O-GlcNAc impacts mitophagy via the PINK1-dependent pathway.

Background: The accumulation of dysfunctional mitochondria is an early feature of Alzheimer's disease (AD). The impaired turnover of damaged mitochondria increases reactive oxygen species production and lowers ATP generation, leading to cellular toxicity and neurodegeneration. Interestingly, AD exhibits a disruption in the global post-translational modification ß-N-acetylglucosamine (O-GlcNAc). O-GlcNAc is a ubiquitous single sugar modification found in the nuclear, cytoplasmic, and mitochondrial proteins. Cells maintain a homeostatic level of O-GlcNAc by cycling the addition and removal of the sugar by O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA), respectively. Methods: We used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma cell lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) or OGT deficiency on mitophagy using biochemical analyses. Results: Here, we established an essential role for O-GlcNAc in regulating mitophagy (mitochondria-selective autophagy). Stimulating mitophagy using urolithin A (UA) decreases cellular O-GlcNAc and elevates mitochondrial O-GlcNAc. Sustained elevation in O-GlcNAcylation via pharmacologically inhibiting OGA using Thiamet-G (TMG) increases the mitochondrial level of mitophagy protein PTEN-induced kinase 1 (PINK1) and autophagy-related protein light chain 3 (LC3). Moreover, we detected O-GlcNAc on PINK1 and TMG increases its O-GlcNAcylation level. Conversely, decreasing cellular O-GlcNAcylation by knocking down OGT decreases both PINK1 protein expression and LC3 protein expression. Mitochondria isolated from CAMKII-OGT-KO mice also had decreased PINK1 and LC3. Moreover, human brain organoids treated with TMG showed significant elevation in LC3 compared to control. However, TMG-treated AD organoids showed no changes in LC3 expression. Conclusion: Collectively, these data demonstrate that O-GlcNAc plays a crucial role in the activation and progression of mitophagy, and this activation is disrupted in AD.

Proactive M2 blockade prevents cognitive decline in GRK5-deficient APP transgenic mice via enhancing cholinergic neuronal resilience.

Alzheimer's disease (AD) poses an immense challenge in healthcare, lacking effective therapies. This study investigates the potential of anthranilamide derivative (AAD23), a selective M2 receptor antagonist, in proactively preventing cognitive impairments and cholinergic neuronal degeneration in G protein-coupled receptor kinase-5-deficient Swedish APP (GAP) mice. GAP mice manifest cognitive deficits by 7 months and develop senile plaques by 9 months. A 6-month AAD23 treatment was initiated at 5 months and stopped at 11 months before behavioral assessments without the treatment. AAD23-treated mice exhibited preserved cognitive abilities and improved cholinergic axonal health in the nucleus basalis of Meynert akin to wildtype mice. Conversely, vehicle-treated GAP mice displayed memory deficits and pronounced cholinergic axonal swellings in the nucleus basalis of Meynert. Notably, AAD23 treatment did not alter senile plaques and microgliosis. These findings highlight AAD23's efficacy in forestalling AD-related cognitive decline in G protein-coupled receptor kinase-5-deficient subjects, attributing its success to restoring cholinergic neuronal integrity and resilience, enhancing resistance against diverse degenerative insults.

Efficacy and Safety of Exogenous Ketones in People with Mild Neurocognitive Disorder and Alzheimer's Disease: A Systematic Literature Review.

CONTEXT: Mild neurocognitive disorder (NCD), formally known as mild cognitive impairment, is usually the clinical stage preceding the development of Alzheimer's disease (AD), the most prevalent major NCD, and other causes of dementia. Glucose is a major source of energy for human brain metabolism and the uptake of glucose is reduced in patients with mild NCD, AD, and other NCDs. Unlike glucose, the uptake of ketones remains normal in people with mild NCD and AD, suggesting that the use of ketone bodies may compensate for glucose energy deficiency in patients with mild NCD and AD. OBJECTIVE: The aim of this systematic review was to summarize the efficacy and safety of exogenic ketones, including medium chain triglycerides (MCTs), on cognitive function in patients with mild NCD and AD. DATA SOURCES: The Embase, MEDLINE, MEDLINE In-Process, PubMed Ahead-of-Print, Cochrane Central Register of Controlled Trials, Europe PMC databases were searched from inception to April 2022. Studies reporting cognitive function efficacy and safety outcomes from randomized controlled trials of exogenic ketones in patients with mild NCD and AD were included. DATA EXTRACTION: Data were extracted by 1 reviewer and checked by a second reviewer. Risk of bias was assessed using the Cochrane risk of bias tool, version 2. DATA ANALYSIS: This review identified 13 individual trials investigating the efficacy and safety of MCT or coconut oil for patients with mild NCD or with AD. Because of the heterogeneity of the studies, a narrative synthesis was used. CONCLUSION: Overall, improvements associated with exogenic ketones were observed in multiple aspects of cognitive abilities, although the large heterogeneity between the included studies makes it difficult to draw firm conclusions from the current literature. Although some studies investigated the impact of the apolipoprotein E ε4 allele status on treatment efficacy, the current data are insufficient to conclude whether such an effect is present. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration No. CRD42022336664.

Adaptive and Maladaptive DNA Breaks in Neuronal Physiology and Alzheimer's Disease.

DNA strand breaks excessively accumulate in the brains of patients with Alzheimer's disease (AD). While traditionally considered random, deleterious events, neuron activity itself induces DNA breaks, and these "adaptive" breaks help mediate synaptic plasticity and memory formation. Recent studies mapping the brain DNA break landscape reveal that despite a net increase in DNA breaks in ectopic genomic hotspots, adaptive DNA breaks around synaptic genes are lost in AD brains, and this is associated with transcriptomic dysregulation. Additionally, relationships exist between mitochondrial dysfunction, a hallmark of AD, and DNA damage, such that mitochondrial dysfunction may perturb adaptive DNA break formation, while DNA breaks may conversely impair mitochondrial function. A failure of DNA break physiology could, therefore, potentially contribute to AD pathogenesis.

Identifying subgroups of urge suppression in Obsessive-Compulsive Disorder using machine learning.

Obsessive-compulsive disorder (OCD) is phenomenologically heterogeneous. While predominant models suggest fear and harm prevention drive compulsions, many patients also experience uncomfortable sensory-based urges ("sensory phenomena") that may be associated with heightened interoceptive sensitivity. Using an urge-to-blink eyeblink suppression paradigm to model sensory-based urges, we previously found that OCD patients as a group had more eyeblink suppression failures and greater activation of sensorimotor-interoceptive regions than controls. However, conventional approaches assuming OCD homogeneity may obscure important within-group variability, impeding precision treatment development. This study investigated the heterogeneity of urge suppression failure in OCD and examined relationships with clinical characteristics and neural activation. Eighty-two patients with OCD and 38 controls underwent an fMRI task presenting 60-s blocks of eyeblink suppression alternating with free-blinking blocks. Latent profile analysis identified OCD subgroups based on number of erroneous blinks during suppression. Subgroups were compared on behavior, clinical characteristics, and brain activation during task. Three patient subgroups were identified. Despite similar overall OCD severity, the subgroup with the most erroneous eyeblinks had the highest sensory phenomena severity, interoceptive sensitivity, and subjective urge intensity. Compared to other subgroups, this subgroup exhibited more neural activity in somatosensory and interoceptive regions during the early phase (first 30 s) of blink suppression and reduced activity in the middle frontal gyrus during the late phase (second 30 s) as the suppression period elapsed. Heterogeneity of urge suppression in OCD was associated with clinical characteristics and brain function. Our results reveal potential treatment targets that could inform personalized medicine.

A Label-Efficient Framework for Automated Sinonasal CT Segmentation in Image-Guided Surgery.

OBJECTIVE: Segmentation, the partitioning of patient imaging into multiple, labeled segments, has several potential clinical benefits but when performed manually is tedious and resource intensive. Automated deep learning (DL)-based segmentation methods can streamline the process. The objective of this study was to evaluate a label-efficient DL pipeline that requires only a small number of annotated scans for semantic segmentation of sinonasal structures in CT scans. STUDY DESIGN: Retrospective cohort study. SETTING: Academic institution. METHODS: Forty CT scans were used in this study including 16 scans in which the nasal septum (NS), inferior turbinate (IT), maxillary sinus (MS), and optic nerve (ON) were manually annotated using an open-source software. A label-efficient DL framework was used to train jointly on a few manually labeled scans and the remaining unlabeled scans. Quantitative analysis was then performed to obtain the number of annotated scans needed to achieve submillimeter average surface distances (ASDs). RESULTS: Our findings reveal that merely four labeled scans are necessary to achieve median submillimeter ASDs for large sinonasal structures-NS (0.96 mm), IT (0.74 mm), and MS (0.43 mm), whereas eight scans are required for smaller structures-ON (0.80 mm). CONCLUSION: We have evaluated a label-efficient pipeline for segmentation of sinonasal structures. Empirical results demonstrate that automated DL methods can achieve submillimeter accuracy using a small number of labeled CT scans. Our pipeline has the potential to improve pre-operative planning workflows, robotic- and image-guidance navigation systems, computer-assisted diagnosis, and the construction of statistical shape models to quantify population variations. LEVEL OF EVIDENCE: N/A.

Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype.

INTRODUCTION: Proteome changes associated with APOE4 variant carriage that are independent of Alzheimer's disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment. METHODS: Clinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning. RESULTS: We found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells. DISCUSSION: APOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers' vulnerability to cognitive decline and AD.

Hippocampal transcriptome-wide association study and pathway analysis of mitochondrial solute carriers in Alzheimer's disease.

The etiopathogenesis of late-onset Alzheimer's disease (AD) is increasingly recognized as the result of the combination of the aging process, toxic proteins, brain dysmetabolism, and genetic risks. Although the role of mitochondrial dysfunction in the pathogenesis of AD has been well-appreciated, the interaction between mitochondrial function and genetic variability in promoting dementia is still poorly understood. In this study, by tissue-specific transcriptome-wide association study (TWAS) and further meta-analysis, we examined the genetic association between mitochondrial solute carrier family (SLC25) genes and AD in three independent cohorts and identified three AD-susceptibility genes, including SLC25A10, SLC25A17, and SLC25A22. Integrative analysis using neuroimaging data and hippocampal TWAS-predicted gene expression of the three susceptibility genes showed an inverse correlation of SLC25A22 with hippocampal atrophy rate in AD patients, which outweighed the impacts of sex, age, and apolipoprotein E4 (ApoE4). Furthermore, SLC25A22 downregulation demonstrated an association with AD onset, as compared with the other two transcriptome-wide significant genes. Pathway and network analysis related hippocampal SLC25A22 downregulation to defects in neuronal function and development, echoing the enrichment of SLC25A22 expression in human glutamatergic neurons. The most parsimonious interpretation of the results is that we have identified AD-susceptibility genes in the SLC25 family through the prediction of hippocampal gene expression. Moreover, our findings mechanistically yield insight into the mitochondrial cascade hypothesis of AD and pave the way for the future development of diagnostic tools for the early prevention of AD from a perspective of precision medicine by targeting the mitochondria-related genes.

Spatial Dissection of the Distinct Cellular Responses to Normal Aging and Alzheimer's Disease in Human Prefrontal Cortex at Single-Nucleus Resolution.

Aging significantly elevates the risk for Alzheimer's disease (AD), contributing to the accumulation of AD pathologies, such as amyloid-ß (Aß), inflammation, and oxidative stress. The human prefrontal cortex (PFC) is highly vulnerable to the impacts of both aging and AD. Unveiling and understanding the molecular alterations in PFC associated with normal aging (NA) and AD is essential for elucidating the mechanisms of AD progression and developing novel therapeutics for this devastating disease. In this study, for the first time, we employed a cutting-edge spatial transcriptome platform, STOmics® SpaTial Enhanced Resolution Omics-sequencing (Stereo-seq), to generate the first comprehensive, subcellular resolution spatial transcriptome atlas of the human PFC from six AD cases at various neuropathological stages and six age, sex, and ethnicity matched controls. Our analyses revealed distinct transcriptional alterations across six neocortex layers, highlighted the AD-associated disruptions in laminar architecture, and identified changes in layer-to-layer interactions as AD progresses. Further, throughout the progression from NA to various stages of AD, we discovered specific genes that were significantly upregulated in neurons experiencing high stress and in nearby non-neuronal cells, compared to cells distant from the source of stress. Notably, the cell-cell interactions between the neurons under the high stress and adjacent glial cells that promote Aß clearance and neuroprotection were diminished in AD in response to stressors compared to NA. Through cell-type specific gene co-expression analysis, we identified three modules in excitatory and inhibitory neurons associated with neuronal protection, protein dephosphorylation, and negative regulation of Aß plaque formation. These modules negatively correlated with AD progression, indicating a reduced capacity for toxic substance clearance in AD subject samples. Moreover, we have discovered a novel transcription factor, ZNF460, that regulates all three modules, establishing it as a potential new therapeutic target for AD. Overall, utilizing the latest spatial transcriptome platform, our study developed the first transcriptome-wide atlas with subcellular resolution for assessing the molecular alterations in the human PFC due to AD. This atlas sheds light on the potential mechanisms underlying the progression from NA to AD.

An endoscopic chisel: intraoperative imaging carves 3D anatomical models.

PURPOSE: Preoperative imaging plays a pivotal role in sinus surgery where CTs offer patient-specific insights of complex anatomy, enabling real-time intraoperative navigation to complement endoscopy imaging. However, surgery elicits anatomical changes not represented in the preoperative model, generating an inaccurate basis for navigation during surgery progression. METHODS: We propose a first vision-based approach to update the preoperative 3D anatomical model leveraging intraoperative endoscopic video for navigated sinus surgery where relative camera poses are known. We rely on comparisons of intraoperative monocular depth estimates and preoperative depth renders to identify modified regions. The new depths are integrated in these regions through volumetric fusion in a truncated signed distance function representation to generate an intraoperative 3D model that reflects tissue manipulation RESULTS: We quantitatively evaluate our approach by sequentially updating models for a five-step surgical progression in an ex vivo specimen. We compute the error between correspondences from the updated model and ground-truth intraoperative CT in the region of anatomical modification. The resulting models show a decrease in error during surgical progression as opposed to increasing when no update is employed. CONCLUSION: Our findings suggest that preoperative 3D anatomical models can be updated using intraoperative endoscopy video in navigated sinus surgery. Future work will investigate improvements to monocular depth estimation as well as removing the need for external navigation systems. The resulting ability to continuously update the patient model may provide surgeons with a more precise understanding of the current anatomical state and paves the way toward a digital twin paradigm for sinus surgery.

OneSLAM to map them all: a generalized approach to SLAM for monocular endoscopic imaging based on tracking any point.

PURPOSE: Monocular SLAM algorithms are the key enabling technology for image-based surgical navigation systems for endoscopic procedures. Due to the visual feature scarcity and unique lighting conditions encountered in endoscopy, classical SLAM approaches perform inconsistently. Many of the recent approaches to endoscopic SLAM rely on deep learning models. They show promising results when optimized on singular domains such as arthroscopy, sinus endoscopy, colonoscopy or laparoscopy, but are limited by an inability to generalize to different domains without retraining. METHODS: To address this generality issue, we propose OneSLAM a monocular SLAM algorithm for surgical endoscopy that works out of the box for several endoscopic domains, including sinus endoscopy, colonoscopy, arthroscopy and laparoscopy. Our pipeline builds upon robust tracking any point (TAP) foundation models to reliably track sparse correspondences across multiple frames and runs local bundle adjustment to jointly optimize camera poses and a sparse 3D reconstruction of the anatomy. RESULTS: We compare the performance of our method against three strong baselines previously proposed for monocular SLAM in endoscopy and general scenes. OneSLAM presents better or comparable performance over existing approaches targeted to that specific data in all four tested domains, generalizing across domains without the need for retraining. CONCLUSION: OneSLAM benefits from the convincing performance of TAP foundation models but generalizes to endoscopic sequences of different anatomies all while demonstrating better or comparable performance over domain-specific SLAM approaches. Future research on global loop closure will investigate how to reliably detect loops in endoscopic scenes to reduce accumulated drift and enhance long-term navigation capabilities.

Stand in surgeon's shoes: virtual reality cross-training to enhance teamwork in surgery.

PURPOSE: Teamwork in surgery depends on a shared mental model of success, i.e., a common understanding of objectives in the operating room. A shared model leads to increased engagement among team members and is associated with fewer complications and overall better outcomes for patients. However, clinical training typically focuses on role-specific skills, leaving individuals to acquire a shared model indirectly through on-the-job experience. METHODS: We investigate whether virtual reality (VR) cross-training, i.elet@tokeneonedotexposure to other roles, can enhance a shared mental model for non-surgeons more directly. Our study focuses on X-ray guided pelvic trauma surgery, a procedure where successful communication depends on the shared model between the surgeon and a C-arm technologist. We present a VR environment supporting both roles and evaluate a cross-training curriculum in which non-surgeons swap roles with the surgeon. RESULTS: Exposure to the surgical task resulted in higher engagement with the C-arm technologist role in VR, as measured by the mental demand and effort expended by participants ( p < 0.001 ). It also has a significant effect on non-surgeon's mental model of the overall task; novice participants' estimation of the mental demand and effort required for the surgeon's task increases after training, while their perception of overall performance decreases ( p < 0.05 ), indicating a gap in understanding based solely on observation. This phenomenon was also present for a professional C-arm technologist. CONCLUSION: Until now, VR applications for clinical training have focused on virtualizing existing curricula. We demonstrate how novel approaches which are not possible outside of a virtual environment, such as role swapping, may enhance the shared mental model of surgical teams by contextualizing each individual's role within the overall task in a time- and cost-efficient manner. As workflows grow increasingly sophisticated, we see VR curricula as being able to directly foster a shared model for success, ultimately benefiting patient outcomes through more effective teamwork in surgery.

C-Reactive Protein Does Not Predict Future Depression Onset in Adolescents: Preliminary Findings from a Longitudinal Study.

Introduction: Neuroinflammatory processes have been extensively implicated in the underlying neurobiology of numerous neuropsychiatric disorders. Elevated C-reactive protein (CRP), an indicator of nonspecific inflammation commonly utilized in clinical practice, has been associated with depression in adults. In adolescents, our group previously found CRP to be associated with altered neural reward function but not with mood and anxiety symptoms assessed cross-sectionally. We hypothesized that the distinct CRP findings in adolescent versus adult depression may be due to chronicity, with neuroinflammatory effects on psychiatric disorders gradually accumulating over time. Here, we conducted a longitudinal study to evaluate if CRP levels predicted future onset or progression of depression in adolescents. Methods: Participants were 53 adolescents (age = 14.74 ± 1.92 years, 35 female), 40 with psychiatric symptoms and 13 healthy controls. At baseline, participants completed semistructured diagnostic evaluations; dimensional assessments for anxiety, depression, anhedonia, and suicidality severity; and bloodwork to quantify CRP levels. Clinical assessments were repeated at longitudinal follow-up after ∼1.5 years. Spearman's correlation between CRP levels and follow-up symptom severity were controlled for body mass index, age, sex, and follow-up interval and considered significant at the two-tailed, Bonferroni-adjusted p < 0.05 level. Results: After correction for multiple comparisons, no relationships were identified between baseline CRP levels and follow-up symptom severity. Conclusion: CRP levels were not significantly associated with future psychiatric symptoms in adolescents in this preliminary analysis. This may suggest that CRP is not a useful biomarker for adolescent depression and anxiety. However, future longitudinal studies with larger sample sizes and incorporating additional indicators of neuroinflammation are needed.

Multi-Omics after O-GlcNAc Alteration Identifies Cellular Processes Working Synergistically to Promote Aneuploidy.

Pharmacologic or genetic manipulation of O-GlcNAcylation, an intracellular, single sugar post-translational modification, are difficult to interpret due to the pleotropic nature of O-GlcNAc and the vast signaling pathways it regulates. To address this issue, we employed either OGT (O-GlcNAc transferase), OGA (O-GlcNAcase) liver knockouts, or pharmacological inhibition of OGA coupled with multi-Omics analysis and bioinformatics. We identified numerous genes, proteins, phospho-proteins, or metabolites that were either inversely or equivalently changed between conditions. Moreover, we identified pathways in OGT knockout samples associated with increased aneuploidy. To test and validate these pathways, we induced liver growth in OGT knockouts by partial hepatectomy. OGT knockout livers showed a robust aneuploidy phenotype with disruptions in mitosis, nutrient sensing, protein metabolism/amino acid metabolism, stress response, and HIPPO signaling demonstrating how OGT is essential in controlling aneuploidy pathways. Moreover, these data show how a multi-Omics platform can discern how OGT can synergistically fine-tune multiple cellular pathways.

The Impact of Involvement in Whole Health System for Veterans or Participating in It for Oneself on Job Attitudes in VA Employees.

OBJECTIVE: The aim of the study is to examine how involvement in the Whole Health System of care, clinically and personally (through employee-focused activities), would affect employee satisfaction, engagement, burnout, and turnover intent in the Veterans Health Administration. METHODS: Multivariate logistic regression analysis of cross-sectional survey from Veterans Health Administration employees was used to determine the influence of Whole Health System involvement and Employee Whole Health participation on job attitudes. RESULTS: Whole Health System involvement was associated higher job satisfaction, higher levels of engagement, lower burnout, and lower turnover intent. A similar pattern of results was identified when looking specifically at Employee Whole Health participation and associated job attitudes. CONCLUSIONS: Employees who are either directly involved in delivering Whole Health services to veterans or who have participated in Whole Health programming for their own benefit may experience a meaningful positive impact on their well-being and how they experience the workplace.

Tremor Assessment in Robot-Assisted Microlaryngeal Surgery Using Computer Vision-Based Tool Tracking.

OBJECTIVE: Use microscopic video-based tracking of laryngeal surgical instruments to investigate the effect of robot assistance on instrument tremor. STUDY DESIGN: Experimental trial. SETTING: Tertiary Academic Medical Center. METHODS: In this randomized cross-over trial, 36 videos were recorded from 6 surgeons performing left and right cordectomies on cadaveric pig larynges. These recordings captured 3 distinct conditions: without robotic assistance, with robot-assisted scissors, and with robot-assisted graspers. To assess tool tremor, we employed computer vision-based algorithms for tracking surgical tools. Absolute tremor bandpower and normalized path length were utilized as quantitative measures. Wilcoxon rank sum exact tests were employed for statistical analyses and comparisons between trials. Additionally, surveys were administered to assess the perceived ease of use of the robotic system. RESULTS: Absolute tremor bandpower showed a significant decrease when using robot-assisted instruments compared to freehand instruments (P = .012). Normalized path length significantly decreased with robot-assisted compared to freehand trials (P = .001). For the scissors, robot-assisted trials resulted in a significant decrease in absolute tremor bandpower (P = .002) and normalized path length (P < .001). For the graspers, there was no significant difference in absolute tremor bandpower (P = .4), but there was a significantly lower normalized path length in the robot-assisted trials (P = .03). CONCLUSION: This study demonstrated that computer-vision-based approaches can be used to assess tool motion in simulated microlaryngeal procedures. The results suggest that robot assistance is capable of reducing instrument tremor.

Proposed minimal standards for description of new taxa of the class Halobacteria.

Halophilic archaea of the class Halobacteria are the most salt-requiring prokaryotes within the domain Archaea. In 1997, minimal standards for the description of new taxa in the order Halobacteriales were proposed. From then on, the taxonomy of the class Halobacteria provides an excellent example of how changing concepts on prokaryote taxonomy and the development of new methods were implemented. The last decades have witnessed a rapid expansion of the number of described taxa within the class Halobacteria coinciding with the era of genome sequencing development. The current members of the International Committee on Systematics of Prokaryotes Subcommittee on the Taxonomy of Halobacteria propose these revisions to the recommended minimal standards and encourage the use of advanced technologies in the taxonomic description of members of the Halobacteria. Most previously required and some recommended minimal standards for the description of new taxa in the class Halobacteria were retained in the present revision, but changes have been proposed in line with the new methodologies. In addition to the 16S rRNA gene, the rpoB' gene is an important molecular marker for the identification of members of the Halobacteria. Phylogenomic analysis based on concatenated conserved, single-copy marker genes is required to infer the taxonomic status of new taxa. The overall genome relatedness indexes have proven to be determinative in the classification of the taxa within the class Halobacteria. Average nucleotide identity, digital DNA-DNA hybridization, and average amino acid identity values should be calculated for rigorous comparison among close relatives.

Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity.

Alcohol consumption is believed to affect Alzheimer's disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is in turn regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression. To explore the effect of alcohol on brain TFEB and autophagy, we exposed young (3-month old) and aged (23-month old) mice to two alcohol-feeding paradigms and assessed biochemical, transcriptome, histology, and behavioral endpoints. In young mice, alcohol decreased hippocampal nuclear TFEB staining but increased SQSTM1/p62, LC3-II, ubiquitinated proteins, and phosphorylated Tau. Hippocampal TFEB activity was lower in aged mice than it was in young mice, and Gao-binge alcohol feeding did not worsen the age-related reduction in TFEB activity. To better assess the impact of chronic alcohol exposure, we fed young and aged mice alcohol for four weeks before completing Morris Water and Barnes Maze spatial memory testing. The aged mice showed worse spatial memory on both tests. While alcohol feeding slightly impaired spatial memory in the young mice, it had little effect or even slightly improved spatial memory in the aged mice. These findings suggest that aging is a far more important driver of spatial memory impairment and reduced autophagy flux than alcohol consumption.

The Effects of Rearing Environment on Organization of the Olfactory System and Brain of Juvenile Sockeye Salmon, Oncorhynchus nerka.

Pacific salmon (Oncorhynchus spp.) hatch and feed in freshwater habitats, migrate to sea to mature, and return to spawn at natal sites. The final, riverine stages of the return migrations are mediated by chemical properties of the natal stream that they learned as juveniles. Like some other fish, salmon growth is asymptotic; they grow continuously throughout life toward a maximum size. The continued growth of the nervous system may be plastic in response to environmental variables. Due to the ecological, cultural, and economic importance of Pacific salmon, individuals are often reared in hatcheries and released into the wild as juveniles to supplement natural populations. However, hatchery-reared individuals display lower survivorship and may also stray (i.e., spawn in a non-natal stream) at higher rates than their wild counterparts. Hatchery environments may lack stimuli needed to promote normal development of the nervous system, thus leading to behavioral deficits and a higher incidence of straying. This study compared the peripheral olfactory system and brain organization of hatchery-reared and wild-origin sockeye salmon fry (Oncorhynchus nerka). Surface area of the olfactory rosette, diameter of the olfactory nerve, total brain size, and size of major brain regions were measured from histological sections and compared between wild and hatchery-origin individuals. Hatchery-origin fish had significantly larger optic tecta, and marginally insignificant, yet noteworthy trends, existed in the valvula cerebelli (hatchery > wild) and olfactory bulbs (hatchery < wild). We also found a putative difference in olfactory nerve diameter (dmin) (hatchery > wild), but the validity of this finding needs further analyses with higher resolution methods. Overall, these results provide insight into the potential effects of hatchery rearing on nervous system development in salmonids, and may explain behavioral deficits displayed by hatchery-origin individuals post-release.

Loss of Adaptive DNA Breaks in Alzheimer's Disease Brains.

Background: DNA breaks accumulate in Alzheimer's disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes. This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks. Objective: To characterize how AD impacts adaptive DNA breaks at nervous system genes. Methods: We leveraged the ability of DNA single- and double-strand breaks to activate poly(ADP-ribose) polymerases (PARPs) that conjugate poly(ADP-ribose) (PAR) to adjacent proteins. To characterize the genomic sites harboring DNA breaks in AD brains, nuclei extracted from 3 AD and 3 non-demented autopsy brains (frontal cortex, all male donors, age 78 to 91 years of age) were analyzed through CUT&RUN in which we targeted PAR with subsequent DNA sequencing. Results: Although the AD brains contained 19.9 times more PAR peaks than the non-demented brains, PAR peaks at nervous system genes were profoundly lost in AD brains, and the expression of these genes was downregulated. This result is consistent with our previous CUT&RUN targeting γH2AX, which marks DNA double-strand breaks. In addition, TOP2B expression was significantly decreased in the AD brains. Conclusions: Although AD brains contain a net increase in DNA breaks, adaptive DNA breaks at nervous system genes are lost in AD brains. This could potentially reflect diminished TOP2B expression and contribute to impaired neuron function and cognition in AD patients.