Methods: 25 Sprague Dawley adult male rats were randomly divided into five groups. Rats were supplemented orally once a day with 0.25 ml Tween 20 solution containing non-polar hexane extract of PM at one of the following concentrations: 0, 6, 12, and 60 mg/kg for seven weeks. Commercial testosterone hormone was used as positive control. On the last day of supplementation period, all rats were sacrificed and orchidectomy technique was performed to collect semen sample from cauda epididymis of the testis. The sperm count, motility, viability and morphology were determined. Results: The results showed that the sperm motility was significantly improved by non-polar PM extract (p<0.05) with the value of 66.98% (6 mg/kg), 63.96% (12 mg/kg) and 65.21% (60 mg/kg) compared to 44.08% for 0 mg/kg group. The supplementation of PM extract however did not improved the sperm count, sperm viability and sperm morphology. The sperm count was 852 (0 mg/kg), 918 (6 mg/kg), 906 (12 mg/kg), 1030 (60 mg/kg) and 1027 million cells/ml (commercial testosterone). The sperm viability was 85.90 (0 mg/kg), 85.26 (6 mg/kg), 85.45 (12 mg/kg), 87.88 (60 mg/kg), and 89.32% (commercial testosterone). The sperm morphology was 62.5% (0 mg/kg), 63.7% (6 mg/kg), 72.2% (12 mg/kg), 67.0% (60 mg/kg) and 64.5% (commercial testosterone). The results showed that non-polar PM extract only improved the sperm motility and did not have any effect on the sperm count, morphology and viability. Conclusion: The study concludes that non-polar extract of PM has no compound that can improve sperm quality except on the motility of the sperm. [ABSTRACT FROM AUTHOR]

Introduction: Fertility is the natural capability of giving live. In male, fertility requires the production of large numbers of normal and mature spermatozoa by testes through a complex process call spermatogenesis. Evidence shows increase male age is associated with the decline of mature sperm in seminiferous tubule. Aqueous extract of Phaleria macrocarpa (PM) has been shown to improve fertility in rats by increasing the spermatogenesis. Materials and Methods: Hexane extract of Phaleria Macrocarpa was prepared by extracting grinded dried slices of fruit followed with drying of the extract using rotary evaporator. A total of 30 male rats were divided into 5 different groups and subjected to daily treatments with PM extract at one of the following concentration: 0. 6, 12, 60 mg/kg of hexane extract, or commercial testosterone hormone for seven consecutive weeks. They will be fed with pellet once a day in the morning and drinking water will be given ad libitum. Body weight was measured once a week. On the last day of supplementation period, the rats were sacrificed and the testis was isolated for histological evaluation. Results: The result showed that no significant effect of non-polar extract of PM on testes size and volume, thickness of seminiferous tubules and spermatogonia cell number. The mean thickness of seminiferous tubules were 62, 68, 62, 60, 60 pm for 60, 12, 6, 0 mg/kg of PM extract and commercial testosterone respectively. The mean for spermatogonia cell count in rats treated with 60, 12, 6 and 0 mg/kg and commercial testosterone were 52.8, 43.8, 47.0, 52.6, 52.0 cells respectively. Conclusion: The study concludes that the non-polar extract of PM has no effect on the fertility of male. [ABSTRACT FROM AUTHOR]

Introduction: Phaleria macrocarpa (PM) has been claimed to overcome male fertility problems related to reduction of testosterone level. Materials and Methods: Non-polar hexane extract of PM was prepared using soxhlet extraction technique, dried to powder using rotary evaporator and been kept for later use. In total 30 male adult Spraque Dawley rats weight about 250 gr were divided into five groups. For libido study, 30 female rats weight about 250 gr each were used for the purpose of mounting latency and mounting frequency study. The male rats were kept in individual cage while for female rats, there were five rats for one cage. Three groups of rats were given three different concentration of PM non-polar extract [High dose (60 mg/kg), Medium dose (12 mg/kg) and Low dose (6 mg/kg)]. One group was given tween 20 solution (negative control) and another group was given commercial testosterone hormone (positive control) orally for seven weeks. At the end of experiment period each male rat was introduced to one female rat to determine the libido behavior. Blood sample was then collected using cardiac puncture and the testosterone level was determined by radioimmunoassay kit (TESTO-CTK P3093). Results: Administration of non-polar hexane extract of PM showed no significant changed for the serum testosterone level and mounting latency of the rats. While, there was a significant change (p<0.05) in the mounting frequency in different groups; 6, 14, 14, 4 and 7 times for the negative control, low dose, medium dose, high dose, and positive control respectively. Conclusion: PM non-polar hexane extract did not show a potential value as an alternative way to improve the sexual strength. However it showed a potential for the improvement of the mounting frequency. [ABSTRACT FROM AUTHOR]

Objective: With respect to the high failure rate of conventional IANB technique and other associated disadvantages, in this study we focused on an alternative called Water on Tray technique and assessed the efficiency of this method compared to the conventional technique., Materials and Methods: This single-blind, single center randomized controlled trial was carried out among 90 individuals referred to the dental clinic of the International Branch of Guilan University of Medical Sciences (IB-GUMS) from November to December of 2017. The patients were randomly assigned into two groups. Injection pain was assessed using Numeric Rating Scale (NRS) and patients were asked to report any tingling sensation on the lip and tongue on the side of injection. Electric pulp test (EPT) and the stick test were also performed. If no numbness was report within 15 min, the injection was deemed unsuccessful. SPSS software version 25 was used with the significance level of p < 0.05., Results: The WOT technique demonstrated a significantly higher success rate of achieving adequate anesthesia on the first attempt (p < 0.05). Additionally, the WOT technique exhibited other significant advantages, including no instances of positive aspiration, rapid onset of action coupled with lingual nerve block, and reduced pain during injection., Conclusion: The Water on Tray is a favorable technique to achieve inferior alveolar nerve block due to its ease and high success rate compared to the conventional technique., Clinical Relevance: This technique allows dentists to achieve a higher success rate with inferior alveolar nerve blocks and reduce injection pain in patients., Competing Interests: Declarations. Ethical approval: Ethical approval was obtained from the Research Ethics Committee of Guilan University of Medical Sciences (approval no. IR.GUMS.REC.1396.329). Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The accumulation of heavy metals is closely related to biochemical parameters and the overall health of both animals and humans. Given the high nutritional value of turkey meat, this study aimed to assess the concentrations of toxic and non-toxic heavy metals in the breast, thigh, and liver tissues of turkeys and examine their relationship with oxidative stress biomarkers. In this cross-sectional study, 150 samples of turkey breast, thigh, and liver from Kurdistan province were collected using a cluster random sampling method. The concentrations of toxic and non-toxic heavy metals were measured using ICP-MS. The correlation between oxidative stress parameters and metal concentrations was investigated. Additionally, the target hazard quotient (THQ) and total risk (TR) for toxic heavy metals were calculated as health indicators. The results indicated that toxic heavy metals, including arsenic, cadmium, and mercury, had significantly higher accumulation in the liver compared to other turkey tissues (P < 0.05). Non-toxic metals, except for magnesium, also demonstrated higher levels in the liver (P < 0.01). The lowest antioxidant enzyme activities of SOD and GPx were observed in the liver, while the highest activities were found in the breast. However, the MDA concentration in the liver (8.96 ± 1.67) was significantly higher than in other tissues (P = 0.016). There was a significant negative correlation between the concentrations of arsenic, cadmium, and mercury and the activities of SOD and GPx enzymes. Conversely, the correlation between MDA and non-toxic metals, including selenium, zinc, and magnesium, was negative (P < 0.05). The accumulation of metals such as arsenic, mercury, copper, and cobalt exceeded permissible levels. The THQ for toxic metals was acceptable; however, the TR for arsenic in the breast, thigh, and liver tissues was within the carcinogenic range. Therefore, reducing and controlling the sources of arsenic as a toxic metal with oxidative effects in turkeys in Kurdistan province requires stringent monitoring and management., Competing Interests: Declarations. Conflict of interest: None of the authors have stated a conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker., Methods: To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization., Results: Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia., Conclusion: Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression., (© 2024. The Author(s).)

Cost-efficient and easily integrable broadband mid-infrared (mid-IR) sources would significantly enhance the application space of photonic integrated circuits (PICs). Thermal incandescent sources are superior to other common mid-IR emitters based on semiconductor materials in terms of PIC compatibility, manufacturing costs, and bandwidth. Ideal thermal emitters would radiate directly into the desired modes of the PIC waveguides via near-field coupling and would be stable at very high temperatures. Graphene is a semimetallic two-dimensional material with comparable emissivity to thin metallic thermal emitters. It allows maximum coupling into waveguides by placing it directly into their evanescent fields. Here, we demonstrate graphene mid-IR emitters integrated with photonic waveguides that couple directly into the fundamental mode of silicon waveguides designed to work in the so-called "fingerprint region" relevant for gas sensing. High broadband emission intensity is observed at the waveguide-integrated graphene emitter. The emission at the output grating couplers confirms successful coupling into the waveguide mode. Thermal simulations predict emitter temperatures up to 1000 °C, where the blackbody radiation covers the mid-IR region. A coupling efficiency η, defined as the light emitted into the waveguide divided by the total emission, of up to 68% is estimated, superior to data published for other waveguide-integrated emitters., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

It has recently become well-established that there is a connection between Alzheimer's disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis.Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each other's experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice.Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses.Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimer's disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels., (© 2024. The Author(s).)

A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer's Disease (AD) caused by a PSEN1-E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear. We generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model. We injected AD-tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Similar to the case report, APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque-associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans. APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ-induced tau seeding and spreading. The results reveal new possibilities to target Aβ-induced tauopathy., Competing Interests: Declaration of interests D.M.H. is an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech, and Cajal Neuroscience and consults for Asteroid, and is on the Advisory Board for Cell. M.C. is a member of Vigil Neuro scientific advisory board (SAB), is consultant for Cell Signaling Technology and NGM Bio. The rest of the authors have no conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Heavy metal accumulation changes the immune system and leads to oxidative damage in aquatic animals. The present study evaluated the correlation between heavy metal accumulation, with immunological and oxidative stress parameters, in various species in the aquatic environment of Western Iran. Fresh samples included fish (trout and carp) and shrimp obtained from Sanandaj aquaculture. After blood sampling and serum isolation for immunological study, meat sections of these animals were used to measure heavy metal concentrations to determine the oxidative stress and immunological parameters. The highest concentrations of Pb (0.82 ± 0.10), As (0.53 ± 0.18), Hg (0.47 ± 0.08), and Zn (28.77 ± 1.88) (µg/g) were found in trout, while the lowest accumulation of heavy metals except for Cd (0.24 ± 0.11) and Se (1.57 ± 0.42) (µg/g) were observed in shrimp. The antioxidant enzymes glutathione peroxidase (GPx) (1.89 ± 0.13) and superoxide dismutase (SOD) (1.96 ± 0.62) U/mg showed the highest concentrations in shrimp and lowest in the trout. Significant negative correlations were found between these enzymes with As and Pb in trout and carp. A significant positive correlation was determined between Se and Zn with GPx and a negative correlation with malondialdehyde (MDA) in shrimp. Immunological biomarkers indicated the concentrations of IL-6, TNF-α, and IFN-Ƴ were higher in fish than in shrimp, and the lowest IgM level was obtained in Shrimp. Increased Pb and Cd showed a significant relationship with increased IL-6 and TNF-α in trout compared to shrimp and carp. An increase in As and Se concentration beyound maximum permissible limits (MPL) were recorded in fish and shrimp, while a Zn level less than MPL was recorded. The target hazard quotients (THQ) and target cancer risk (TR) values of non-essential heavy metals were obtained under acceptable ranges. We suggest reducing the As and Pb content under aquaculture farms and increase in the amount of Zn through diets to keep healthy immunological and physiological conditions for aquatic species in the west of Iran., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alzheimer's disease (AD) is the most common cause of dementia. The APOE-ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD. The APOE genotype modulates the effect of sleep disruption on AD risk, suggesting a possible link between apoE and sleep in AD pathogenesis, which is relatively unexplored. We hypothesized that apoE modifies Aβ deposition and Aβ plaque-associated tau seeding and spreading in the form of neuritic plaque-tau (NP-tau) pathology in response to chronic sleep deprivation (SD) in an apoE isoform-dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-ε3 or -ε4 with or without AD-tau injection. We found that SD in APPPS1 mice significantly increased Aβ deposition and peri-plaque NP-tau pathology in the presence of APOE4 but not APOE3. SD in APPPS1 mice significantly decreased microglial clustering around plaques and aquaporin-4 (AQP4) polarization around blood vessels in the presence of APOE4 but not APOE3. We also found that sleep-deprived APPPS1:E4 mice injected with AD-tau had significantly altered sleep behaviors compared with APPPS1:E3 mice. These findings suggest that the APOE-ε4 genotype is a critical modifier in the development of AD pathology in response to SD.

Sleep loss is associated with cognitive decline in the aging population and is a risk factor for Alzheimer's disease (AD). Considering the crucial role of immunomodulating genes such as that encoding the triggering receptor expressed on myeloid cells type 2 (TREM2) in removing pathogenic amyloid-β (Aβ) plaques and regulating neurodegeneration in the brain, our aim was to investigate whether and how sleep loss influences microglial function in mice. We chronically sleep-deprived wild-type mice and the 5xFAD mouse model of cerebral amyloidosis, expressing either the humanized TREM2 common variant, the loss-of-function R47H AD-associated risk variant, or without TREM2 expression. Sleep deprivation not only enhanced TREM2-dependent Aβ plaque deposition compared with 5xFAD mice with normal sleeping patterns but also induced microglial reactivity that was independent of the presence of parenchymal Aβ plaques. We investigated lysosomal morphology using transmission electron microscopy and found abnormalities particularly in mice without Aβ plaques and also observed lysosomal maturation impairments in a TREM2-dependent manner in both microglia and neurons, suggesting that changes in sleep modified neuro-immune cross-talk. Unbiased transcriptome and proteome profiling provided mechanistic insights into functional pathways triggered by sleep deprivation that were unique to TREM2 and Aβ pathology and that converged on metabolic dyshomeostasis. Our findings highlight that sleep deprivation directly affects microglial reactivity, for which TREM2 is required, by altering the metabolic ability to cope with the energy demands of prolonged wakefulness, leading to further Aβ deposition, and underlines the importance of sleep modulation as a promising future therapeutic approach.

Low-cost, easily integrable photodetectors (PDs) for silicon (Si) photonics are still a bottleneck for photonic-integrated circuits (PICs), especially for wavelengths above 1.8 μm. Multilayered platinum diselenide (PtSe 2 ) is a semi-metallic two-dimensional (2D) material that can be synthesized below 450 °C. We integrate PtSe 2 -based PDs directly by conformal growth on Si waveguides. The PDs operate at 1550 nm wavelength with a maximum responsivity of 11 mA/W and response times below 8.4 μs. Fourier-transform IR spectroscopy in the wavelength range from 1.25 to 28 μm indicates the suitability of PtSe 2 for PDs far into the IR wavelength range. Our PtSe 2 PDs integrated by direct growth outperform PtSe 2 PDs manufactured by standard 2D layer transfer. The combination of IR responsivity, chemical stability, selective and conformal growth at low temperatures, and the potential for high carrier mobility makes PtSe 2 an attractive 2D material for optoelectronics and PICs., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

β-amyloid (Aβ) PET is an important tool for quantification of amyloidosis in the brain of suspected Alzheimer disease (AD) patients and transgenic AD mouse models. Despite the excellent correlation of Aβ PET with gold standard immunohistochemical assessments, the relative contributions of fibrillar and nonfibrillar Aβ components to the in vivo Aβ PET signal remain unclear. Thus, we obtained 2 murine cerebral amyloidosis models that present with distinct Aβ plaque compositions and performed regression analysis between immunohistochemistry and Aβ PET to determine the biochemical contributions to Aβ PET signal in vivo. Methods: We investigated groups of App NL-G-F and APPPS1 mice at 3, 6, and 12 mo of age by longitudinal 18 F-florbetaben Aβ PET and with immunohistochemical analysis of the fibrillar and total Aβ burdens. We then applied group-level intermodality regression models using age- and genotype-matched sets of fibrillar and nonfibrillar Aβ data (predictors) and Aβ PET results (outcome) for both Aβ mouse models. An independent group of double-hit APPPS1 mice with dysfunctional microglia due to knockout of triggering receptor expression on myeloid cells 2 (Trem2 -/- ) served for validation and evaluation of translational impact. Results: Neither fibrillar nor nonfibrillar Aβ content alone sufficed to explain the Aβ PET findings in either AD model. However, a regression model compiling fibrillar and nonfibrillar Aβ together with the estimate of individual heterogeneity and age at scanning could explain a 93% of variance of the Aβ PET signal ( P  < 0.001). Fibrillar Aβ burden had a 16-fold higher contribution to the Aβ PET signal than nonfibrillar Aβ. However, given the relatively greater abundance of nonfibrillar Aβ, we estimate that nonfibrillar Aβ produced 79% ± 25% of the net in vivo Aβ PET signal in App NL-G-F mice and 25% ± 12% in APPPS1 mice. Corresponding results in separate groups of APPPS1/Trem2 -/- and APPPS1/Trem2 +/+ mice validated the calculated regression factors and revealed that the altered fibrillarity due to Trem2 knockout impacts the Aβ PET signal. Conclusion: Taken together, the in vivo Aβ PET signal derives from the composite of fibrillar and nonfibrillar Aβ plaque components. Although fibrillar Aβ has inherently higher PET tracer binding, the greater abundance of nonfibrillar Aβ plaque in AD-model mice contributes importantly to the PET signal., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Neuroinflammation is a central mechanism involved in neurodegeneration as observed in Alzheimer's disease (AD), the most prevalent form of neurodegenerative disease. Apolipoprotein E4 (APOE4), the strongest genetic risk factor for AD, directly influences disease onset and progression by interacting with the major pathological hallmarks of AD including amyloid-β plaques, neurofibrillary tau tangles, as well as neuroinflammation. Microglia and astrocytes, the two major immune cells in the brain, exist in an immune-vigilant state providing immunological defense as well as housekeeping functions that promote neuronal well-being. It is becoming increasingly evident that under disease conditions, these immune cells become progressively dysfunctional in regulating metabolic and immunoregulatory pathways, thereby promoting chronic inflammation-induced neurodegeneration. Here, we review and discuss how APOE and specifically APOE4 directly influences amyloid-β and tau pathology, and disrupts microglial as well as astroglial immunomodulating functions leading to chronic inflammation that contributes to neurodegeneration in AD., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rare coding variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2) confer an increased risk for Alzheimer's disease (AD) characterized by the progressive accumulation of aggregated forms of amyloid β peptides (Aβ). Aβ peptides are generated by proteolytic processing of the amyloid precursor protein (APP). Heterogeneity in proteolytic cleavages and additional post-translational modifications result in the production of several distinct Aβ variants that could differ in their aggregation behavior and toxic properties. Here, we sought to assess whether post-translational modifications of Aβ affect the interaction with TREM2. Biophysical and biochemical methods revealed that TREM2 preferentially interacts with oligomeric Aβ, and that phosphorylation of Aβ increases this interaction. Phosphorylation of Aβ also affected the TREM2 dependent interaction and phagocytosis by primary microglia and in APP transgenic mouse models. Thus, TREM2 function is important for sensing phosphorylated Aβ variants in distinct aggregation states and reduces the accumulation and deposition of these toxic Aβ species in preclinical models of Alzheimer's disease., (© 2021 The Authors. GLIA published by Wiley Periodicals LLC.)

Progressive accumulation of Amyloid-β (Aβ) deposits in the brain is a characteristic neuropathological hallmark of Alzheimer's disease (AD). During disease progression, extracellular Aβ plaques undergo specific changes in their composition by the sequential deposition of different modified Aβ species. Microglia are implicated in the restriction of amyloid deposits and play a major role in internalization and degradation of Aβ. Recent studies showed that rare variants of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are associated with an increased risk for AD. Post-translational modifications of Aβ could modulate the interaction with TREM2, and the uptake by microglia. Here, we demonstrate that genetic deletion of TREM2 or expression of a disease associated TREM2 variant in mice lead to differential accumulation of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits. Human brains with rare TREM2 AD risk variants also showed altered deposition of modified Aβ species in the different brain lesions as compared to cases with the common variant of TREM2. These findings indicate that TREM2 plays a critical role in the development and the composition of Aβ deposits, not only in extracellular plaques, but also intraneuronally, that both could contribute to the pathogenesis of AD., (© 2021. The Author(s).)

In Alzheimer's disease (AD) models, AD risk variants in the microglial-expressed TREM2 gene decrease Aβ plaque-associated microgliosis and increase neuritic dystrophy as well as plaque-associated seeding and spreading of tau aggregates. Whether this Aβ-enhanced tau seeding/spreading is due to loss of microglial function or a toxic gain of function in TREM2-deficient microglia is unclear. Depletion of microglia in mice with established brain amyloid has no effect on amyloid but results in less spine and neuronal loss. Microglial repopulation in aged mice improved cognitive and neuronal deficits. In the context of AD pathology, we asked whether microglial removal and repopulation decreased Aβ-driven tau seeding and spreading. We show that both TREM2KO and microglial ablation dramatically enhance tau seeding and spreading around plaques. Interestingly, although repopulated microglia clustered around plaques, they had a reduction in disease-associated microglia (DAM) gene expression and elevated tau seeding/spreading. Together, these data suggest that TREM2-dependent activation of the DAM phenotype is essential in delaying Aβ-induced pathological tau propagation., Competing Interests: Disclosures: M. Colonna reported "other" from Vigil Neuroscience, and grants from Ono and Pfizer outside the submitted work; in addition, M. Colonna had a patent to TREM2 pending. J.D. Ulrich reported a patent to anti-TREM2 agonist antibodies pending. D.M. Holtzman reported grants from NIH, JPB Foundation, Charles and Helen Schwab Foundation, and Edward N. and Della L. Thome Memorial Foundation during the conduct of the study; "other" from C2N Diagnostics; and personal fees from Denali, Genentech, Merck, Cajal Neurosciences, and Takeda outside the submitted work; in addition, D.M. Holtzman had a patent to anti-tau antibodies licensed and a provisional patent on anti-TREM2 antibodies pending. No other disclosures were reported., (© 2021 Gratuze et al.)

Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer's disease (AD) progression. However, the mechanisms of microbiome-brain interaction in AD were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Aβ deposition. Germ-free (GF) AD mice exhibit a substantially reduced Aβ plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice increased the Aβ plaque load to levels of conventionally colonized (specific pathogen-free [SPF]) animals and SCFA supplementation to SPF mice even further exacerbated plaque load. This was accompanied by the pronounced alterations in microglial transcriptomic profile, including upregulation of ApoE. Despite increased microglial recruitment to Aβ plaques upon SCFA supplementation, microglia contained less intracellular Aβ. Taken together, our results demonstrate that microbiota-derived SCFA are critical mediators along the gut-brain axis which promote Aβ deposition likely via modulation of the microglial phenotype., Competing Interests: AC, RS, GL, VS, SR, SH, LS, AV, FP, SP, FK, MG, EW, JH, CB, MD, HS, MG, CH, ST, AL No competing interests declared, AM Reviewing editor, eLife, (© 2021, Colombo et al.)

Introduction: In Iran, the rate of cesarean section is three times more than the acceptable rate considered by the World Health Organization. This study aimed at reducing the selection of cesarean section by primigravida through an intervention based on social marketing in Boyer-Ahmad County, Iran, 2015., Methods: In this field trial, 39 of primigravida women were identified and selected as a target group. Formative research (a quantitative survey and a qualitative study) was done to achieve the social marketing mix. The tailored intervention was developed based on the findings of formative research. The intervention was implemented for one month for pregnant women who had cesarean section intention. Their intention for the cesarean section was studied again one month after the implementation of the intervention. The effectiveness of the intervention was evaluated by the proportion test., Results: The average age of the women was 25.82. All of the women 38.5 percent had a diploma degree and lower than and 61.5 percent had a university degree. Before the intervention, 39 women intended to do Cesarean. The intention of 30 pregnant women was changed significantly one month after the intervention., Conclusion: The study showed the effectiveness of an intervention based on consumer-oriented social marketing theory and could be used to reduce Cesarean intention. More studies about related factors of vaginal delivery selection especially from behavioral intention up to behavior are suggested., Competing Interests: We have no conflict of interests to declare., (Copyright © 2021 Mostafa Maleki et al.)

Asymmetries of amyloid-β (Aβ) burden are well known in Alzheimer disease (AD) but did not receive attention in Aβ mouse models of Alzheimer disease. Therefore, we investigated Aβ asymmetries in Aβ mouse models examined by Aβ small-animal PET and tested if such asymmetries have an association with microglial activation. Methods: We analyzed 523 cross-sectional Aβ PET scans of 5 different Aβ mouse models (APP/PS1, PS2APP, APP-SL70, App NL-G-F , and APPswe) together with 136 18-kDa translocator protein (TSPO) PET scans for microglial activation. The asymmetry index (AI) was calculated between tracer uptake in both hemispheres. AIs of Aβ PET were analyzed in correlation with TSPO PET AIs. Extrapolated required sample sizes were compared between analyses of single and combined hemispheres. Results: Relevant asymmetries of Aβ deposition were identified in at least 30% of all investigated mice. There was a significant correlation between AIs of Aβ PET and TSPO PET in 4 investigated Aβ mouse models (APP/PS1: R = 0.593, P = 0.001; PS2APP: R = 0.485, P = 0.019; APP-SL70: R = 0.410, P = 0.037; App NL-G-F : R = 0.385, P = 0.002). Asymmetry was associated with higher variance of tracer uptake in single hemispheres, leading to higher required sample sizes. Conclusion: Asymmetry of fibrillar plaque neuropathology occurs frequently in Aβ mouse models and acts as a potential confounder in experimental designs. Concomitant asymmetry of microglial activation indicates a neuroinflammatory component to hemispheric predominance of fibrillary amyloidosis., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Microglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimer's disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) expressed in myeloid lineage cells was recently identified and shown to reduce the risk for AD., Methods: To assess the role of the protective variant in the context of immune cell functions, we generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing., Results: Functional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plcγ2 as a Pip2-metabolizing enzyme. This was associated with improved survival and increased acute inflammatory response of the KI macrophages. Enhanced phagocytosis was observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Immunohistochemical analyses did not reveal changes in the number or morphology of microglia in the cortex of Plcγ2-P522R KI mice. However, the brain mRNA signature together with microglia-related PET imaging suggested enhanced microglial functions in Plcγ2-P522R KI mice., Conclusion: The AD-associated protective Plcγ2-P522R variant promotes protective functions associated with TREM2 signaling. Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLCγ2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD.

Violence against women is an urgent health priority in Iran. Designing effective programs for preventing and controlling the problem necessitates a thorough understanding of Iranian women and their perspectives regarding domestic violence. This study was aimed at exploring the domestic violence-related views of married women who were referred to health care facilities in Ahvaz, Iran. In this qualitative research, data were collected through four focus group discussions with 30 married women. All the discussions were recorded and transcribed, after which the data were classified separately. The main themes and subthemes were then manually derived from the data and analyzed. The five main themes identified were domestic violence against women in Ahvaz, behavioral influencing factors, nonbehavioral influencing factors, the necessity to empower women to prevent domestic violence, and recommendations for developing special training programs for Ahvazi women. Most of the participants were aware that domestic violence against women is a common occurrence in Iran. They were well aware of the definition of violence and expressed a belief that behavioral factors exert an important effect on the occurrence of the problem. They recommended the development of appropriate training programs that empower women to prevent the problem, the use of mass media to educate citizens about domestic violence, and the involvement of opinion leaders in eliminating the taboo against considering such violence a crime against Iranian women. Considering the views and ideas of women as consumers of educational services is a principle used to develop effective programs for preventing and controlling domestic violence. As indicated by the findings, the participants believe that empowering women must be treated as a priority in the Iranian health care system. However, they recommended differing approaches and methods of empowerment on the basis of their individual views and concerns.

Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease-associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full-length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α-secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α-secretase-mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho-SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β-peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9-bound. Moreover, in a mouse model for Alzheimer's disease-related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease-associated state., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non-canonical translation of the expanded repeat results in abundant poly-GA inclusion pathology throughout the CNS. (GA) 149 -CFP expression in mice triggers motor deficits and neuroinflammation. Since poly-GA is transmitted between cells, we investigated the therapeutic potential of anti-GA antibodies by vaccinating (GA) 149 -CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin-(GA) 10 conjugates and pre-aggregated carrier-free (GA) 15 . Only ovalbumin-(GA) 10 immunization induced a strong anti-GA response. The resulting antisera detected poly-GA aggregates in cell culture and patient tissue. Ovalbumin-(GA) 10 immunization largely rescued the motor function in (GA) 149 -CFP transgenic mice and reduced poly-GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin-(GA) 10 -immunized poly-GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP-43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Among these genes are progranulin ( GRN ) and the triggering receptor expressed on myeloid cells 2 ( TREM2 ). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from Grn -/- mice and compared their transcriptomes to those of Trem2 -/- mice Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn -/- mice showed a reciprocal activation of the MGnD molecular signature and suppression of gene characteristic for HM The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro-2-deoxy-d-glucose)-μPET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer's disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associated apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque-associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss-of-function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2, early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque-associated ApoE.

Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD-like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock-in mouse model for the disease-associated Trem2 p.T66M mutation. Consistent with a loss-of-function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p.T66M mutation. Trem2 p.T66M knock-in mice show delayed resolution of inflammation upon in vivo lipopolysaccharide stimulation and cultured macrophages display significantly reduced phagocytic activity. Immunohistochemistry together with in vivo TSPO small animal positron emission tomography (μPET) demonstrates an age-dependent reduction in microglial activity. Surprisingly, perfusion magnetic resonance imaging and FDG-μPET imaging reveal a significant reduction in cerebral blood flow and brain glucose metabolism. Thus, we demonstrate that a TREM2 loss-of-function mutation causes brain-wide metabolic alterations pointing toward a possible function of microglia in regulating brain glucose metabolism., (© 2017 The Authors.)

Background: Given that mothers play a role in the sexual education of their daughters, it is important to understand their views of sexual health and related programs. This study was aimed at exploring mothers' perspectives regarding sexual health education for their adolescent daughters in Mahshahr, Iran., Methods: In this qualitative study, in-depth interviews with ten key informants and five focus group discussions involving 28 mothers with daughters aged 12-18 were conducted. All the discussions were audio-recorded and later transcribed. The data were classified, after which the main themes and sub-themes were manually extracted and analyzed., Results: The five main themes determined were: the necessity of sexual health education for adolescent girls, the sources of information that mothers use, barriers to sexual health education, the need to empower mothers to provide sexual education to their daughters, and recommendations for developing special training programs for mothers. Most participants believed in limiting sexual health education for adolescent girls; nevertheless, they stated that trained mothers were best equipped to educate their daughters. The major barriers identified by the mothers were their own insufficient knowledge about sexual issues, embarrassment surrounding discussions of this issue with their daughters, fear of the arrogance and curiosity of girls, and a lack of skills for effective communication., Conclusion: The results showed that empowering mothers to provide sexual health education is important. Tailored educational programs, based on mothers' views, should be developed and implemented.

Microglia activation has emerged as a potential key factor in the pathogenesis of Alzheimer's disease. Metabolite levels assessed by magnetic resonance spectroscopy (MRS) are used as markers of neuroinflammation in neurodegenerative diseases, but how they relate to microglial activation in health and chronic disease is incompletely understood. Using MRS, we monitored the brain metabolic response to lipopolysaccharides (LPS)-induced microglia activation in vivo in a transgenic mouse model of Alzheimer's disease (APP/PS1) and healthy controls (wild-type (WT) littermates) over 4 hours. We assessed reactive gliosis by immunohistochemistry and correlated metabolic and histological measures. In WT mice, LPS induced a microglial phenotype consistent with activation, associated with a sustained increase in macromolecule and lipid levels (ML9). This effect was not seen in APP/PS1 mice, where LPS did not lead to a microglial response measured by histology, but induced a late increase in the putative inflammation marker myoinositol (mI) and metabolic changes in total creatine and taurine previously reported to be associated with amyloid load. We argue that ML9 and mI distinguish the response of WT and APP/PS1 mice to immune mediators. Lipid and macromolecule levels may represent a biomarker of activation of healthy microglia, while mI may not be a glial marker.

Objective: Menopause is the condition when regular menstrual periods cease and may be accompanied by psychological and physical symptoms. The purpose of current study was to determine Nigella sativa effects on reproductive system in experimental menopause animal models., Materials and Methods: A series of experiments was conducted to investigate the effects of different dosages of N. sativa (first experiment), various extracts of N. sativa (second experiment) and some of its ingredients (third experiment) on selected menopausal parameters of ovariectomized (OVX) rats. Forty different OVX rats were equally divided into 5 groups and administered with one of the following treatments for 21 days: conjugated equine estrogen (positive control), distilled water or olive oil (negative control), treatment groups (N. sativa300, 600 and 1200 mg/kg in the first experiment), (300mg/kg methanol, hexane and SFE extracts of N. sativa in the second experiment) and (linoleic acid 50 mg/kg, gamma linolenic acid 10mg/kg, and thymoquinone 15mg/kg in the third experiment)., Results: The results demonstrated that N.sativa exert estrogenic effect were exhibited through uterotrophic assay and vaginal cell cornification as well as blood estrogen level. Furthermore, low dose N. sativa, methanol extract and linoleic acid had prominent estrogenic like effects which were significantly different from those of control group (p<0.05) in different experiments., Conclusion: The finding indicated the probable beneficial role for N. sativa in the treatment of postmenopausal symptoms and possibility of using N. sativa as an alternative to hormone replacement therapy (HRT) for post menopause in human.

Objectives: The aim of this open label crossover study was to investigate the effects of Nigella sativa on reproductive health and metabolic profile of perimenopausal women in Rawang, Malaysia., Materials and Methods: Sixty nine perimenopausal women aged 45 to 65 were allocated into the experimental group treated orally with 1600mg/day of encapsulated pure powdered N. sativa compared to control groups treated with placebo for 12 weeks. At the end of study, participants underwent washout period for fourteen days before being crossed over and continued for another cycle of treatment. Participants were abstained from taking any other drugs, herbal preparations or food supplements throughout the study. Body weight, height, waist circumference, blood pressure, biochemical parameters and hormonal levels were measured at baseline and at the end of experiment for both cycles. Face to face interview was carried out at baseline and every week to check for compliance, minimize dropouts and to record reproductive health and quality of life indicators using Greene climacteric and SF-36 instruments., Results: The treatment groups in both cycles showed significant improvement with reference to low density lipoprotein cholesterol and blood glucose (P<0.05). There were no significant differences between groups in total cholesterol, high density lipoprotein and triglyceride concentration. Treatment with N. sativa induced a significant reduction of prevalence and severity of menopausal symptomsas well as significant improvement in some components of quality of life (P<0.05)., Conclusion: These results suggested that treatment with N. sativa exert a therapeutic and protective effect by modifying weight gain, improving lipid profile and blood glucose as well as hormonal level which is believed to play an important role in the pathogenesis of metabolic syndrome during menopause.