Dormant state of quiescent neural stem cells links Shank3 mutation to autism development.

Autism spectrum disorders (ASDs) are common neurodevelopmental disorders characterized by deficits in social interactions and communication, restricted interests, and repetitive behaviors. Despite extensive study, the molecular targets that control ASD development remain largely unclear. Here, we report that the dormancy of quiescent neural stem cells (qNSCs) is a therapeutic target for controlling the development of ASD phenotypes driven by Shank3 deficiency. Using single-cell RNA sequencing (scRNA-seq) and transposase accessible chromatin profiling (ATAC-seq), we find that abnormal epigenetic features including H3K4me3 accumulation due to up-regulation of Kmt2a levels lead to increased dormancy of qNSCs in the absence of Shank3. This result in decreased active neurogenesis in the Shank3 deficient mouse brain. Remarkably, pharmacological and molecular inhibition of qNSC dormancy restored adult neurogenesis and ameliorated the social deficits observed in Shank3-deficient mice. Moreover, we confirmed restored human qNSC activity rescues abnormal neurogenesis and autism-like phenotypes in SHANK3-targeted human NSCs. Taken together, our results offer a novel strategy to control qNSC activity as a potential therapeutic target for the development of autism.

Nac1 facilitates pluripotency gene activation for establishing somatic cell reprogramming.

Transcription factors play a central role in pluripotency transcription circuitry for establishing pluripotent reprogramming. Master transcription factors Oct4, Nanog, and Sox2 are known to form the core of the pluripotency transcription network. Other transcription factors also play critical roles for further refining the core circuitry for pluripotency in induced pluripotent stem (iPS) cells. Here, we reported that Nac1 interacted with the master pluripotent factors Oct4 and Nanog co-occupies gene promoters bound by these transcriptional factors for establishing pluripotency. Moreover, this interaction coordinates gene expression with H3K4me3 in the somatic cell reprogramming. Knockdown of Nac1 suppressed somatic cell reprogramming, whereas overexpression of Nac1 resulted in enhanced efficiency of induced pluripotent cell generation. Altogether, these results reveal the genome wide role for Nac1 in the contribution to the pluripotency circuitry and the regulation of the establishing pluripotent state.

NOON-state interference in the frequency domain.

The examination of entanglement across various degrees of freedom has been pivotal in augmenting our understanding of fundamental physics, extending to high dimensional quantum states, and promising the scalability of quantum technologies. In this paper, we demonstrate the photon number path entanglement in the frequency domain by implementing a frequency beam splitter that converts the single-photon frequency to another with 50% probability using Bragg scattering four-wave mixing. The two-photon NOON state in a single-mode fiber is generated in the frequency domain, manifesting the two-photon interference with two-fold enhanced resolution compared to that of single-photon interference, showing the outstanding stability of the interferometer. This successful translation of quantum states in the frequency domain will pave the way toward the discovery of fascinating quantum phenomena and scalable quantum information processing.

Epigenetic Dynamics in Reprogramming to Dopaminergic Neurons for Parkinson's Disease.

Direct lineage reprogramming into dopaminergic (DA) neurons holds great promise for the more effective production of DA neurons, offering potential therapeutic benefits for conditions such as Parkinson's disease. However, the reprogramming pathway for fully reprogrammed DA neurons remains largely unclear, resulting in immature and dead-end states with low efficiency. In this study, using single-cell RNA sequencing, the trajectory of reprogramming DA neurons at multiple time points, identifying a continuous pathway for their reprogramming is analyzed. It is identified that intermediate cell populations are crucial for resetting host cell fate during early DA neuronal reprogramming. Further, longitudinal dissection uncovered two distinct trajectories: one leading to successful reprogramming and the other to a dead end. Notably, Arid4b, a histone modifier, as a crucial regulator at this branch point, essential for the successful trajectory and acquisition of mature dopaminergic neuronal identity is identified. Consistently, overexpressing Arid4b in the DA neuronal reprogramming process increases the yield of iDA neurons and effectively reverses the disease phenotypes observed in the PD mouse brain. Thus, gaining insights into the cellular trajectory holds significant importance for devising regenerative medicine strategies, particularly in the context of addressing neurodegenerative disorders like Parkinson's disease.

Central Role of Hypothalamic Circuits for Acupuncture's Anti-Parkinsonian Effects.

Despite clinical data stretching over millennia, the neurobiological basis of the effectiveness of acupuncture in treating diseases of the central nervous system has remained elusive. Here, using an established model of acupuncture treatment in Parkinson's disease (PD) model mice, we show that peripheral acupuncture stimulation activates hypothalamic melanin-concentrating hormone (MCH) neurons via nerve conduction. We further identify two separate neural pathways originating from anatomically and electrophysiologically distinct MCH neuronal subpopulations, projecting to the substantia nigra and hippocampus, respectively. Through chemogenetic manipulation specifically targeting these MCH projections, their respective roles in mediating the acupuncture-induced motor recovery and memory improvements following PD onset are demonstrated, as well as the underlying mechanisms mediating recovery from dopaminergic neurodegeneration, reactive gliosis, and impaired hippocampal synaptic plasticity. Collectively, these MCH neurons constitute not only a circuit-based explanation for the therapeutic effectiveness of traditional acupuncture, but also a potential cellular target for treating both motor and non-motor PD symptoms.

Late HIV detection among adult males in Los Angeles County, 2000-2004.

We analyzed HIV surveillance data on white, black, and Latino males diagnosed with HIV between 2000 and 2004 in Los Angeles County (LAC) to identify associations between individual- and community-level factors and late HIV detection by race/ethnicity. We defined late HIV detection as an AIDS diagnosis within 6 months of HIV diagnosis. We conducted multilevel analysis to determine individual- and community-level risk factors associated with late HIV detection stratified by race/ethnicity. We mapped HIV-positive males with late HIV detection by race/ethnicity at the zip code level within LAC to determine high burden areas. Overall, 38% of all males met the definition of late HIV detection. By race/ethnicity, 44% of Latinos, 38% of blacks, and 30% of whites were detected late in their course of HIV infection. Latinos and whites had multiple individual-level risk factors associated with late HIV detection. Among black males, only older age at HIV diagnosis was associated with late HIV detection. The only community-level risk factor associated with late HIV detection was among Latinos living in communities with less than 6% of men who have sex with men (proxy for stigma). Mapping the distribution of late HIV detection showed late detection areas generalized across LAC for Latino males in comparison with white and black males whose maps showed clustered areas of late HIV detection. Analysis and mapping of individual- and community-level risk factors associated with late HIV detection provides an important tool for targeting prevention resources to areas and populations with the highest burden of disease.

Transcriptional activation of endogenous Oct4 via the CRISPR/dCas9 activator ameliorates Hutchinson-Gilford progeria syndrome in mice.

Partial cellular reprogramming via transient expression of Oct4, Sox2, Klf4, and c-Myc induces rejuvenation and reduces aged-cell phenotypes. In this study, we found that transcriptional activation of the endogenous Oct4 gene by using the CRISPR/dCas9 activator system can efficiently ameliorate hallmarks of aging in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). We observed that the dCas9-Oct4 activator induced epigenetic remodeling, as evidenced by increased H3K9me3 and decreased H4K20me3 levels, without tumorization. Moreover, the progerin accumulation in HGPS aorta was significantly suppressed by the dCas9 activator-mediated Oct4 induction. Importantly, CRISPR/dCas9-activated Oct4 expression rescued the HGPS-associated vascular pathological features and lifespan shortening in the mouse model. These results suggest that partial rejuvenation via CRISPR/dCas9-mediated Oct4 activation can be used as a novel strategy in treating geriatric diseases.

Modeling the impact of social discrimination and financial hardship on the sexual risk of HIV among Latino and Black men who have sex with men.

OBJECTIVES: We examined the impact of social discrimination and financial hardship on unprotected anal intercourse with a male sex partner of serodiscordant or unknown HIV status in the past 3 months among 1081 Latino and 1154 Black men who have sex with men (MSM; n = 2235) residing in Los Angeles County, California; New York, New York; and Philadelphia, Pennsylvania. METHODS: We administered HIV testing and a questionnaire assessing 6 explanatory variables. We combined traditional mediation analysis with the results of a path analysis to simultaneously examine the direct, indirect, and total effects of these variables on the outcome variable. RESULTS: Bivariate analysis showed that homophobia, racism, financial hardship, and lack of social support were associated with unprotected anal intercourse with a serodiscordant or sero-unknown partner. Path analysis determined that these relations were mediated by participation in risky sexual situations and lack of social support. However, paths between the explanatory variable and 2 mediating variables varied by participants' serostatus. CONCLUSIONS: Future prevention research and program designs should specifically address the differential impact of social discrimination and financial hardship on lack of social support and risky sexual situations among Latino and Black MSM.

Perceptions of HIV/AIDS in one's community predict HIV testing.

Using a subsample of respondents to the 2005 Los Angeles County health survey, we examined the relationship between perceptions of the seriousness of HIV/AIDS in one's community and HIV testing. We constructed a propensity score-based matched sample of three groups with differing perceptions of the seriousness of HIV in their community: high perceived seriousness, low perceived seriousness, and uncertain about seriousness. We compared HIV testing behavior in the three groups before and after using propensity score matching to control for selection on observed covariates. The unadjusted comparison showed a testing rate of 30.2 % among those perceiving high seriousness, 11.4 percentage points higher than the 18.8 % testing rate among those perceiving low seriousness. After propensity score matching, the adjusted testing difference was 7.0 percentage points (p < 0.05). Those uncertain about the seriousness of HIV did not differ significantly in their testing behavior from those perceiving high seriousness.

White Matter Microstructural Alterations in Newly Diagnosed Parkinson's Disease: A Whole-Brain Analysis Using dMRI.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by cardinal motor symptoms and other non-motor symptoms. Studies have investigated various brain areas in PD by detecting white matter alterations using diffusion magnetic resonance imaging processing techniques, which can produce diffusion metrics such as fractional anisotropy and quantitative anisotropy. In this study, we compared the quantitative anisotropy of whole brain regions throughout the subcortical and cortical areas between newly diagnosed PD patients and healthy controls. Additionally, we evaluated the correlations between the quantitative anisotropy of each region and respective neuropsychological test scores to identify the areas most affected by each neuropsychological dysfunction in PD. We found significant quantitative anisotropy differences in several subcortical structures such as the basal ganglia, limbic system, and brain stem as well as in cortical structures such as the temporal lobe, occipital lobe, and insular lobe. Additionally, we found that quantitative anisotropy of some subcortical structures such as the basal ganglia, cerebellum, and brain stem showed the highest correlations with motor dysfunction, whereas cortical structures such as the temporal lobe and occipital lobe showed the highest correlations with olfactory dysfunction in PD. Our study also showed evidence regarding potential neural compensation by revealing higher diffusion metric values in early-stage PD than in healthy controls. We anticipate that our results will improve our understanding of PD's pathophysiology.

Comparison of vital sign stability and cost effectiveness between midazolam and dexmedetomidine during third molar extraction under intravenous sedation.

Objectives: To compare the vital sign stability and cost of two commonly used sedatives, midazolam (MDZ) and dexmedetomidine (DEX). Patients and. Methods: This retrospective study targeted patients who underwent mandibular third molar extractions under intravenous sedation using MDZ or DEX. The predictor variable was the type of sedative used. The primary outcome variables were vital signs (heart rate and blood pressure), vital sign outliers, and cost of the sedatives. A vital sign outlier was defined as a 30% or more change in vital signs during sedation; the fewer changes, the higher the vital sign stability. The secondary outcome variables included the observer's assessment of alertness/sedation scale, level of amnesia, patient satisfaction, and bispectral index score. Covariates were sex, age, body mass index, sleeping time, dental anxiety score, and Pederson scale. Descriptive statistics were computed including propensity score matching (PSM). The P-value was set at 0.05. Results: The study enrolled 185 patients, 103 in the MDZ group and 82 in the DEX group. Based on the data after PSM, the two samples had similar baseline covariates. The sedative effect of both agents was satisfactory. Heart rate outliers were more common with MDZ than with DEX (49.3% vs 22.7%, P=0.001). Heart rate was higher with MDZ (P=0.000). The cost was higher for DEX than for MDZ (29.27±0.00 USD vs 0.37±0.04 USD, P=0.000). Conclusion: DEX showed more vital sign stability, while MDZ was more economical. These results could be used as a reference to guide clinicians during sedative selection.

Screw-and-cement-retained prosthesis versus cement-retained prosthesis: Which is more appropriate for the upper premolar area?

Background/purpose: The narrow alveolar ridge in the maxillary premolars area limits the angle of implant placement and the shape of the prosthesis. The aim of this study was to evaluate which implant prosthesis, screw-and-cement-retained prosthesis (SCRP) or cement-retained prosthesis (CRP), was more suitable for the maxillary premolar area. Materials and methods: We conducted virtual implantation on 58 implant images from 47 patients obtained using cone beam computed tomography (CBCT). The width and buccal inclination of the alveolar bone, the angulation of the implant fixture, and the angulation of abutment were measured and calculated. Results: We determined that SCRP was feasible in 52% and 78.8% of first and second premolar areas, respectively. There was a positive relationship between the feasibility of SCRP and the premolar region in general (P = 0.031), although SCRP was more likely to be a possibility in the second premolar area. On multiple logistic regression analysis, the difference in the angle between the axis of the prosthesis and the axis of the alveolar bone (RA) was significantly associated with the type of prosthesis (P = 0.001). The RA was significantly higher for CRP implants (OR = 1.885; 95% CI: 1.31 to 2.70). Conclusion: SCRP is not always feasible in the maxillary premolar area, especially in the first premolar area. If the difference between the angle of the axis of the prosthesis and the axis of the alveolar bone is large, it may be necessary for the clinician to consider CRP in the treatment planning stage.

Racial/ethnic and gender differences among older adults in nonmonogamous partnerships, time spent single, and human immunodeficiency virus testing.

BACKGROUND: A higher frequency of nonmonogamy, due in part to lower marriage prevalence, may contribute to elevated human immunodeficiency virus (HIV)/sexually transmitted disease rates among older blacks. METHODS: To examine race and gender differences in nonmonogamy, time spent single (i.e., not married or cohabiting), and HIV testing in older adults, we analyzed US population-based data from the 2005-2006 National Social Life, Health, and Aging Project for 2825 heterosexual participants ages 57 to 85 years. RESULTS: Blacks spent greater portions of their adult lives single than did Hispanics or whites and were far more likely to report recent nonmonogamous partnerships (23.4% vs. 10.0% and 8.2%). Among individuals reporting sex in the prior 5 years, nonmonogamous partnerships were strongly associated with time spent single during the period. Control for time spent single and other covariates reduced the association of black race with nonmonogamous partnerships for men, but increased it for women. Less than 20% reported ever testing for HIV; less than 6% had been recommended testing by a provider. Testing rates, highest in black men and white women, differed little by history of nonmonogamous partnerships within gender strata. CONCLUSIONS: Singlehood helps to explain higher nonmonogamous partnership rates in older black men but not in older black women. Older adults rarely receive or are recommended HIV testing, a key strategy for reducing heterosexual HIV transmission.

Electromagnetized gold nanoparticles improve neurogenesis and cognition in the aged brain.

Adult neurogenesis is the lifelong process by which new neurons are generated in the dentate gyrus. However, adult neurogenesis capacity decreases with age, and this decrease is closely linked to cognitive and memory decline. Our study demonstrated that electromagnetized gold nanoparticles (AuNPs) promote adult hippocampal neurogenesis, thereby improving cognitive function and memory consolidation in aged mice. According to single-cell RNA sequencing data, the numbers of neural stem cells (NSCs) and neural progenitors were significantly increased by electromagnetized AuNPs. Additionally, electromagnetic stimulation resulted in specific activation of the histone acetyltransferase Kat2a, which led to histone H3K9 acetylation in adult NSCs. Moreover, in vivo electromagnetized AuNP stimulation efficiently increased hippocampal neurogenesis in aged and Hutchinson-Gilford progeria mouse brains, thereby alleviating the symptoms of aging. Therefore, our study provides a proof-of-concept for the in vivo stimulation of hippocampal neurogenesis using electromagnetized AuNPs as a promising therapeutic strategy for the treatment of age-related brain diseases.

Modelling neurodegenerative diseases with 3D brain organoids.

Neurodegenerative diseases are incurable and debilitating conditions characterized by the deterioration of brain function. Most brain disease models rely on human post-mortem brain tissue, non-human primate tissue, or in vitro two-dimensional (2D) experiments. Resource limitations and the complexity of the human brain are some of the reasons that make suitable human neurodegenerative disease models inaccessible. However, recently developed three-dimensional (3D) brain organoids derived from pluripotent stem cells (PSCs), including embryonic stem cells and induced PSCs, may provide suitable models for the study of the pathological features of neurodegenerative diseases. In this review, we provide an overview of existing 3D brain organoid models and discuss recent advances in organoid technology that have increased our understanding of brain development. Moreover, we explain how 3D organoid models recapitulate aspects of specific neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, and explore the utility of these models, for therapeutic applications.

Epitranscriptomic N6-Methyladenosine Modification Is Required for Direct Lineage Reprogramming into Neurons.

N6-methyladenosine (m6A), a conserved epitranscriptomic modification of eukaryotic mRNA (mRNA), plays a critical role in a variety of biological processes. Here, we report that m6A modification plays a key role in governing direct lineage reprogramming into induced neuronal cells (iNs). We found that m6A modification is required for the remodeling of specific mRNAs required for the neuronal direct conversion. Inhibition of m6A methylation by Mettl3 knockdown decreased the efficiency of direct lineage reprogramming, whereas increased m6A methylation by Mettl3 overexpression increased the efficiency of iN generation. Moreover, we found that transcription factor Btg2 is a functional target of m6A modification for efficient iN generation. Taken together, our results suggest the importance of establishing epitranscriptomic remodeling for the cell fate conversion into iNs.

Acceleration of somatic cell reprogramming into the induced pluripotent stem cell using a mycosporine-like amino acid, Porphyra 334.

Porphyra 334 (P334), a mycosporine-like amino acid (MAA), is a secondary metabolite found in diverse marine and terrestrial organisms and has several beneficial effects on fibroblast proliferation, wound healing, and antioxidant activity. Here, we report that P334 accelerates the cell reprogramming process of mouse tail-tip fibroblasts (TTFs) and human dermal papilla (HDP) cells into induced pluripotent stem cells (iPSCs). We found that P334 significantly improved the cell reprogramming efficiency by activating the tri-methylation of histone 3 lysine 4 (H3K4me3), which controls mesenchymal to epithelial transition (MET) during the reprogramming process. Thus, we found that P334 directly regulates epigenetic changes, providing an efficient approach for natural compound-based cell reprogramming.

Efficient in vivo direct conversion of fibroblasts into cardiomyocytes using a nanoparticle-based gene carrier.

The reprogramming of induced cardiomyocytes (iCMs) has shown potential in regenerative medicine. However, in vivo reprogramming of iCMs is significantly inefficient, and novel gene delivery systems are required to more efficiently and safely induce in vivo reprogramming of iCMs for therapeutic applications in heart injury. In this study, we show that cationic gold nanoparticles (AuNPs) loaded with Gata4, Mef2c, and Tbx5 function as nanocarriers for cardiac reprogramming. The AuNP/GMT/PEI nanocomplexes show high reprogramming efficiency in human and mouse somatic cells with low cytotoxicity and direct conversion into iCMs without integrating factors into the genome. Importantly, AuNP/GMT/PEI nanocomplexes led to efficient in vivo conversion into cardiomyocytes after myocardial infarction (MI), resulting in the effective recovery of cardiac function and scar area. Taken together, these results show that the AuNP/GMT/PEI nanocarrier can be used to develop effective therapeutics for heart regeneration in cardiac disease patients.

Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids.

Recent advances in generating three-dimensional (3D) organoid systems from stem cells offer new possibilities for disease modeling and drug screening because organoids can recapitulate aspects of in vivo architecture and physiology. In this study, we generate isogenic 3D midbrain organoids with or without a Parkinson's disease-associated LRRK2 G2019S mutation to study the pathogenic mechanisms associated with LRRK2 mutation. We demonstrate that these organoids can recapitulate the 3D pathological hallmarks observed in patients with LRRK2-associated sporadic Parkinson's disease. Importantly, analysis of the protein-protein interaction network in mutant organoids revealed that TXNIP, a thiol-oxidoreductase, is functionally important in the development of LRRK2-associated Parkinson's disease in a 3D environment. These results provide proof of principle for the utility of 3D organoid-based modeling of sporadic Parkinson's disease in advancing therapeutic discovery.

In vivo neuronal gene editing via CRISPR-Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer's disease.

In vivo gene editing in post-mitotic neurons of the adult brain may be a useful strategy for treating neurological diseases. Here, we develop CRISPR-Cas9 nanocomplexes and show they were effective in the adult mouse brain, with minimal off-target effects. Using this system to target Bace1 suppressed amyloid beta (Aß)-associated pathologies and cognitive deficits in two mouse models of Alzheimer's disease. These results broaden the potential application of CRISPR-Cas9 systems to neurodegenerative diseases.