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Microglia are the brain-resident immune cells responsible for surveilling and protecting the central nervous system. These cells can express a wide array of immune genes, and that expression can become highly dynamic in response to changes in the environment, such as traumatic injury or neurological disease. Though microglial immune responses are well studied, we still do not know many mechanisms and regulators underlying all the varied microglial responses. Serpin E2 is a serine protease inhibitor that acts on a wide variety of serine proteases, with particularly potent affinity for the blood clotting enzyme thrombin. In the brain, Serpin E2 is highly expressed by many cell types, especially glia, and loss of Serpin E2 leads to behavioral changes as well as deficits in synaptic plasticity. To determine whether Serpin E2 is important for maintaining homeostasis in glia, we performed RNA sequencing of microglia and astrocytes from Serpin E2-deficient mice in a healthy state or under immune activation due to lipopolysaccharide (LPS) injection. We found that microglia in Serpin E2-deficient mice had higher expression of antimicrobial genes, while astrocytes did not display any robust changes in transcription. Furthermore, the lack of Serpin E2 did not affect transcriptional responses to LPS in either microglia or astrocytes. Overall, we find that Serpin E2 is a regulator of antimicrobial genes in microglia.

Abstract Using 40 countries’ subnational data, we estimate age-specific mortality-temperature relationships and extrapolate them to countries without data today and into a future with climate change. We uncover a U-shaped relationship where extre6me cold and hot temperatures increase mortality rates, especially for the elderly. Critically, this relationship is flattened by higher incomes and adaptation to local climate. Using a revealed-preference approach to recover unobserved adaptation costs, we estimate that the mean global increase in mortality risk due to climate change, accounting for adaptation benefits and costs, is valued at roughly 3.2% of global GDP in 2100 under a high-emissions scenario. Notably, today’s cold locations are projected to benefit, while today’s poor and hot locations have large projected damages. Finally, our central estimates indicate that the release of an additional ton of CO2 today will cause mortality-related damages of $36.6 under a high-emissions scenario, with an interquartile range accounting for both econometric and climate uncertainty of [−$7.8, $73.0]. These empirically grounded estimates exceed the previous literature’s estimates by an order of magnitude.

The inability of neurons to regenerate long axons within the CNS is a major impediment to improving outcome after spinal cord injury, stroke, and other CNS insults. Recent advances have uncovered an intrinsic program that involves coordinate regulation by multiple transcription factors that can be manipulated to enhance growth in the peripheral nervous system. Here, we use a systems genomics approach to characterize regulatory relationships of regeneration-associated transcription factors, identifying RE1-Silencing Transcription Factor (REST; Neuron-Restrictive Silencer Factor, NRSF) as a predicted upstream suppressor of a pro-regenerative gene program associated with axon regeneration in the CNS. We validate our predictions using multiple paradigms, showing that mature mice bearing cell type-specific deletions of REST or expressing dominant-negative mutant REST show improved regeneration of the corticospinal tract and optic nerve after spinal cord injury and optic nerve crush, which is accompanied by upregulation of regeneration-associated genes in cortical motor neurons and retinal ganglion cells, respectively. These analyses identify a role for REST as an upstream suppressor of the intrinsic regenerative program in the CNS and demonstrate the utility of a systems biology approach involving integrative genomics and bio-informatics to prioritize hypotheses relevant to CNS repair.

Current technologies designed for mental health support often have low adoption rates and may not fit people's routines. However, recent literature demonstrates that individuals managing mental illness often incorporate a variety of technologies into their self-management routines, including texting, music, wearables, online communities, games, and social media. Therefore, adopting a perspective focused on understanding the technology ecosystem of mental health management may be a better approach than focusing on singular platforms and applications. In this CHI workshop, we will examine a constellation of digital and non-digital mental health support resources. We will discuss the needs and practices of individuals managing mental illness, how these needs relate to future ecosystems of technologies and services, and the potentials and repercussions of current technologies. By convening a group of interdisciplinary researchers and practitioners, we will collectively address these topics to create resources attentive to individuals' lived experiences with mental illness, goals with respect to management and recovery, and interactions with existing forms of resources, care, and technology.

Background/Objectives: This study investigates whether there is an increased propensity to systemic conditions in patients with both age-related macular degeneration (AMD) and glaucoma in order to provide greater insight into patients' overall health and response to physiologic stress. Methods: A large retrospective dataset review was conducted between April 2004 and June 2018, distinguishing four groups based on international classification of diseases (ICD) codes: glaucoma only, AMD only, glaucoma and AMD, and cataracts only (as an age-matched control). The systemic disease prevalence of each group was calculated, and a Friedman analysis was used to compare the prevalence between the groups. Results: This study identified 5243 patients with glaucoma only, 6726 with AMD only, 402 with combined disease, and 25,450 with cataracts only. Age and racial distributions varied between groups in a predictable manner. Two conditions, heart failure (HF) and dementia, had a statistically higher prevalence in patients with both glaucoma and AMD compared to those with glaucoma alone (HF p = 0.036, dementia p = 0.024) and cataracts alone (HF p = 0.003, dementia p = 0.036). There was no significant difference observed in terms of ethnicity and gender among the different disease groups (p > 0.05). Conclusions: Both AMD and glaucoma individually portend a higher rate of comorbidities than age-matched controls. Patients with concomitant AMD and glaucoma demonstrate a uniquely higher prevalence of heart failure and dementia than those with either disease alone. The underlying association and pathologic mechanisms warrant further investigation to improve the overall health management and prognostication for these individuals. [ABSTRACT FROM AUTHOR]

IntroductionNon-alcoholic fatty liver disease (NAFLD) has become the most common etiology for abnormal aminotransferase levels and chronic liver disease. Its growing prevalence is largely linked to the presence of metabolic syndrome, particularly diabetes and insulin resistance. It is estimated that 60-80% of the type 2 diabetic population has NAFLD. NAFLD encompasses a range of conditions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). A subset of patients with hepatic steatosis progress to NASH, while 15-20% of patients with NASH develop cirrhosis. This progression is thought to be multifactorial, and there are currently no FDA-approved medications for the treatment of NASH.Areas coveredWe review drugs currently in Phase II and III clinical trials for treatment of NAFLD and NASH, including their mechanisms of action, relationship to the pathophysiology of NASH, and rationale for their development.Expert opinionThe treatment of NASH is complex and necessitates targeting a number of different pathways. Combination therapy, preferably tailored toward the disease stage and severity, will be needed to achieve maximum therapeutic effect. With multiple agents currently being developed, there may soon be an ability to effectively slow or even reverse the disease process in many NAFLD/NASH patients.

RationaleThe clinical course of chronic lung allograft dysfunction (CLAD) is heterogeneous. Forced vital capacity (FVC) loss at onset, which may suggest a restrictive phenotype, was associated with worse survival for bilateral lung transplant recipients in one previously published single-center study.ObjectivesWe sought to replicate the significance of FVC loss in an independent, retrospectively identified cohort of bilateral lung transplant recipients and to investigate extended application of this approach to single lung recipients.MethodsFVC loss and other potential predictors of survival after the onset of CLAD were assessed using Kaplan-Meier and Cox proportional hazards models.Measurements and main resultsFVC loss at the onset of CLAD was associated with higher mortality in an independent cohort of bilateral lung transplant recipients (hazard ratio [HR], 2.75; 95% confidence interval [CI], 2.02-3.73; P

The regenerative capacity of the injured CNS in adult mammals is severely limited, yet axons in the peripheral nervous system (PNS) regrow, albeit to a limited extent, after injury. We reasoned that coordinate regulation of gene expression in injured neurons involving multiple pathways was central to PNS regenerative capacity. To provide a framework for revealing pathways involved in PNS axon regrowth after injury, we applied a comprehensive systems biology approach, starting with gene expression profiling of dorsal root ganglia (DRGs) combined with multi-level bioinformatic analyses and experimental validation of network predictions. We used this rubric to identify a drug that accelerates DRG neurite outgrowth in vitro and optic nerve outgrowth in vivo by inducing elements of the identified network. The work provides a functional genomics foundation for understanding neural repair and proof of the power of such approaches in tackling complex problems in nervous system biology.

Presenters Alice Zhang, MD, Joseph Balles, MS, Jennifer Nyland, PhD, Thao Nguyen, Aleksandra Zgierska, MD, [...], Context: Those with untreated substance use disorder (SUD) are often involved with the criminal justice system during the course of addiction and continue to experience negative outcomes following arrest and incarceration. Law enforcement-led pre-arrest diversion programs aimed to redirect those who commit drug use-related offenses to treatment may improve addiction treatment engagement and associated clinical outcomes. Objective: To identify predictors of treatment engagement and evaluate the impact of a city-wide pre-arrest diversion program on participants' clinical characteristics. Study Design and Analysis: Prospective evaluation of a community-based pre-arrest diversion program (one-way ANOVA for continuous, chi-square test for categorical outcome variables). Baseline characteristics differing between those who completed ("completers," n=100) and those who did not complete the program ("non-completers," n=60) were used in a logistic regression model to estimate adjusted odds ratio for predictors of program retention. Setting: A medium-sized Midwestern city. Population: Adults who committed an eligible, drug use-related crime. Intervention: A 6-month pre-arrest diversion-to-treatment program. Outcome Measures: Depression, anxiety, and addiction symptom severity scores, and demographic and addiction treatment-related characteristics collected upon initial clinical assessment (baseline) and at program completion for completers. Results: Baseline predictors of program completion included: being in treatment (p=0.028), having a recovery support network (p=0.041), having a higher level of awareness of relapse triggers (p=0.023), having relapse prevention coping skills (p=0.001), and having relapse protective factors (p=0.008). The logistic regression model showed those with better coping skills and in treatment were 3 times more likely to finish the program than their counterparts (p Conclusions: A law enforcement-led pre-arrest diversion program may help engage those who commit drug use-related minor crimes in addiction treatment and improve clinical outcomes, particularly in those at lower relapse risk. Future iterations of the program may consider a more intensive support for those at higher relapse risk.

Genetic studies have identified dozens of autism spectrum disorder (ASD) susceptibility genes, raising two critical questions: (1) do these genetic loci converge on specific biological processes, and (2) where does the phenotypic specificity of ASD arise, given its genetic overlap with intellectual disability (ID)? To address this, we mapped ASD and ID risk genes onto coexpression networks representing developmental trajectories and transcriptional profiles representing fetal and adult cortical laminae. ASD genes tightly coalesce in modules that implicate distinct biological functions during human cortical development, including early transcriptional regulation and synaptic development. Bioinformatic analyses suggest that translational regulation by FMRP and transcriptional coregulation by common transcription factors connect these processes. At a circuit level, ASD genes are enriched in superficial cortical layers and glutamatergic projection neurons. Furthermore, we show that the patterns of ASD and ID risk genes are distinct, providing a biological framework for further investigating the pathophysiology of ASD.