Machine learning: a new era for cardiovascular pregnancy physiology and cardio-obstetrics research.

The maternal cardiovascular system undergoes functional and structural adaptations during pregnancy and postpartum to support increased metabolic demands of offspring and placental growth, labor, and delivery, as well as recovery from childbirth. Thus, pregnancy imposes physiological stress upon the maternal cardiovascular system, and in the absence of an appropriate response it imparts potential risks for cardiovascular complications and adverse outcomes. The proportion of pregnancy-related maternal deaths from cardiovascular events has been steadily increasing, contributing to high rates of maternal mortality. Despite advances in cardiovascular physiology research, there is still no comprehensive understanding of maternal cardiovascular adaptations in healthy pregnancies. Furthermore, current approaches for the prognosis of cardiovascular complications during pregnancy are limited. Machine learning (ML) offers new and effective tools for investigating mechanisms involved in pregnancy-related cardiovascular complications as well as the development of potential therapies. The main goal of this review is to summarize existing research that uses ML to understand mechanisms of cardiovascular physiology during pregnancy and develop prediction models for clinical application in pregnant patients. We also provide an overview of ML platforms that can be used to comprehensively understand cardiovascular adaptations to pregnancy and discuss the interpretability of ML outcomes, the consequences of model bias, and the importance of ethical consideration in ML use.

Novel Targets for Alzheimer's Disease: A View Beyond Amyloid.

Genetic studies of autosomal dominant Alzheimer's disease (AD) revealed that ß-amyloid is central to disease pathogenesis. However, amyloid-targeted therapies have generally failed to slow progression in patients with symptomatic disease. This result suggests a transition from an early amyloid-dependent phase to a later amyloid-independent one, during which neurodegeneration occurs and symptoms arise. Microglia, the brain's resident myeloid cells, envelop amyloid and express the majority of genes linked to risk for sporadic late-onset AD. Their activation is associated spatially and temporally with the accumulation of pathological tau. Microglial facilitation of tau pathology may involve apolipoprotein E, the most important genetic risk factor for AD. Once formed, pathological tau spreads between connected neurons, eventually accumulating in the somatic compartment where catastrophic nuclear damage ensues. This emerging understanding of the postamyloid processes leading to neurodegeneration affords the opportunity to develop therapeutics that interrupt this pathological cascade and prevent or delay dementia, even after amyloid deposition.

Dual Leucine Zipper Kinase Is Constitutively Active in the Adult Mouse Brain and Has Both Stress-Induced and Homeostatic Functions.

Dual leucine zipper kinase (DLK, Map3k12) is an axonal protein that governs the balance between degeneration and regeneration through its downstream effectors c-jun N-terminal kinase (JNK) and phosphorylated c-jun (p-c-Jun). In peripheral nerves DLK is generally inactive until induced by injury, after which it transmits signals to the nucleus via retrograde transport. Here we report that in contrast to this mode of regulation, in the uninjured adult mouse cerebellum, DLK constitutively drives nuclear p-c-Jun in cerebellar granule neurons, whereas in the forebrain, DLK is similarly expressed and active, but nuclear p-c-Jun is undetectable. When neurodegeneration results from mutant human tau in the rTg4510 mouse model, p-c-Jun then accumulates in neuronal nuclei in a DLK-dependent manner, and the extent of p-c-Jun correlates with markers of synaptic loss and gliosis. This regional difference in DLK-dependent nuclear p-c-Jun accumulation could relate to differing levels of JNK scaffolding proteins, as the cerebellum preferentially expresses JNK-interacting protein-1 (JIP-1), whereas the forebrain contains more JIP-3 and plenty of SH3 (POSH). To characterize the functional differences between constitutive- versus injury-induced DLK signaling, RNA sequencing was performed after DLK inhibition in the cerebellum and in the non-transgenic and rTg4510 forebrain. In all contexts, DLK inhibition reduced a core set of transcripts that are associated with the JNK pathway. Non-transgenic forebrain showed almost no other transcriptional changes in response to DLK inhibition, whereas the rTg4510 forebrain and the cerebellum exhibited distinct differentially expressed gene signatures. In the cerebellum, but not the rTg4510 forebrain, pathway analysis indicated that DLK regulates insulin growth factor-1 (IGF1) signaling through the transcriptional induction of IGF1 binding protein-5 (IGFBP5), which was confirmed and found to be functionally relevant by measuring signaling through the IGF1 receptor. Together these data illuminate the complex multi-functional nature of DLK signaling in the central nervous system (CNS) and demonstrate its role in homeostasis as well as tau-mediated neurodegeneration.

Five Residues in the Apical Loop of the Respiratory Syncytial Virus Fusion Protein F2 Subunit Are Critical for Its Fusion Activity.

The respiratory syncytial virus (RSV) fusion (F) protein is a trimeric, membrane-anchored glycoprotein capable of mediating both virus-target cell membrane fusion to initiate infection and cell-cell fusion, even in the absence of the attachment glycoprotein. The F protein is initially expressed in a precursor form, whose functional capabilities are activated by proteolysis at two sites between the F1 and F2 subunits. This cleavage results in expression of the metastable and high-energy prefusion conformation. To mediate fusion, the F protein is triggered by an unknown stimulus, causing the F1 subunit to refold dramatically while F2 changes minimally. Hypothesizing that the most likely site for interaction with a target cell component would be the top, or apex, of the protein, we determined the importance of the residues in the apical loop of F2 by alanine scanning mutagenesis analysis. Five residues were not important, two were of intermediate importance, and all four lysines and one isoleucine were essential. Alanine replacement did not result in the loss of the pre-F conformation for any of these mutants. Each of the four lysines required its specific charge for fusion function. Alanine replacement of the three essential lysines on the ascent to the apex hindered fusion following a forced fusion event, suggesting that these residues are involved in refolding. Alanine mutations at Ile64, also on the ascent to the apex, and Lys75 did not prevent fusion following forced triggering, suggesting that these residues are not involved in refolding and may instead be involved in the natural triggering of the F protein.IMPORTANCE RSV infects virtually every child by the age of 3 years, causing nearly 33 million acute lower respiratory tract infections (ALRI) worldwide each year in children younger than 5 years of age (H. Nair et al., Lancet 375:1545-1555, 2010). RSV is also the second leading cause of respiratory system-related death in the elderly (A. R. Falsey and E. E. Walsh, Drugs Aging 22:577-587, 2005; A. R. Falsey, P. A. Hennessey, M. A. Formica, C. Cox, and E. E. Walsh, N Engl J Med 352:1749-1759, 2005). The monoclonal antibody palivizumab is approved for prophylactic use in some at-risk infants, but healthy infants remain unprotected. Furthermore, its expense limits its use primarily to developed countries. No vaccine or effective small-molecule drug is approved for preventing disease or treating infection (H. M. Costello, W. Ray, S. Chaiwatpongsakorn, and M. E. Peeples, Infect Disord Drug Targets, 12:110-128, 2012). The essential residues identified in the apical domain of F2 are adjacent to the apical portion of F1, which, upon triggering, refolds into a long heptad repeat A (HRA) structure with the fusion peptide at its N terminus. These essential residues in F2 are likely involved in triggering and/or refolding of the F protein and, as such, may be ideal targets for antiviral drug development.

Comparison of the Lund and Browder table to computed tomography scan three-dimensional surface area measurement for a pediatric cohort.

BACKGROUND: Treating burns effectively requires accurately assessing the percentage of the total body surface area (%TBSA) affected by burns. Current methods for estimating %TBSA, such as Lund and Browder (L&B) tables, rely on historic body statistics. An increasingly obese population has been blamed for increasing errors in %TBSA estimates. However, this assumption has not been experimentally validated. We hypothesized that errors in %TBSA estimates using L&B were due to differences in the physical proportions of today's children compared with children in the early 1940s when the chart was developed and that these differences would appear as body mass index (BMI)-associated systematic errors in the L&B values versus actual body surface areas. MATERIALS AND METHODS: We measured the TBSA of human pediatric cadavers using computed tomography scans. Subjects ranged from 9 mo to 15 y in age. We chose outliers of the BMI distribution (from the 31st percentile at the low through the 99th percentile at the high). We examined surface area proportions corresponding to L&B regions. RESULTS: Measured regional proportions based on computed tomography scans were in reasonable agreement with L&B, even with subjects in the tails of the BMI range. The largest deviation was 3.4%, significantly less than the error seen in real-world %TBSA estimates. CONCLUSIONS: While today's population is more obese than those studied by L&B, their body region proportions scale surprisingly well. The primary error in %TBSA estimation is not due to changing physical proportions of today's children and may instead lie in the application of the L&B table.

Facilitating surgeon understanding of complex anatomy using a three-dimensional printed model.

BACKGROUND: 3-dimensional prints (3DP) anecdotally facilitate surgeon understanding of anatomy and decision-making. However, the actual benefit to surgeons or patients has not been quantified. This study investigates how surgeon understanding of complex anatomy is altered by a 3DP compared to computed tomography (CT) scan or CT + digital reconstruction (CT + DR). MATERIALS AND METHODS: Key anatomic features were segmented from a CT-abdomen/pelvis of pygopagus twins to build a DR and printed in color on a 3D printer. Pediatric surgery trainees and attendings (n = 21) were tested regarding anatomy identification and their understanding of point-to-point distances, scale, and shape. RESULTS: There was no difference between media regarding point-to-point distances. The 3DP led to an increased number of correct answers for questions of scale and shape compared to CT (P < 0.05). CT + DR performance was intermediate but not statistically different from 3DP or CT. Identification of anatomy was inconsistent between media; however, answers were significantly closer to correct when using the 3DP. Participants completed the test faster with the 3DP (6.6 ± 0.5 min) (P < 0.05) than with CT (18.9 ± 2.5 min) or CT + 3DR (14.9 ± 1.5 min). CONCLUSIONS: Although point-to-point measurements were not different, 3DP increased the understanding of shape, scale, and anatomy. It enabled understanding significantly faster than other media. In difficult surgical cases with complex anatomy and a need for efficient multidisciplinary coordination, 3D printed models should be considered for surgical planning.

Valve Endothelial Cell-Derived Tgfß1 Signaling Promotes Nuclear Localization of Sox9 in Interstitial Cells Associated With Attenuated Calcification.

OBJECTIVE: Aortic valve disease, including calcification, affects >2% of the human population and is caused by complex interactions between multiple risk factors, including genetic mutations, the environment, and biomechanics. At present, there are no effective treatments other than surgery, and this is because of the limited understanding of the mechanisms that underlie the condition. Previous work has shown that valve interstitial cells within the aortic valve cusps differentiate toward an osteoblast-like cell and deposit bone-like matrix that leads to leaflet stiffening and calcific aortic valve stenosis. However, the mechanisms that promote pathological phenotypes in valve interstitial cells are unknown. APPROACH AND RESULTS: Using a combination of in vitro and in vivo tools with mouse, porcine, and human tissue, we show that in valve interstitial cells, reduced Sox9 expression and nuclear localization precedes the onset of calcification. In vitro, Sox9 nuclear export and calcific nodule formation is prevented by valve endothelial cells. However, in vivo, loss of Tgfß1 in the endothelium leads to reduced Sox9 expression and calcific aortic valve disease. CONCLUSIONS: Together, these findings suggest that reduced nuclear localization of Sox9 in valve interstitial cells is an early indicator of calcification, and therefore, pharmacological targeting to prevent nuclear export could serve as a novel therapeutic tool in the prevention of calcification and stenosis.

Phenolic Metabolites of Dalea ornata Affect Both Survival and Motility of the Human Pathogenic Hookworm Ancylostoma ceylanicum.

Hookworms are ubiquitous human parasites, infecting nearly one billion people worldwide, and are the leading cause of anemia and malnutrition in resource-limited countries. Current drug treatments rely on the benzimidazole derivatives albendazole and mebendazole, but there is emerging resistance to these drugs. As part of a larger screening effort, using a hamster-based ex vivo assay, anthelmintic activity toward Ancylostoma ceylanicum was observed in the crude extract of aerial parts of Dalea ornata. These studies have led to the isolation and characterization of phenolic metabolites 1-10. The structures were determined by 1D and 2D NMR spectroscopy, and the absolute configuration of 1 was assigned using electronic circular dichroism data. The new compound, (2S)-8-(3-methylbut-2-en-1-yl)-6,7,4'-trihydroxyflavanone (1), was weakly active at 7.3 µM, with 17% reduction in survival of the hookworms after 5 days. The rotenoids deguelin (9) and tephrosin (10), predictably perhaps, were the most active, with complete worm mortality observed by day 4 (or earlier) at 6.3 and 6.0 µM, respectively. The effects of 1-10 on hookworm motility and on toxicity to hamster splenocytes were also explored as important measures of treatment potential.

Milk protein composition and stability changes affected by iron in water sources.

Water makes up more than 80% of the total weight of milk. However, the influence of water chemistry on the milk proteome has not been extensively studied. The objective was to evaluate interaction of water-sourced iron (low, medium, and high levels) on milk proteome and implications on milk oxidative state and mineral content. Protein composition, oxidative stability, and mineral composition of milk were investigated under conditions of iron ingestion through bovine drinking water (infused) as well as direct iron addition to commercial milk in 2 studies. Four ruminally cannulated cows each received aqueous infusions (based on water consumption of 100L) of 0, 2, 5, and 12.5mg/L Fe(2+) as ferrous lactate, resulting in doses of 0, 200, 500 or 1,250mg of Fe/d, in a 4×4Latin square design for a 14-d period. For comparison, ferrous sulfate solution was directly added into commercial retail milk at the same concentrations: control (0mg of Fe/L), low (2mg of Fe/L), medium (5mg of Fe/L), and high (12.5mg of Fe/L). Two-dimensional electrophoresis coupled with matrix-assisted laser desorption/ionization-tandem time-of-flight (MALDI-TOF/TOF) high-resolution tandem mass spectrometry analysis was applied to characterize milk protein composition. Oxidative stability of milk was evaluated by the thiobarbituric acid reactive substances (TBARS) assay for malondialdehyde, and mineral content was measured by inductively coupled plasma mass spectrometry. For milk from both abomasal infusion of ferrous lactate and direct addition of ferrous sulfate, an iron concentration as low as 2mg of Fe/L was able to cause oxidative stress in dairy cattle and infused milk, respectively. Abomasal infusion affected both caseins and whey proteins in the milk, whereas direct addition mainly influenced caseins. Although abomasal iron infusion did not significantly affect oxidation state and mineral balance (except iron), it induced oxidized off-flavor and partial degradation of whey proteins. Direct iron addition to milk led to lipid oxidation during storage at 4°C. Oxidation level was positively associated with the concentration of added iron. Minerals (Mg, P, Na, K, Ca, Zn) in milk were not affected by the added iron in milk. This study indicated that a small amount of iron contamination in bovine drinking water at the farm or incidental iron addition from potable water sources causes oxidation, affects milk protein composition and stability, and affects final milk quality.

Enhanced histamine H2 excitation of striatal cholinergic interneurons in L-DOPA-induced dyskinesia.

Levodopa is the most effective therapy for the motor deficits of Parkinson's disease (PD), but long term treatment leads to the development of L-DOPA-induced dyskinesia (LID). Our previous studies indicate enhanced excitability of striatal cholinergic interneurons (ChIs) in mice expressing LID and reduction of LID when ChIs are selectively ablated. Recent gene expression analysis indicates that stimulatory H2 histamine receptors are preferentially expressed on ChIs at high levels in the striatum, and we tested whether a change in H2 receptor function might contribute to the elevated excitability in LID. Using two different mouse models of PD (6-hydroxydopamine lesion and Pitx3(ak/ak) mutation), we chronically treated the animals with either vehicle or l-DOPA to induce dyskinesia. Electrophysiological recordings indicate that histamine H2 receptor-mediated excitation of striatal ChIs is enhanced in mice expressing LID. Additionally, H2 receptor blockade by systemic administration of famotidine decreases behavioral LID expression in dyskinetic animals. These findings suggest that ChIs undergo a pathological change in LID with respect to histaminergic neurotransmission. The hypercholinergic striatum associated with LID may be dampened by inhibition of H2 histaminergic neurotransmission. This study also provides a proof of principle of utilizing selective gene expression data for cell-type-specific modulation of neuronal activity.

Vital Signs: Estimated Effects of a Coordinated Approach for Action to Reduce Antibiotic-Resistant Infections in Health Care Facilities - United States.

BACKGROUND: Treatments for health care-associated infections (HAIs) caused by antibiotic-resistant bacteria and Clostridium difficile are limited, and some patients have developed untreatable infections. Evidence-supported interventions are available, but coordinated approaches to interrupt the spread of HAIs could have a greater impact on reversing the increasing incidence of these infections than independent facility-based program efforts. METHODS: Data from CDC's National Healthcare Safety Network and Emerging Infections Program were analyzed to project the number of health care-associated infections from antibiotic-resistant bacteria or C. difficile both with and without a large scale national intervention that would include interrupting transmission and improved antibiotic stewardship. As an example, the impact of reducing transmission of one antibiotic-resistant infection (carbapenem-resistant Enterobacteriaceae [CRE]) on cumulative prevalence and number of HAI transmission events within interconnected groups of health care facilities was modeled using two distinct approaches, a large scale and a smaller scale health care network. RESULTS: Immediate nationwide infection control and antibiotic stewardship interventions, over 5 years, could avert an estimated 619,000 HAIs resulting from CRE, multidrug-resistant Pseudomonas aeruginosa, invasive methicillin-resistant Staphylococcus aureus (MRSA), or C. difficile. Compared with independent efforts, a coordinated response to prevent CRE spread across a group of inter-connected health care facilities resulted in a cumulative 74% reduction in acquisitions over 5 years in a 10-facility network model, and 55% reduction over 15 years in a 102-facility network model. CONCLUSIONS: With effective action now, more than half a million antibiotic-resistant health care-associated infections could be prevented over 5 years. Models representing both large and small groups of interconnected health care facilities illustrate that a coordinated approach to interrupting transmission is more effective than historical independent facilitybased efforts. IMPLICATIONS FOR PUBLIC HEALTH: Public health-led coordinated prevention approaches have the potential to more completely address the emergence and dissemination of these antibiotic-resistant organisms and C. difficile than independent facility-based efforts.

Addressing the unmet need for visualizing conditional random fields in biological data.

BACKGROUND: The biological world is replete with phenomena that appear to be ideally modeled and analyzed by one archetypal statistical framework - the Graphical Probabilistic Model (GPM). The structure of GPMs is a uniquely good match for biological problems that range from aligning sequences to modeling the genome-to-phenome relationship. The fundamental questions that GPMs address involve making decisions based on a complex web of interacting factors. Unfortunately, while GPMs ideally fit many questions in biology, they are not an easy solution to apply. Building a GPM is not a simple task for an end user. Moreover, applying GPMs is also impeded by the insidious fact that the "complex web of interacting factors" inherent to a problem might be easy to define and also intractable to compute upon. DISCUSSION: We propose that the visualization sciences can contribute to many domains of the bio-sciences, by developing tools to address archetypal representation and user interaction issues in GPMs, and in particular a variety of GPM called a Conditional Random Field(CRF). CRFs bring additional power, and additional complexity, because the CRF dependency network can be conditioned on the query data. CONCLUSIONS: In this manuscript we examine the shared features of several biological problems that are amenable to modeling with CRFs, highlight the challenges that existing visualization and visual analytics paradigms induce for these data, and document an experimental solution called StickWRLD which, while leaving room for improvement, has been successfully applied in several biological research projects. Software and tutorials are available at http://www.stickwrld.org/.

Structure and function of respiratory syncytial virus surface glycoproteins.

The two major glycoproteins on the surface of the respiratory syncytial virus (RSV) virion, the attachment glycoprotein (G) and the fusion glycoprotein (F), control the initial phases of infection. G targets the ciliated cells of the airways, and F causes the virion membrane to fuse with the target cell membrane. The F protein is the major target for antiviral drug development, and both G and F glycoproteins are the antigens targeted by neutralizing antibodies induced by infection. In this chapter, we review the structure and function of the RSV surface glycoproteins, including recent X-ray crystallographic data of the F glycoprotein in its pre- and postfusion conformations, and discuss how this information informs antigen selection and vaccine development.

Identification of a methoxynaphthalene scaffold as a core replacement in quinolizidinone amide M(1) positive allosteric modulators.

A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M1 positive allosteric modulators. A methoxy group was optimal for M1 activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series.

Adenosine analogue inhibitors of S-adenosylhomocysteine hydrolase.

Elevated plasma homocysteine (Hcy) levels are an independent risk factor for the onset and progression of Alzheimer's disease. Reduction of Hcy to normal levels therefore presents a new approach for disease modification. Hcy is produced by the cytosolic enzyme S-adenosylhomocysteine hydrolase (AHCY), which converts S-adenosylhomocysteine (SAH) to Hcy and adenosine. Herein we describe the design and characterization of novel, substrate-based S-adenosylhomocysteine hydrolase inhibitors with low nanomolar potency in vitro and robust activity in vivo.

Pathogenic tau decreases nuclear tension in cultured neurons.

Neurodegenerative tauopathies, including Alzheimer's disease, are pathologically defined by the presence of aggregated forms of tau protein in brains of affected individuals. Previous studies report that the negative effects of pathogenic tau on the actin cytoskeleton and microtubules cause a toxic destabilization of the lamin nucleoskeleton and formation of nuclear invaginations and blebs. Based on the known function of the nucleus as a mechanosensor, as well as the high incidence of nuclear pleomorphism in human Alzheimer's disease and related tauopathies, we investigated the effects of pathogenic tau on nuclear tension. We first find that tau-dependent nuclear envelope invagination and relocalization of LInker of Nucleoskeleton and Cytoskeleton (LINC) complex components are conserved in a newly-developed neuroblastoma cell line that features doxycycline-inducible expression of a tau mutant associated with autosomal dominant frontotemporal dementia. We next determine that a Förster resonance energy transfer (FRET)-based sensor of nuclear tension responds to cytoskeletal stabilization and destabilization when expressed in neuroblastoma cells. Using this nuclear tension sensor, we find that induced expression of pathogenic tau is sufficient to decrease nuclear tension. This work provides the initial proof-of-concept evidence that pathogenic forms of tau alter nuclear tension, paving the way for the future study of altered nuclear mechanosensing in the context of tau-mediated neurodegenerative disorders.

Moesin is an effector of tau-induced actin overstabilization, cell cycle activation, and neurotoxicity in Alzheimer's disease.

In Alzheimer's disease, neurons acquire phenotypes that are also present in various cancers, including aberrant activation of the cell cycle. Unlike cancer, cell cycle activation in post-mitotic neurons is sufficient to induce cell death. Multiple lines of evidence suggest that abortive cell cycle activation is a consequence of pathogenic forms of tau, a protein that drives neurodegeneration in Alzheimer's disease and related "tauopathies." Here we combine network analyses of human Alzheimer's disease and mouse models of Alzheimer's disease and primary tauopathy with studies in Drosophila to discover that pathogenic forms of tau drive cell cycle activation by disrupting a cellular program involved in cancer and the epithelial-mesenchymal transition (EMT). Moesin, an EMT driver, is elevated in cells harboring disease-associated phosphotau, over-stabilized actin, and ectopic cell cycle activation. We further find that genetic manipulation of Moesin mediates tau-induced neurodegeneration. Taken together, our study identifies novel parallels between tauopathy and cancer.

Invasive or More Direct Measurements Can Provide an Objective Early-Stopping Ceiling for Training Deep Neural Networks on Non-invasive or Less-Direct Biomedical Data.

Early stopping is an extremely common tool to minimize overfitting, which would otherwise be a cause of poor generalization of the model to novel data. However, early stopping is a heuristic that, while effective, primarily relies on ad hoc parameters and metrics. Optimizing when to stop remains a challenge. In this paper, we suggest that for some biomedical applications, a natural dichotomy of invasive/non-invasive measurements, or more generally proximal vs distal measurements of a biological system can be exploited to provide objective advice on early stopping. We discuss the conditions where invasive measurements of a biological process should provide better predictions than non-invasive measurements, or at best offer parity. Hence, if data from an invasive measurement are available locally, or from the literature, that information can be leveraged to know with high certainty whether a model of non-invasive data is overfitted. We present paired invasive/non-invasive cardiac and coronary artery measurements from two mouse strains, one of which spontaneously develops type 2 diabetes, posed as a classification problem. Examination of the various stopping rules shows that generalization is reduced with more training epochs and commonly applied stopping rules give widely different generalization error estimates. The use of an empirically derived training ceiling is demonstrated to be helpful as added information to leverage early stopping in order to reduce overfitting.

Pathogenic tau-induced transposable element-derived dsRNA drives neuroinflammation.

Deposition of tau protein aggregates in the brain of affected individuals is a defining feature of "tauopathies," including Alzheimer's disease. Studies of human brain tissue and various model systems of tauopathy report that toxic forms of tau negatively affect nuclear and genomic architecture, identifying pathogenic tau-induced heterochromatin decondensation and consequent retrotransposon activation as a causal mediator of neurodegeneration. On the basis of their similarity to retroviruses, retrotransposons drive neuroinflammation via toxic intermediates, including double-stranded RNA (dsRNA). We find that dsRNA and dsRNA sensing machinery are elevated in astrocytes of postmortem brain tissue from patients with Alzheimer's disease and progressive supranuclear palsy and in brains of tau transgenic mice. Using a Drosophila model of tauopathy, we identify specific tau-induced retrotransposons that form dsRNA and find that pathogenic tau and heterochromatin decondensation causally drive dsRNA-mediated neurodegeneration and neuroinflammation. Our study suggests that pathogenic tau-induced heterochromatin decondensation and retrotransposon activation cause elevation of inflammatory, transposable element-derived dsRNA in the adult brain.

A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation.

Pervasive neuroinflammation occurs in many neurodegenerative diseases, including Alzheimer's disease (AD). SPI1/PU.1 is a transcription factor located at a genome-wide significant AD-risk locus and its reduced expression is associated with delayed onset of AD. We analyzed single-cell transcriptomic datasets from microglia of human AD patients and found an enrichment of PU.1-binding motifs in the differentially expressed genes. In hippocampal tissues from transgenic mice with neurodegeneration, we found vastly increased genomic PU.1 binding. We then screened for PU.1 inhibitors using a PU.1 reporter cell line and discovered A11, a molecule with anti-inflammatory efficacy and nanomolar potency. A11 regulated genes putatively by recruiting a repressive complex containing MECP2, HDAC1, SIN3A, and DNMT3A to PU.1 motifs, thus representing a novel mechanism and class of molecules. In mouse models of AD, A11 ameliorated neuroinflammation, loss of neuronal integrity, AD pathology, and improved cognitive performance. This study uncovers a novel class of anti-inflammatory molecules with therapeutic potential for neurodegenerative disorders.