Adaptation in Unstable Environments and Global Gene Losses: Small but Stable Gene Networks by the May-Wigner Theory.

Although gene loss is common in evolution, it remains unclear whether it is an adaptive process. In a survey of seven major mangrove clades that are woody plants in the intertidal zones of daily environmental perturbations, we noticed that they generally evolved reduced gene numbers. We then focused on the largest clade of Rhizophoreae and observed the continual gene set reduction in each of the eight species. A great majority of gene losses are concentrated on environmental interaction processes, presumably to cope with the constant fluctuations in the tidal environments. Genes of the general processes for woody plants are largely retained. In particular, fewer gene losses are found in physiological traits such as viviparous seeds, high salinity, and high tannin content. Given the broad and continual genome reductions, we propose the May-Wigner theory (MWT) of system stability as a possible mechanism. In MWT, the most effective solution for buffering continual perturbations is to reduce the size of the system (or to weaken the total genic interactions). Mangroves are unique as immovable inhabitants of the compound environments in the land-sea interface, where environmental gradients (such as salinity) fluctuate constantly, often drastically. Extending MWT to gene regulatory network (GRN), computer simulations and transcriptome analyses support the stabilizing effects of smaller gene sets in mangroves vis-à-vis inland plants. In summary, we show the adaptive significance of gene losses in mangrove plants, including the specific role of promoting phenotype innovation and a general role in stabilizing GRN in unstable environments as predicted by MWT.

DREADD-mediated amygdala activation is sufficient to induce anxiety-like responses in young nonhuman primates.

Anxiety disorders are among the most prevalent psychiatric disorders, with symptoms often beginning early in life. To model the pathophysiology of human pathological anxiety, we utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in a nonhuman primate model of anxious temperament to selectively increase neuronal activity of the amygdala. Subjects included 10 young rhesus macaques; 5 received bilateral infusions of AAV5-hSyn-HA-hM3Dq into the dorsal amygdala, and 5 served as controls. Subjects underwent behavioral testing in the human intruder paradigm following clozapine or vehicle administration, prior to and following surgery. Behavioral results indicated that clozapine treatment post-surgery increased freezing across different threat-related contexts in hM3Dq subjects. This effect was again observed approximately 1.9 years following surgery, indicating the long-term functional capacity of DREADD-induced neuronal activation. [11C]deschloroclozapine PET imaging demonstrated amygdala hM3Dq-HA specific binding, and immunohistochemistry revealed that hM3Dq-HA expression was most prominent in basolateral nuclei. Electron microscopy confirmed expression was predominantly on neuronal membranes. Together, these data demonstrate that activation of primate amygdala neurons is sufficient to induce increased anxiety-related behaviors, which could serve as a model to investigate pathological anxiety in humans.

Responses to pathogen exposure in sentinel juvenile fall-run Chinook salmon in the Sacramento River, CA.

This study investigated how the deployment of juvenile Chinook salmon in ambient river conditions and the subsequent exposure to and infection by pathogens was associated with the changes in the expression of genes involved in immune system functioning, general stress and host development. Juvenile fish were deployed in sentinel cages for 21 days in the Sacramento River, CA, USA. Gill, kidney and intestinal tissue were sampled at 0, 7, 14 and 21 days post-deployment. Pathogen detection and host response were assessed by a combination of molecular and histopathological evaluation. Our findings showed that fish became infected by the parasites Ceratonova shasta, Parvicapsula minibicornis and Ichthyophthirius multifiliis, and to a lesser extent, the bacteria Flavobacterium columnare and Rickettsia-like organisms. Co-infection was common among sentinel fish. Expression of investigated genes was altered following deployment and was often associated with pathogen abundance. This study provides a foundation for future avenues of research investigating pathogens that affect out-migrating Chinook salmon in the Sacramento River, and offers crucial knowledge related to conservation efforts.

Waterborne exposure during non-consumptive domestic use of surface water: a population study across WASH service levels in rural India.

Exposure to pathogens from domestic use of surface water is understudied. In many low- and middle-income countries, surface water is used for hygiene, sanitation, amenity, and recreational purposes. In this study, self-reported use of and structured observations at community ponds were collected to measure waterborne exposure across water and sanitation service levels in a rural population of Khorda District, India. Overall, 86% of households (n = 200) reported using ponds on a regular basis. Among observed people (n = 765), 82% put water into their mouth at least once, with a median frequency of five occurrences per visit. Reported and observation data were combined to estimate the proportion (p) of the population that put water in their mouth at least once per day, and their mean daily rate of oral exposure (OE). These were highest for individuals with neither safely managed water nor basic sanitation access (p = 93%, OE = 14 day-1), but still high among those with both (p = 67%, OE = 6 day-1). The results suggest widespread exposure to waterborne pathogens in settings where non-potable surface water bodies continue to be used for domestic purposes, even among households with access to safely managed drinking water.

DREADD-mediated amygdala activation is sufficient to induce anxiety-like responses in young nonhuman primates.

Anxiety disorders are among the most prevalent psychiatric disorders, with symptoms often beginning early in life. To model the pathophysiology of human pathological anxiety, we utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in a nonhuman primate model of anxious temperament to selectively increase neuronal activity of the amygdala. Subjects included 10 young rhesus macaques; 5 received bilateral infusions of AAV5-hSyn-HA-hM3Dq into the dorsal amygdala, and 5 served as controls. Subjects underwent behavioral testing in the human intruder paradigm following clozapine or vehicle administration, prior to and following surgery. Behavioral results indicated that clozapine treatment post-surgery increased freezing across different threat-related contexts in hM3Dq subjects. This effect was again observed approximately 1.9 years following surgery, indicating the long-term functional capacity of DREADD-induced neuronal activation. [11C]deschloroclozapine PET imaging demonstrated amygdala hM3Dq-HA specific binding, and immunohistochemistry revealed that hM3Dq-HA expression was most prominent in basolateral nuclei. Electron microscopy confirmed expression was predominantly on neuronal membranes. Together, these data demonstrate that activation of primate amygdala neurons is sufficient to induce increased anxiety-related behaviors, which could serve as a model to investigate pathological anxiety in humans.

An updated profile of the bovine acute phase response following an intravenous lipopolysaccharide challenge.

The objective was to provide an updated profile of the bovine acute-phase response to include recent advancements in technologies and expanded hematological, cytokine, and serum chemistry variables. Beef steers (n = 32; body weight [BW] = 251 ±â€…19.5 kg) were fitted with indwelling jugular catheters 1 d before lipopolysaccharide (LPS; 0.25 µg LPS/kg BW from Escherichia coli O111:B4) administration to facilitate serial blood collection. Rectal temperature was measured using indwelling probes, and ocular temperature was measured using infrared thermal imaging. Blood samples were collected for subsequent analysis of serum chemistry, hematology, and cytokine concentrations. Pearson correlation of rectal temperature and ocular infrared temperature was 0.61 (P < 0.01) and the Spearman correlation coefficient was 0.56 (P < 0.01). Interactions of hour × method were observed for ocular and rectal measurements of body temperature in response to endotoxin exposure. Maximum observed temperature was 39.6 °C at 2.5 h for both rectal and ocular measurements. Body temperature differed by method at hours 0.5, 2.5, 4.5, 7.5, 12.5, 36.5, and 47.5 (P < 0.01), but were not different otherwise. All variables of serum chemistry and complete blood count were influenced by LPS administration, except creatinine, serum glucose, and percent basophils (P ≤ 0.02). Alanine aminotransferase and alkaline phosphatase peaked at hour 2 relative to LPS administration, returned to baseline at hour 12 and continued to decrease below the baseline value at hour 48 (P < 0.01). Total protein concentration decreased 3% in response to LPS (P = 0.01). Total white blood cell count decreased 75% after LPS administration at hour 1 (P < 0.01). Lymphocyte count recovered to baseline at hour 6; sooner than neutrophil count at hour 36. Serum cortisol concentration increased 294% relative to baseline at hour 1 followed by a sustained decrease and return to normal concentration at hour 4 (P < 0.01). Additionally, circulating cytokine concentrations changed with time in response to the LPS challenge, excluding aFGF, bFGF, IGF-1, IL-2, IL-4, MCP-1, and ANG-1 (P ≤ 0.08). Maximum observed concentration of TNF-α at hour 1 was 117% greater than the pre-challenge value (P < 0.01). Data presented herein add to existing works to understand the endocrine and immune responses of beef steers administered exogenous LPS, and incorporate recent technologies, additional biomarkers, and an expanded cytokine profile that can be used as referential data in future research.

The acute phase response is a component of innate immunity initiated by infection, inflammation, or tissue damage. Characteristics of these host responses can be emulated by administration of exogenous endotoxin and closely studied in controlled settings to understand the response to inflammatory diseases that are commonplace in livestock production. Beef steers were administered exogenous lipopolysaccharide, and responses of body temperature, serum chemistry, complete blood count, cortisol, and cytokines were quantified. A moderate correlation of body temperature measured via rectal probe or ocular infrared temperature was observed, but both methods had a similar temporal response and were sensitive to changes in body temperature. Response of serum chemistry variables highlighted the links between metabolism and the inflammatory response. The initial inflammatory response was initiated by cortisol and pro-inflammatory cytokines at hour 1 and tempered by anti-inflammatory cytokines at hours 3 and 4. Therefore, these data offer an expanded view to our understanding of the bovine acute phase response.

Evaluation of First Treatment Timing, Fatal Disease Onset, and Days from First Treatment to Death Associated with Bovine Respiratory Disease in Feedlot Cattle.

Bovine respiratory disease (BRD) is a frequent beef cattle syndrome. Improved understanding of the timing of BRD events, including subsequent deleterious outcomes, promotes efficient resource allocation. This study's objective was to determine differences in timing distributions of initial BRD treatments (Tx1), days to death after initial treatment (DTD), and days after arrival to fatal disease onset (FDO). Individual animal records for the first BRD treatment (n = 301,721) or BRD mortality (n = 19,332) were received from 25 feed yards. A subset of data (318-363 kg; steers/heifers) was created and Wasserstein distances were used to compare temporal distributions of Tx1, FDO, and DTD across genders (steers/heifers) and the quarter of arrival. Disease frequency varied by quarter with the greatest Wasserstein distances observed between Q2 and Q3 and between Q2 and Q4. Cattle arriving in Q3 and Q4 had earlier Tx1 events than in Q2. Evaluating FDO and DTD revealed the greatest Wasserstein distance between cattle arriving in Q2 and Q4, with cattle arriving in Q2 having later events. Distributions of FDO varied by gender and quarter and typically had wide distributions with the largest 25-75% quartiles ranging from 20 to 80 days (heifers arriving in Q2). The DTD had right-skewed distributions with 25% of cases occurring by days 3-4 post-treatment. Results illustrate temporal disease and outcome patterns are largely right-skewed and may not be well represented by simple arithmetic means. Knowledge of typical temporal patterns allows cattle health managers to focus disease control efforts on the correct groups of cattle at the appropriate time.

Low Muscle Mass and Radiodensity Associate with Impaired Pulmonary Function and Respiratory Complications in Patients with Esophageal Cancer.

BACKGROUND: Sixty percent of patients with esophageal cancer display signs of cachexia at diagnosis. Changes in body composition are common, and muscle mass and quality are measurable through imaging studies. Cachexia leads to functional impairments that complicate treatments, including surgery. We hypothesize that low muscle mass and quality associate with pulmonary function testing parameters, highlighting ventilatory deficits, and postoperative complications in patients receiving esophagectomy. STUDY DESIGN: We performed a retrospective review of patients receiving esophagectomy between 2012 and 2021 at our facility. PET/CT scans were used to quantify skeletal muscle at the L3 and T4 levels. Patient characteristics were recorded, including pulmonary function testing parameters. Regression models were created to characterize predictive associations. RESULTS: One hundred eight patients were identified. All were included in the final analysis. In linear regression adjusted for sex, age, and COPD status, low L3 muscle mass independently associated with low forced vital capacity (p < 0.005, ß 0.354) and forced expiratory volume in 1 second (p < 0.001, ß 0.392). Similarly, T4 muscle mass independently predicted forced vital capacity (p < 0.005, ß 0.524) and forced expiratory volume in 1 second (p < 0.01, ß 0.480). L3 muscle quality correlated with total lung capacity ( R 0.2463, p < 0.05). Twenty-six patients had pleural effusions postoperatively, associated with low muscle quality on L3 images (p < 0.05). Similarly, patients with hospitalization more than 2 weeks presented with lower muscle quality (p < 0.005). CONCLUSIONS: Cachexia and low muscle mass are common. Reduced muscle mass and quality independently associate with impaired forced vital capacity, forced expiratory volume in 1 second, and total lung capacity. We propose that respiratory muscle atrophy occurs with weight loss. Body composition analyses may aid in stratifying patients. Pulmonary function testing may also serve as a functional endpoint for clinical trials. These findings highlight the need to study mechanisms that lead to respiratory muscle pathology and dysfunction in tumor-bearing hosts.

Real-time trajectory guide tracking for intraoperative MRI-guided neurosurgery.

PURPOSE: In current intraoperative MRI (IMRI) methods, an iterative approach is used to aim trajectory guides at intracerebral targets: image MR-visible features, determine current aim by fitting model to image, manipulate device, repeat. Infrequent updates are produced by such methods, compared to rapid optically tracked stereotaxy used in the operating room. Our goal was to develop a real-time interactive IMRI method for aiming. METHODS: The current trajectory was computed from two points along the guide's central axis, rather than by imaging the entire device. These points were determined by correlating one-dimensional spokes from a radial sequence with the known cross-sectional projection of the guide. The real-time platform RTHawk was utilized to control MR sequences and data acquisition. On-screen updates were viewed by the operator while simultaneously manipulating the guide to align it with the planned trajectory. Accuracy was quantitated in a phantom, and in vivo validation was demonstrated in nonhuman primates undergoing preclinical gene ( n = 5 $$ n=5 $$ ) and cell ( n = 4 $$ n=4 $$ ) delivery surgeries. RESULTS: Updates were produced at 5 Hz In 10 phantom experiments at a depth of 48 mm, the cannula tip was placed with radial error of (min, mean, max) = (0.16, 0.29, 0.68) mm. Successful in vivo delivery of payloads to all 14 targets was demonstrated across nine surgeries with depths of (min, mean, max) = (33.3, 37.9, 42.5) mm. CONCLUSION: A real-time interactive update rate was achieved, reducing operator fatigue without compromising accuracy. Qualitative interpretation of images during aiming was rendered unnecessary by objectively computing device alignment.

Nasopharyngeal Bacterial Prevalence and Microbial Diversity at First Treatment for Bovine Respiratory Disease (BRD) and Its Associations with Health and Mortality Outcomes in Feedyard Cattle.

Bovine respiratory disease (BRD) is an economically important disease in feedyards influencing both animal welfare and antimicrobial utilization. Major pathogens associated with BRD have been identified in previous research, but little information is available on the relationship between nasopharyngeal microbiota and health outcomes. The objective of this study was to identify potential associations between nasopharyngeal microbiota and antimicrobial resistance patterns of clinical cases that lived or died compared to non-diseased controls. Enrolled animals were subdivided based on clinical disease status and case outcome (subsequent mortality). Deep nasopharyngeal swabs were collected on enrolled animals and submitted for bacterial isolation, antimicrobial susceptibility determination, and metagenomics analysis. Enrolled cattle were represented in three groups: animals at first treatment for BRD that subsequently died (BRDM, n = 9), animals at first treatment for BRD that subsequently lived (BRDL, n = 15), and animals that were never treated for BRD during the feeding phase (CONT, n = 11). Antimicrobial resistance patterns for Pasteurella multocida illustrated cattle in each outcome category had isolates that were pan-susceptible or only showed resistance to oxytetracycline. The relative abundance of species and genera illustrated few differences among the three outcomes. Higher alpha diversity was identified in BRDL compared to CONT at the species level, and both BRDL and BRDM showed increased alpha diversity compared to CONT at the general level. Overall, this work illustrated nasopharyngeal microbiota showed relatively few differences among BRD cases that lived or died compared to animals without BRD.

Antimicrobial and Biological Methods to Control Liver Abscesses.

Antimicrobial products are approved for the control of liver abscesses with varying amounts of data. When compared to negative controls, tylosin has the most data to support a reduction in total (risk ratio 0.34) and severe A+ (risk ratio 0.31) liver abscesses. Due to the reduction in the use of antimicrobials, vaccination to control liver abscess prevalence is intriguing. However, available vaccines do not appear to be effective in controlling the prevalence of liver abscesses, especially when the disease prevalence is high.

A case study of adapting a health insurance decision intervention from trial into routine cancer care.

OBJECTIVE: This study adapted Improving Cancer Patients' Insurance Choices (I Can PIC), an intervention to help cancer patients navigate health insurance decisions and care costs. The original intervention improved knowledge and confidence making insurance decisions, however, users felt limited by choices provided in insurance markets. Using decision trees and frameworks to guide adaptations, we modified I Can PIC to focus on using rather than choosing health insurance. The COVID-19 pandemic introduced unforeseen obstacles, prompting changes to study protocols. As a result, we allowed users outside of the study to use I Can PIC (> 1050 guest users) to optimize public benefit. This paper describes the steps took to conduct the study, evaluating both the effectiveness of I Can PIC and the implementation process to improve its impact. RESULTS: Although I Can PIC users had higher knowledge and health insurance literacy compared to the control group, results were not statistically significant. This outcome may be associated with systems-level challenges as well as the number and demographic characteristics of participants. The publicly available tool can be a resource for those navigating insurance and care costs, and researchers can use this flexible approach to intervention delivery and testing as future health emergencies arise.

COVID-19 Countermeasures: An Algorithm to Stay Unlocked.

We describe a visual algorithm to help prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contagion as well as manage COVID-19 disease according to categories of clinical severity. The algorithm is timely, with multiple countries worldwide declaring repeat surges in SARS-CoV-2 infections following the easing of lockdown measures. Its flowchart assimilates key effective interventions in a visual manner that will assist healthcare workers to manage COVID-19 disease algorithmically, and policymakers to suppress further SARS-CoV-2 waves. Importantly, we include the innovative use of topical p-menthane-3,8-diol spray by the British Army for COVID-19 Support Force personnel, which in light of its coronavirucidal properties, deserves wider dissemination. This algorithm has the potential to be updated as numerous studies are concluded globally.

The oral microbiome, pancreatic cancer and human diversity in the age of precision medicine.

Pancreatic cancer is a deadly disease with limited diagnostic and treatment options. Not all populations are affected equally, as disparities exist in pancreatic cancer prevalence, treatment and outcomes. Recently, next-generation sequencing has facilitated a more comprehensive analysis of the human oral microbiome creating opportunity for its application in precision medicine. Oral microbial shifts occur in patients with pancreatic cancer, which may be appreciated years prior to their diagnosis. In addition, pathogenic bacteria common in the oral cavity have been found within pancreatic tumors. Despite these findings, much remains unknown about how or why the oral microbiome differs in patients with pancreatic cancer. As individuals develop, their oral microbiome reflects both their genotype and environmental influences. Genetics, race/ethnicity, smoking, socioeconomics and age affect the composition of the oral microbiota, which may ultimately play a role in pancreatic carcinogenesis. Multiple mechanisms have been proposed to explain the oral dysbiosis found in patients with pancreatic cancer though they have yet to be confirmed. With a better understanding of the interplay between the oral microbiome and pancreatic cancer, improved diagnostic and therapeutic approaches may be implemented to reduce healthcare disparities. Video Abstract.

A pilot study to troubleshoot quality control metrics when assessing circulating miRNA expression data reproducibility across study sites.

BACKGROUND: Given the growing interest in using microRNAs (miRNAs) as biomarkers of early disease, establishment of robust protocols and platforms for miRNA quantification in biological fluids is critical. OBJECTIVE: The goal of this multi-center pilot study was to evaluate the reproducibility of NanoString nCounter™ technology when analyzing the abundance of miRNAs in plasma and cystic fluid from patients with pancreatic lesions. METHODS: Using sample triplicates analyzed across three study sites, we assessed potential sources of variability (RNA isolation, sample processing/ligation, hybridization, and lot-to-lot variability) that may contribute to suboptimal reproducibility of miRNA abundance when using nCounter™, and evaluated expression of positive and negative controls, housekeeping genes, spike-in genes, and miRNAs. RESULTS: Positive controls showed a high correlation across samples from each site (median correlation coefficient, r> 0.9). Most negative control probes had expression levels below background. Housekeeping and spike-in genes each showed a similar distribution of expression and comparable pairwise correlation coefficients of replicate samples across sites. A total of 804 miRNAs showed a similar distribution of pairwise correlation coefficients between replicate samples (p= 0.93). After normalization and selecting miRNAs with expression levels above zero in 80% of samples, 55 miRNAs were identified; heatmap and principal component analysis revealed similar expression patterns and clustering in replicate samples. CONCLUSIONS: Findings from this pilot investigation suggest the nCounter platform can yield reproducible results across study sites. This study underscores the importance of implementing quality control procedures when designing multi-center evaluations of miRNA abundance.

Behavioral and performance response associated with administration of intravenous flunixin meglumine or oral meloxicam immediately prior to surgical castration in bull calves.

The objective of this study was to determine the effects of flunixin meglumine or meloxicam on behavioral response and performance characteristics associated with surgical castration in crossbred bulls. Intact male Bos taurus calves (n = 252; averaging 176 kg) were randomly allocated into one of three treatment groups within pen: control (CON), flunixin meglumine (FLU; 2.2 mg/kg intravenous injection), or meloxicam (MEL; 2.0 mg/kg per os). The individual animal was the experimental unit. Calves were individually weighed on days 0 and 14 of the trial to evaluate performance outcomes. On study day 0, treatments were administered, according to their random allocation, immediately prior to surgical castration using the Henderson tool method. Visual analog scale (VAS) assessment and categorical attitude score (CAS) were collected on days -1, 0 (6 h post-castration), 1, 2, 3, and 4 in the study. The VAS was assigned using a 100 mm horizontal line with "normal" labeled at one end of the line and "moribund" at the other end of the horizontal line. The masked observer assigned a mark on the horizontal line based upon the observed severity of pain exhibited by that individual animal. The CAS was assigned by the same observer using five different categories with a score of 0 being "normal". Average daily gain tended (P = 0.09) to be associated with the treatment group, and MEL had a greater (P = 0.04) average daily gain through day 14 compared with CON. A significant (P < 0.01) treatment by day interaction was indicated for VAS score, and MEL had lower VAS scores on days 0, 1, 2, and 3 post-castration compared with CON; FLU had lower VAS scores on days 0 and 1 compared with CON. A significant treatment by day interaction was not present (P = 0.25) for CAS. The FLU had lesser percent CAS ≥1 (17.5%; P = 0.05) compared with CON (29.4%); MEL has lesser percent CAS ≥1 observations (14.9%; P = 0.01) compared with CON. The median VAS increased as CAS was more severe. Results indicated MEL and FLU calves temporally improved behavioral responses following surgical castration with positive numerical trends for a 14 d average daily gain (ADG). The VAS system appeared to be an effective method of subjective evaluation of pain in beef calves in this study. Route of administration, duration of therapy, and low relative cost make oral meloxicam a reasonable analgesic treatment in calves when administered at the time of surgical castration.

Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses.

Brain kappa-opioid receptors (KORs) are implicated in the pathophysiology of depressive and anxiety disorders, stimulating interest in the therapeutic potential of KOR antagonists. Research on KOR function has tended to focus on KOR-expressing neurons and pathways such as the mesocorticolimbic dopamine system. However, KORs are also expressed on non-neuronal cells including microglia, the resident immune cells in the brain. The effects of KOR antagonists on microglia are not understood despite the potential contributions of these cells to overall responsiveness to this class of drugs. Previous work in vitro suggests that KOR activation suppresses proinflammatory signaling mediated by immune cells including microglia. Here, we examined how KOR antagonism affects microglia function in vivo, together with its effects on physiological and behavioral responses to an immune challenge. Pretreatment with the prototypical KOR antagonist JDTic potentiates levels of proinflammatory cytokines (IL-1ß, IL-6) in blood following administration of lipopolysaccharide (LPS), an immune-activating agent, without triggering effects on its own. Using magnetic-activated cell sorting (MACs), we found that KOR antagonism potentiates LPS-induced cytokine expression within microglia. This effect is accompanied by potentiation of LPS-induced hyperthermia, although reductions in body weight and locomotion were not affected. Histological analyses confirm that LPS produces visible changes in microglia morphology consistent with activation, but this effect is not altered by KOR antagonism. Considering that inflammation is increasingly implicated in depressive and anxiety disorders, these findings raise the possibility that KOR antagonist actions on microglia may detract from actions on neurons that contribute to their therapeutic potential.