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Background: Bibliometric analysis is a useful tool for measuring the scholarly impact of a topic and its more and less heavily studied aspects. The purpose of this study is to use bibliometric analysis to comprehensively analyze the 50 articles with the highest citation indices in studies evaluating the treatment and outcomes of massive rotator cuff tears (mRCTs). Methods: This cross-sectional study identified articles within the Scopus database published through December 2022. Keywords used were “massive rotator cuff tear.” Articles were sorted in chronological order. The year published and number of citations were recorded. A citation index (CI) was calculated for each article by dividing the number of citations by number of years published [1 citation/1 year published (2021) = CI of 1]. Of these, the 50 articles with the highest CIs were carried forward for evaluation. Frequencies and distributions were assessed for data of each variable collected. Results: These search methods produced 625 articles regarding mRCT research (ranging from January 1986 to December 2022). Four of the top 10 most impactful articles were published in the 2010s. The level of evidence (LOE) published with the greatest frequency was level of evidence 4 (41%). The journal Arthroscopy published the highest number within the top 50 (26%) followed by the Journal of Bone and Joint Surgery and the American Journal of Sports Medicine (20% each). Clinical studies composed 88% of the top 50. Case series (38%) predominated, while systematic reviews (20%) and randomized control trials (8%) were less prevalent. The majority of studies concentrated on the clinical outcomes of certain interventions (62%), mainly comparing multiple interventions. Conclusion: Despite the relatively high prevalence of mRCTs (40% of all tears), this topic comprises only a small proportion of all rotator cuff research. This analysis has identified gaps within and limitations of the findings concerning mRCTs for researchers to propose research questions targeting understudied topics and influence the future treatment and outcomes of this clinically difficult diagnosis.

Background: With the increasing amount of elective spine fusion patients presenting with cardiac disease and congestive heart failure, it is becoming difficult to assess when it is safe to proceed with surgery. Assessing the severity of heart failure (HF) through ejection fraction may provide insight into patients' short- and long-term risks. Purpose: The purpose of this study was to assess the severity of HF on perioperative outcomes of spine fusion surgery patients. Study Design/Setting: This was a retrospective cohort study of the PearlDiver database. Patient Sample: We enrolled 670,526 patients undergoing spine fusion surgery. Outcome Measures: Thirty-day and 90-day complication rates, discharge destination, length of stay (LOS), physician reimbursement, and hospital costs. Methods: Patients undergoing elective spine fusion surgery were isolated and stratified by preoperative HF with preserved ejection fraction (P-EF) or reduced ejection fraction (R-EF) (International Classification of Diseases-9: 428.32 [chronic diastolic HF] and 428.22 [chronic systolic HF]). Means comparison tests (Chi-squared and independent samples t-tests, as appropriate) compared differences in demographics, diagnoses, comorbidities, procedural characteristics, LOS, 30-day and 90-day complication outcomes, and total hospital charges between those diagnosed with P-EF and those not R-EF. Binary logistic regression assessed the odds of complication associated with HF, controlling for levels fused (odds ratio [OR] [95% confidence interval]). Statistical significance was set at P < 0.05. Results: Totally 670,526 elective spine fusion patients were included. Four thousand and seventy-seven were diagnosed with P-EF and 2758 R-EF. Overall, P-EF patients presented with higher rates of morbid obesity, chronic kidney disease, chronic obstructive pulmonary disease, diabetes mellitus, and hypertension (all P < 0.001). In relation to No-HF, P-EF patients had higher rates of 30-day major complications including pulmonary embolism, pneumonia, cerebrovascular accident (CVA), myocardial infarctions (MI), sepsis, and death (all P < 0.001). Furthermore, P-EF was associated significantly with increased odds of pneumonia (OR: 2.07 [1.64–2.56], P < 0.001) and sepsis (OR: 2.09 [1.62–2.66], P < 0.001). Relative to No-HF, R-EF was associated with significantly higher odds of MI (OR: 3.66 [2.34–5.47]), CVA (OR: 2.70 [1.67–4.15]), and pneumonia (OR: 1.85 [1.40–2.40]) (all P < 0.001) postoperative within 30 days. Adjusting for prior history of MI, CAD, and the presence of a pacemaker R-EF was a significant predictor of an MI 30 days postoperatively (OR: 2.2 [1.14–4.32], P = 0.021). Further adjusting for history of CABG or stent placement, R-EF was associated with higher odds of CVA (OR: 2.11 [1.09–4.19], P = 0.028) and MI (OR: 2.27 [1.20–4.43], P = 0.013). Conclusions: When evaluating the severity of HF before spine surgery, R-EF was associated with a higher risk of major complications, especially the occurrence of a myocardial infarction 30 days postoperatively. During preoperative risk assessment, congestive HF should be considered thoroughly when thinking of postoperative outcomes with emphasis on R-EF.

Abstract Therapeutic ultrasound can be used to trigger the on-demand release of chemotherapeutic drugs from gold nanoparticles (GNPs). In the previous work, our group achieved doxorubicin (DOX) release from the surface of GNPS under low-intensity pulsed ultrasound (LIPUS) exposure. However, the specific release kinetics of ultrasound-triggered DOX release from GNPs is not known. Here, we present a release kinetics study of DOX from GNPs under ultrasound exposure for the first time. A novel dialysis membrane setup was designed to quantify DOX release from LIPUS-activated GNPs at 37.0 °C and 43.4 °C (hyperthermia temperature range). Contributions of thermal and non-thermal mechanisms of LIPUS-triggered DOX release were also quantified. Non-thermal mechanisms accounted for 40 ± 7% and 34 ± 5% of DOX release for 37.0 °C and 43.4 °C trials, respectively. DOX release under LIPUS exposure was found to follow Korsmeyer–Peppas (K–P) kinetics, suggesting a shift from a Fickian (static) to a non-Fickian (dynamic) release profile with the addition of non-thermal interactions. DOX release was attributed to an anomalous diffusion release mechanism from the GNP surface. A finite element model was also developed to quantify the acoustic radiation force, believed to be the driving force of non-thermal DOX release inside the dialysis bag.

Abstract Age-related disease may be mediated by low levels of chronic inflammation (“inflammaging”). Recent work suggests that gut microbes can contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer’s disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation remains unclear. To investigate whether greater gut inflammation is associated with advanced age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity. Multiple regression with maximum likelihood estimation and Satorra–Bentler corrections were used to test relationships between fecal calprotectin and clinical diagnosis, participant age, cerebrospinal fluid biomarkers of AD pathology, amyloid burden measured using 11C-Pittsburgh compound B positron emission tomography (PiB PET) imaging, and performance on cognitive tests measuring executive function and verbal learning and recall. Calprotectin levels were elevated in advanced age and were higher in participants diagnosed with amyloid-confirmed AD dementia. Additionally, among individuals with AD dementia, higher calprotectin was associated with greater amyloid burden as measured with PiB PET. Exploratory analyses indicated that calprotectin levels were also associated with cerebrospinal fluid markers of AD, and with lower verbal memory function even among cognitively unimpaired participants. Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD.

Staphylococcus aureus (S. aureus) is a prominent Gram-positive bacterial pathogen that expresses numerous cytotoxins known to target human polymorphonuclear leukocytes (PMNs or neutrophils). These include leukocidin G/H (LukGH, also known as LukAB), the Panton–Valentine leukocidin (PVL), γ-hemolysin A/B (HlgAB), γ-hemolysin B/C (HlgBC), leukocidin E/D (LukED), α-hemolysin (Hla), and the phenol-soluble modulin-α peptides (PSMα). However, the relative contribution of each of these cytotoxins in causing human PMN lysis is not clear. In this study, we used a library of cytotoxin deletion mutants in the clinically relevant methicillin-resistant S. aureus (MRSA) isolate LAC (strain ST8:USA300) to determine the relative importance of each for causing human PMN lysis upon exposure to extracellular components as well as following phagocytosis. Using flow cytometry to examine plasma membrane permeability and assays quantifying lactose dehydrogenase release, we found that PVL was the dominant extracellular factor causing human PMN lysis produced by USA300. In contrast, LukGH was the most important cytotoxin causing human PMN lysis immediately following phagocytosis with contributions from the other bicomponent leukocidins only observed at later time points. These results not only clarify the relative importance of different USA300 cytotoxins for causing human PMN destruction but also demonstrate how two apparently redundant virulence factors play distinctive roles in promoting S. aureus pathogenesis.

Abstract Background Multiple forms of electrical stimulation (ES) potentially offer widely varying clinical benefits. Diminished function commonly associated with acute and chronic pain lessens productivity and increases medical costs. This review aims to compare the relative effects of various forms of ES on functional and pain outcomes. Methods A comprehensive literature search focused on studies of commonly marketed forms of ES used for treatment of pain and improvement of function. Peer-reviewed manuscripts were categorized as “Important” (systematic review or meta-analysis, randomized controlled trial, observational cohort study) and “Minor” (retrospective case series, case report, opinion review) for each identified form of ES. Results and Discussion Varying forms of ES have markedly different technical parameters, applications, and indications, based on clinically meaningful impact on pain perception, function improvement, and medication reduction. Despite being around for decades, there is limited quality evidence for most forms of ES, although there are several notable exceptions for treatment of specific indications. Neuromuscular electrical stimulation (NMES) has well-demonstrated beneficial effects for rehabilitation of selective spinal cord injured (SCI), post-stroke, and debilitated inpatients. Functional electrical stimulation (FES) has similarly shown effectiveness in rehabilitation of some stroke, SCI, and foot drop outpatients. H-Wave® device stimulation (HWDS) has moderate supportive evidence for treatment of acute and refractory chronic pain, consistently demonstrating improvements in function and pain measures across diverse populations. Interestingly, transcutaneous electrical nerve stimulation (TENS), the most widely used form of ES, demonstrated insignificant or very low levels of pain and functional improvement. Conclusion Ten of 13 reviewed forms of ES have only limited quality evidence for clinically significant reduction of pain or improvement of function across different patient populations. NMES and FES have reasonably demonstrated effectiveness, albeit for specific clinical rehabilitation indications. HWDS was associated with the most clinically significant outcomes, in terms of functional improvement combined with reduction of pain and medication use. More rigorous long-term clinical trials are needed to further validate appropriate use and specific indications for most forms of ES. Level of Evidence II.

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques followed by intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. An unrestrained immune response by microglia, the resident cells of the central nervous system (CNS), leads to neuroinflammation which can amplify AD pathology. AD pathology is also driven by metabolic dysfunction with strong correlations between dementia and metabolic disorders such as diabetes, hypercholesterolemia, and hypertriglyceridemia. Since elevated cholesterol and triglyceride levels appear to be a major risk factor for developing AD, we investigated the lipid metabolism transcriptome in an AD versus non-AD state using RNA-sequencing (RNA-seq) and microarray datasets from N9 cells and murine microglia. We identified 52 differentially expressed genes (DEG) linked to lipid metabolism in LPS-stimulated N9 microglia versus unstimulated control cells using RNA-seq, 86 lipid metabolism DEG in 5XFAD versus wild-type mice by microarray, with 16 DEG common between both datasets. Functional enrichment and network analyses identified several biological processes and molecular functions, such as cholesterol homeostasis, insulin signaling, and triglyceride metabolism. Furthermore, therapeutic drugs targeting lipid metabolism DEG found in our study were identified. Focusing on drugs that target genes associated with lipid metabolism and neuroinflammation could provide new targets for AD drug development.

Abstract Background Persons with HIV (PWH) can now achieve a near-normal life expectancy due to antiretroviral therapy (ART). Despite widespread availability of ART in the United States (US), many of the country’s approximate 1.1 million PWH are not achieving viral suppression due to poor ART adherence. Viral suppression rates are particularly low in Alabama (AL, 62%) and New York City (NYC, 67%). There is mixed evidence on the efficacy of community health workers (CHW) and mHealth interventions for improving ART adherence and viral suppression in PWH thus, we sought to combine these interventions and test the efficacy for improving health outcomes in PWH. Methods The CHAMPS study is a two-arm randomized controlled trial among 300 PWH with suboptimal primary care appointment adherence (n = 150 in AL and 150 in NYC) over the course of 12 months. Participants are randomly assigned to CHAMPS (intervention) or a standard-of-care (control) arm. Participants in the intervention arm are given a CleverCap pill bottle that syncs to the WiseApp to track medication adherence, reminds users to take their medication at a set time, and enables communication with CHW. All participants complete baseline, 6-month, and 12-month follow-up visits where surveys are administered and, CD4 and HIV-1 viral load are obtained through blood draw. Discussion Maintaining ART adherence has significant implications in HIV management and transmission. mHealth technologies have been shown to optimize the provision of health services, produce positive changes in health behavior, and significantly improve health outcomes. CHW interventions also provide personal support to PWH. The combination of these strategies may provide the necessary intensity to increase ART adherence and clinic attendance among PWH at highest risk for low engagement. Delivering care remotely enables CHW to contact, assess, and support numerous participants throughout the day, reducing burden on CHW and potentially improving intervention durability for PWH. The adoption of the WiseApp coupled with community health worker sessions in the CHAMPS study has the potential to improve HIV health outcomes, and will add to the growing knowledge of mHealth and CHW efforts to improve PWH medication adherence and viral suppression. Trial registration This trial was registered with Clinicaltrials.gov (NCT04562649) on 9/24/20.

Important recent advances in the cognitive neuroscience of language have been made using functional localizers to demarcate language-selective regions in individual brains. Although single-subject localizers offer insights that are unavailable in classic group analyses, they require additional scan time that imposes costs on investigators and participants. In particular, the unique practical challenges of scanning children and other special populations has led to less adoption of localizers for neuroimaging research with these theoretically and clinically important groups. Here, we examined how measurements of the spatial extent and functional response profiles of language regions are affected by the duration of an auditory language localizer. We compared how parametrically smaller amounts of data collected from one scanning session affected (i) consistency of group-level whole-brain parcellations, (ii) functional selectivity of subject-level activation in individually defined functional regions of interest (fROIs), (iii) sensitivity and specificity of subject-level whole-brain and fROI activation, and (iv) test-retest reliability of subject-level whole-brain and fROI activation. For many of these metrics, the localizer duration could be reduced by 50-75% while preserving the stability and reliability of both the spatial extent and functional response profiles of language areas. These results indicate that, for most measures relevant to cognitive neuroimaging studies, the brain's language network can be localized just as effectively with 3.5 min of scan time as it can with 12 min. Minimizing the time required to reliably localize the brain's language network allows more effective localizer use in situations where each minute of scan time is particularly precious.

Introduction:. Orthopaedic surgery is one of the least diverse fields in medicine. In recent decades, there has been a concerted effort to increase diversity, equity, and inclusion (DEI) in the specialty, in addition to the institution of several organizations to establish the pipeline and facilitate underrepresented minority students into orthopaedic surgery. The aim of this study was to examine trends in orthopaedic surgery DEI research. Methods:. A search of DEI articles was conducted in orthopaedic surgery using PubMed, MEDLINE, EMBASE, Scopus, Cumulative Index to Nursing and Allied Health Literature, and Education Resources Information Center. The year of publication, article topic of focus, sex of the primary author, publishing journal, citation index, and primary contributing institution were recorded for each article. Sex of the primary author was predicted by the authors using an online image search of the author and institution. Articles were excluded if the research was conducted outside of the United States or if they were not specific to orthopaedic surgery. Results:. A total of 143 articles met the inclusion criteria. A total of 52.4% of authors (n = 75) were women and 44.1% (n = 63) were men. A total of 42.7% of the articles were written about sex (n = 61), 39.9% about race/ethnicity and sex (n = 57), and 11.9% about race/ethnicity (n = 17). A total of 10 articles were affiliated with Washington University in St. Louis while 51 other institutions wrote the remaining articles, with none having more than 4. Information could not be confirmed for 5 articles. In 2018, 5 articles were published, followed by 17 in 2019, 25 in 2020, 34 in 2021, and 30 in 2022. Conclusion:. DEI research in orthopaedic surgery is a relatively new venture within the specialty and has room to grow, specifically in the examination of race/ethnicity and inclusion strategies. Leading journals and academic institutions in orthopaedic surgery should incentivize productivity and authorship in DEI research. Level of Evidence:. III.

Controlled, localized, and timely activation of nanosized drug delivery systems (NSDDSs), using an external stimulus such as therapeutic ultrasound (TUS), can improve the efficacy of cancer treatments compared to either conventional chemotherapy methods or passive NSDDSs alone. Specifically, TUS induces thermal and mechanical effects that trigger drug release from NSDDSs and overcomes drug delivery barriers in tumor microenvironments to allow nanoparticle drug carriers to penetrate more deeply into tumor tissue while minimizing side effects. This review highlights recent advancements, contemplates future prospects, and addresses challenges in using TUS-mediated NSDDSs for cancer treatment, encompassing preclinical and clinical applications.

Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated up-regulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus, with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.

Background: Chiari malformation (CM) is a cluster of related developmental anomalies of the posterior fossa ranging from asymptomatic to fatal. Cranial and spinal decompression can help alleviate symptoms of increased cerebrospinal fluid pressure and correct spinal deformity. As surgical intervention for CM increases in frequency, understanding predictors of reoperation may help optimize neurosurgical planning. Materials and Methods: This was a retrospective analysis of the prospectively collected Healthcare Cost and Utilization Project's California State Inpatient Database years 2004–2011. Chiari malformation Types 1–4 (queried with ICD-9 CM codes) with associated spinal pathologies undergoing stand-alone spinal decompression (queried with ICD-9 CM procedure codes) were included. Cranial decompressions were excluded. Results: One thousand four hundred and forty-six patients (29.28 years, 55.6% of females) were included. Fifty-eight patients (4.01%) required reoperation (67 reoperations). Patients aged 40–50 years had the most reoperations (11); however, patients aged 15–20 years had a significantly higher reoperation rate than all other groups (15.5% vs. 8.2%, P = 0.048). Female gender was significantly associated with reoperation (67.2% vs. 55.6%, P = 0.006). Medical comorbidities associated with reoperation included chronic lung disease (19% vs. 6.9%, P < 0.001), iron deficiency anemia (10.3% vs. 4.1%, P = 0.024), and renal failure (3.4% vs. 0.9%, P = 0.05). Associated significant cluster anomalies included spina bifida (48.3% vs. 34.8%, P = 0.035), tethered cord syndrome (6.9% vs. 2.1%, P = 0.015), syringomyelia (12.1% vs. 5.9%, P = 0.054), hydrocephalus (37.9% vs. 17.7%, P < 0.001), scoliosis (13.8% vs. 6.4%, P = 0.028), and ventricular septal defect (6.9% vs. 2.3%, P = 0.026). Conclusions: Multiple medical and CM-specific comorbidities were associated with reoperation. Addressing them, where possible, may aid in improving CM surgery outcomes.

Alzheimer’s disease (AD) is a progressive neurological disorder, and increasing evidence suggests AD pathology is driven by metabolic dysfunction in the brain. Zinc is the second most abundant trace element found in the human body and is required by all living organisms. Zinc is used extensively in many biological processes, and alterations in zinc levels are implicated in the pathogenesis of numerous diseases, including AD. Since small fluctuations in brain zinc levels appear to effect AD progression, we investigated the zinc-related transcriptional responses in an AD versus non-AD state using microarray and RNA-sequencing (RNA-seq) datasets from cultured cells, mice, and humans. We identified 582 zinc-related differentially expressed genes (DEG) in human dorsolateral prefrontal cortex samples of late-onset AD (LOAD) versus non-AD controls, 146 zinc-related DEG in 5XFAD versus wild-type mice, and 95 zinc-related DEG in lipopolysaccharide (LPS)-stimulated N9 microglia versus unstimulated control cells, with 19 zinc-related DEG common to all three datasets. Of the 19 common DEG, functional enrichment and network analyses identified several biological processes and molecular functions, such as mRNA destabilization and nucleic acid binding, which may be important in neuroinflammation and AD development. Furthermore, therapeutic drugs targeting zinc-related DEG in the human dataset were identified. Taken together, these data provide insights into zinc utilization for gene transcription during AD progression which may further our understanding of AD pathogenesis and could identify new targets for therapeutic strategies targeted towards AD.

Climate change represents an existential threat to many forest ecosystems because tree populations are often adapted to local climate means and variability. If tree populations cannot migrate or adapt, they risk becoming increasingly maladapted with climate change. This emerging mismatch underscores the need for climate adaptive management techniques, such as assisted migration of tree species, to help mitigate climate change impacts on forest ecosystems. Although biotic and abiotic factors are known to constrain tree establishment success, the extent to which they may determine the success of assisted migration plantings is poorly understood. Thus, defining the extent to which trees affect—and in turn are affected by local soil environments and microbial communities (i.e., plant-soil feedbacks; hereafter PSFs) remains important for guiding effective climate-adaptive forest management. Our objectives were to synthesize the current state of knowledge about the direction and magnitude of PSF effects on temperate tree species of eastern North America, and to identify key hypotheses important for guiding future research. To accomplish these goals, we conducted a meta-analysis of 26 peer-reviewed publications that addressed our criteria. Our compiled database included 61 tree species and was composed primarily of short-term greenhouse experiments that studied PSF effects by manipulating the soil biota in three ways: (1) soil was previously inoculated by a conspecific or heterospecific tree species (i.e., home vs. away), (2) soil was live or sterilized, or (3) soil was untreated or treated with fungicide. We found that PSF had significant effects on tree growth, with the direction and magnitude of PSF strongly dependent on tree mycorrhizal guild. Arbuscular mycorrhizal tree species grown in live or home soils grew 13–33% less than those in sterile or away soils, while ectomycorrhizal tree species grew 11–44% more in live or home than sterile or away soils. PSF effects were associated with several plant functional traits, including specific leaf area, tissue nitrogen, and specific root length. We provide suggestions on incorporating PSFs into assisted migration trials and outline key knowledge gaps for future research. Our synthesis of context-dependent effects of PSFs on tree performance will help inform management decisions involving assisted migration.

Abstract Background Alzheimer’s disease (AD) is a neurodegenerative disorder and is the most common cause of late-onset dementia. Microglia, the primary innate immune cells of the central nervous system (CNS), have a complex role in AD neuropathology. In the initial stages of AD, microglia play a role in limiting pathology by removing amyloid-β (Aβ) by phagocytosis. In contrast, microglia also release pro-inflammatory cytokines and chemokines to promote neuroinflammation and exacerbate AD neuropathology. Therefore, investigating microglial gene networks could identify new targets for therapeutic strategies for AD. Results We identified 465 differentially expressed genes (DEG) in 5XFAD versus wild-type mice by microarray, 354 DEG in lipopolysaccharide (LPS)-stimulated N9 microglia versus unstimulated control cells using RNA-sequencing (RNA-seq), with 32 DEG common between both datasets. Analyses of the 32 common DEG uncovered numerous molecular functions and pathways involved in Aβ phagocytosis and neuroinflammation associated with AD. Furthermore, multiplex ELISA confirmed the induction of several cytokines and chemokines in LPS-stimulated microglia. Conclusions In summary, AD triggered multiple signaling pathways that regulate numerous genes in microglia, contributing to Aβ phagocytosis and neuroinflammation. Overall, these data identified several regulatory factors and biomarkers in microglia that could be useful in further understanding AD neuropathology.

Individuals with autism spectrum disorder (ASD) commonly display speech processing abnormalities. Binding of acoustic features of speech distributed across different frequencies into coherent speech objects is fundamental in speech perception. Here, we tested the hypothesis that the cortical processing of bottom-up acoustic cues for speech binding may be anomalous in ASD. We recorded magnetoencephalography while ASD children (ages 7–17) and typically developing peers heard sentences of sine-wave speech (SWS) and modulated SWS (MSS) where binding cues were restored through increased temporal coherence of the acoustic components and the introduction of harmonicity. The ASD group showed increased long-range feedforward functional connectivity from left auditory to parietal cortex with concurrent decreased local functional connectivity within the parietal region during MSS relative to SWS. As the parietal region has been implicated in auditory object binding, our findings support our hypothesis of atypical bottom-up speech binding in ASD. Furthermore, the long-range functional connectivity correlated with behaviorally measured auditory processing abnormalities, confirming the relevance of these atypical cortical signatures to the ASD phenotype. Lastly, the group difference in the local functional connectivity was driven by the youngest participants, suggesting that impaired speech binding in ASD might be ameliorated upon entering adolescence.

Nonword repetition, a common clinical measure of phonological working memory, involves component processes of speech perception, working memory, and speech production. Autistic children often show behavioral challenges in nonword repetition, as do many individuals with communication disorders. It is unknown which subprocesses of phonological working memory are vulnerable in autistic individuals, and whether the same brain processes underlie the transdiagnostic difficulty with nonword repetition. We used functional magnetic resonance imaging (fMRI) to investigate the brain bases for nonword repetition challenges in autism. We compared activation during nonword repetition in functional brain networks subserving speech perception, working memory, and speech production between neurotypical and autistic children. Autistic children performed worse than neurotypical children on nonword repetition and had reduced activation in response to increasing phonological working memory load in the supplementary motor area. Multivoxel pattern analysis within the speech production network classified shorter vs longer nonword-repetition trials less accurately for autistic than neurotypical children. These speech production motor-specific differences were not observed in a group of children with reading disability who had similarly reduced nonword repetition behavior. These findings suggest that atypical function in speech production brain regions may contribute to nonword repetition difficulties in autism.

Childhood socioeconomic status (SES) strongly predicts disparities in reading development, yet it is unknown whether early environments also moderate the cognitive and neurobiological bases of reading disorders (RD) such as dyslexia, the most prevalent learning disability. SES-diverse 6–9-year-old children (n = 155, half with RD) completed behavioral and functional magnetic resonance imaging (fMRI) tasks engaging phonological and orthographic processing, which revealed corresponding double-dissociations in neurocognitive deficits. At the higher end of the SES spectrum, RD was most strongly explained by differences in phonological skill and corresponding activation in left inferior frontal and temporoparietal regions during phonological processing—widely considered the “core deficit” of RD. However, at the lower end of the SES spectrum, RD was most strongly explained by differences in rapid naming skills and corresponding activation in left temporoparietal and fusiform regions during orthographic processing. Findings indicate that children’s early environments systematically moderate the neurocognitive systems underlying RD, which has implications for assessment and treatment approaches to reduce SES disparities in RD outcomes. Further, results suggest that reliance on high-SES convenience samples may mask critical heterogeneity in the foundations of both typical and disordered reading development.

There is a growing need to understand the role of non-cognitive factors in relation to university students’ academic performance and successful adaptation to university life. This study investigated the relationship between the non-cognitive factor “resilience” and student success (academic performance, turnover intentions, brain-body optimisation) among South African university students. This cross-sectional correlational study analysed data from 360 first-year students. Self-report data were collected using the Neurozone Assessment, comprising two subscales: the Brain Performance Diagnostic and the Resilience Index. Turnover intentions were assessed using the Neurozone Assessment, and students’ academic marks were obtained via the university’s management information system. Correlational analyses revealed significant positive relationships between the Stress Mastery and Positive Affect components of resilience and academic performance, a significant negative relationship between the Positive Affect component of resilience and turnover intentions, as well as significant positive relationships between brain-body optimisation and all three components of resilience (Stress Mastery, Positive Affect, and Early-Life Stability). Through regression analyses, we identified the behavioural predictors that underlie resilience and outline a framework for implementing behavioural interventions to enhance resilience and increase student success. Resilience is an important non-cognitive determinant of student success in first-year students.

Abstract Background Patterns of multi-locus differentiation (i.e., genomic clines) often extend broadly across hybrid zones and their quantification can help diagnose how species boundaries are shaped by adaptive processes, both intrinsic and extrinsic. In this sense, the transitioning of loci across admixed individuals can be contrasted as a function of the genome-wide trend, in turn allowing an expansion of clinal theory across a much wider array of biodiversity. However, computational tools that serve to interpret and consequently visualize ‘genomic clines’ are limited, and users must often write custom, relatively complex code to do so. Results Here, we introduce the ClineHelpR R-package for visualizing genomic clines and detecting outlier loci using output generated by two popular software packages, bgc and Introgress. ClineHelpR bundles both input generation (i.e., filtering datasets and creating specialized file formats) and output processing (e.g., MCMC thinning and burn-in) with functions that directly facilitate interpretation and hypothesis testing. Tools are also provided for post-hoc analyses that interface with external packages such as ENMeval and RIdeogram. Conclusions Our package increases the reproducibility and accessibility of genomic cline methods, thus allowing an expanded user base and promoting these methods as mechanisms to address diverse evolutionary questions in both model and non-model organisms. Furthermore, the ClineHelpR extended functionality can evaluate genomic clines in the context of spatial and environmental features, allowing users to explore underlying processes potentially contributing to the observed patterns and helping facilitate effective conservation management strategies.

Abstract Approximately 100 years ago, unregulated harvest nearly eliminated white‐tailed deer (Odocoileus virginianus) from eastern North America, which subsequently served to catalyze wildlife management as a national priority. An extensive stock‐replenishment effort soon followed, with deer broadly translocated among states as a means of re‐establishment. However, an unintended consequence was that natural patterns of gene flow became obscured and pretranslocation signatures of population structure were replaced. We applied cutting‐edge molecular and biogeographic tools to disentangle genetic signatures of historical management from those reflecting spatially heterogeneous dispersal by evaluating 35,099 single nucleotide polymorphisms (SNPs) derived via reduced‐representation genomic sequencing from 1143 deer sampled statewide in Arkansas. We then employed Simpson's diversity index to summarize ancestry assignments and visualize spatial genetic transitions. Using sub‐sampled transects across these transitions, we tested clinal patterns across loci against theoretical expectations of their response under scenarios of re‐colonization and restricted dispersal. Two salient results emerged: (A) Genetic signatures from historic translocations are demonstrably apparent; and (B) Geographic filters (major rivers; urban centers; highways) now act as inflection points for the distribution of this contemporary ancestry. These results yielded a statewide assessment of contemporary population structure in deer as driven by historic translocations as well as ongoing processes. In addition, the analytical framework employed herein to effectively decipher extant/historic drivers of deer distribution in Arkansas is also applicable for other biodiversity elements with similarly complex demographic histories.

The neural representation of a repeated stimulus is the standard against which a deviant stimulus is measured in the brain, giving rise to the well-known mismatch response. It has been suggested that individuals with dyslexia have poor implicit memory for recently repeated stimuli, such as the train of standards in an oddball paradigm. Here, we examined how the neural representation of a standard emerges over repetitions, asking whether there is less sensitivity to repetition and/or less accrual of “standardness” over successive repetitions in dyslexia. We recorded magnetoencephalography (MEG) as adults with and without dyslexia were passively exposed to speech syllables in a roving-oddball design. We performed time-resolved multivariate decoding of the MEG sensor data to identify the neural signature of standard vs. deviant trials, independent of stimulus differences. This “multivariate mismatch” was equally robust and had a similar time course in the two groups. In both groups, standards generated by as few as two repetitions were distinct from deviants, indicating normal sensitivity to repetition in dyslexia. However, only in the control group did standards become increasingly different from deviants with repetition. These results suggest that many of the mechanisms that give rise to neural adaptation as well as mismatch responses are intact in dyslexia, with the possible exception of a putatively predictive mechanism that successively integrates recent sensory information into feedforward processing.

Rodents have been the dominant animal models in neurobiology and neurological disease research over the past 60 years. The prevalent use of rats and mice in neuroscience research has been driven by several key attributes including their organ physiology being more similar to humans, the availability of a broad variety of behavioral tests and genetic tools, and widely accessible reagents. However, despite the many advances in understanding neurobiology that have been achieved using rodent models, there remain key limitations in the questions that can be addressed in these and other mammalian models. In particular, in vivo imaging in mammals at the cell-resolution level remains technically difficult and demands large investments in time and cost. The simpler nervous systems of many non-mammalian models allow for precise mapping of circuits and even the whole brain with impressive subcellular resolution. The types of non-mammalian neuroscience models available spans vertebrates and non-vertebrates, so that an appropriate model for most cell biological questions in neurodegenerative disease likely exists. A push to diversify the models used in neuroscience research could help address current gaps in knowledge, complement existing rodent-based bodies of work, and bring new insight into our understanding of human disease. Moreover, there are inherent aspects of many non-mammalian models such as lifespan and tissue transparency that can make them specifically advantageous for neuroscience studies. Crispr/Cas9 gene editing and decreased cost of genome sequencing combined with advances in optical microscopy enhances the utility of new animal models to address specific questions. This review seeks to synthesize current knowledge of established and emerging non-mammalian model organisms with advances in cellular-resolution in vivo imaging techniques to suggest new approaches to understand neurodegeneration and neurobiological processes. We will summarize current tools and in vivo imaging approaches at the single cell scale that could help lead to increased consideration of non-mammalian models in neuroscience research.

Abstract Alzheimer’s disease (AD) is a progressive, late-onset dementia with no effective treatment available. Recent studies suggest that AD pathology is driven by age-related changes in metabolism. Alterations in metabolism, such as placing patients on a ketogenic diet, can alter cognition by an unknown mechanism. One of the ketone bodies produced as a result of ketogenesis, β-hydroxybutyrate (BHB), is known to inhibit NLRP3 inflammasome activation. Therefore, we tested if BHB inhibition of the NLRP3 inflammasome reduces overall AD pathology in the 5XFAD mouse model of AD. Here, we find BHB levels are lower in red blood cells and brain parenchyma of AD patients when compared with non-AD controls. Furthermore, exogenous BHB administration reduced plaque formation, microgliosis, apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) speck formation, and caspase-1 activation in the 5XFAD mouse model of AD. Taken together, our findings demonstrate that BHB reduces AD pathology by inhibiting NLRP3 inflammasome activation. Additionally, our data suggest dietary or pharmacological approaches to increase BHB levels as promising therapeutic strategies for AD.

Abstract Throughout the world, numerous tree species are reported to be in decline, either due to increased mortality of established trees or reduced recruitment. The situation appears especially acute for oaks, which are dominant features of many landscapes in the northern hemisphere. Although numerous factors have been hypothesized to explain reductions in tree performance, vertebrate herbivores and granivores may serve as important drivers of these changes. Here, using data from 8‐ and 14‐year‐old exclosure experiments, we evaluated the individual and interactive effects of large and small mammalian herbivores on the performance of three widespread oak species in California—coast live oak (Quercus agrifolia), California black oak (Q. kelloggii), and Oregon white oak (Q. garryana). Although impacts varied somewhat by species and experiment, herbivory by black‐tailed deer (Odocoileus hemionus columbianus) reduced the height and survival of juvenile coast live oaks and altered their architecture, as well as reduced the abundance of black oak seedlings, the richness of woody species and the cover of nonoak woody species. Small mammals (Microtus californicus and Peromyscus maniculatus) had even more widespread effects, reducing the abundance of black oak seedlings and the height and cover of all three oak species. We also detected numerous interactions between small mammals and deer, with one herbivore having positive or negative effects on oak abundance and cover when the other herbivore was either present or absent. For example, deer often had negative effects on seedling abundance only when, or even more so when, small mammals were present. In summary, mammalian consumers play crucial roles in limiting oak recruitment by reducing seedling abundance, maintaining trees in stunted states, and preventing them from reaching sapling stages and becoming reproductive. Interactions between large and small mammals can also alter the intensity and direction of their effects on trees.

Abstract The delimitation of species boundaries, particularly those obscured by reticulation, is a critical step in contemporary biodiversity assessment. It is especially relevant for conservation and management of indigenous fishes in western North America, represented herein by two species with dissimilar life histories codistributed in the highly modified Colorado River (i.e., flannelmouth sucker, Catostomus latipinnis; bluehead sucker, C. (Pantosteus) discobolus). To quantify phylogenomic patterns and examine proposed taxonomic revisions, we first employed double‐digest restriction site‐associated DNA sequencing (ddRAD), yielding 39,755 unlinked SNPs across 139 samples. These were subsequently evaluated with multiple analytical approaches and by contrasting life history data. Three phylogenetic methods and a Bayesian assignment test highlighted similar phylogenomic patterns in each, but with considerable difference in presumed times of divergence. Three lineages were detected in bluehead sucker, supporting elevation of C. (P.) virescens to species status and recognizing C. (P.) discobolus yarrowi (Zuni bluehead sucker) as a discrete entity. Admixture in the latter necessitated a reevaluation of its contemporary and historic distributions, underscoring how biodiversity identification can be confounded by complex evolutionary histories. In addition, we defined three separate flannelmouth sucker lineages as ESUs (evolutionarily significant units), given limited phenotypic and genetic differentiation, contemporary isolation, and lack of concordance (per the genealogical concordance component of the phylogenetic species concept). Introgression was diagnosed in both species, with the Little Colorado and Virgin rivers in particular. Our diagnostic methods, and the agreement of our SNPs with previous morphological, enzymatic, and mitochondrial work, allowed us to partition complex evolutionary histories into requisite components, such as isolation versus secondary contact.

Abstract Background Research on the molecular ecology of non-model organisms, while previously constrained, has now been greatly facilitated by the advent of reduced-representation sequencing protocols. However, tools that allow these large datasets to be efficiently parsed are often lacking, or if indeed available, then limited by the necessity of a comparable reference genome as an adjunct. This, of course, can be difficult when working with non-model organisms. Fortunately, pipelines are currently available that avoid this prerequisite, thus allowing data to be a priori parsed. An oft-used molecular ecology program (i.e., Structure), for example, is facilitated by such pipelines, yet they are surprisingly absent for a second program that is similarly popular and computationally more efficient (i.e., Admixture). The two programs differ in that Admixture employs a maximum-likelihood framework whereas Structure uses a Bayesian approach, yet both produce similar results. Given these issues, there is an overriding (and recognized) need among researchers in molecular ecology for bioinformatic software that will not only condense output from replicated Admixture runs, but also infer from these data the optimal number of population clusters (K). Results Here we provide such a program (i.e., AdmixPipe) that (a) filters SNPs to allow the delineation of population structure in Admixture, then (b) parses the output for summarization and graphical representation via Clumpak. Our benchmarks effectively demonstrate how efficient the pipeline is for processing large, non-model datasets generated via double digest restriction-site associated DNA sequencing (ddRAD). Outputs not only parallel those from Structure, but also visualize the variation among individual Admixture runs, so as to facilitate selection of the most appropriate K-value. Conclusions AdmixPipe successfully integrates Admixture analysis with popular variant call format (VCF) filtering software to yield file types readily analyzed by Clumpak. Large population genomic datasets derived from non-model organisms are efficiently analyzed via the parallel-processing capabilities of Admixture. AdmixPipe is distributed under the GNU Public License and freely available for Mac OSX and Linux platforms at: https://github.com/stevemussmann/admixturePipeline .

The recurrence of similar evolutionary patterns within different habitats often reflects parallel selective pressures acting upon either standing or independently occurring genetic variation to produce a convergence of phenotypes. This interpretation (i.e. parallel divergences within adjacent streams) has been hypothesized for drainage-specific morphological ‘ecotypes’ observed in polyploid snowtrout (Cyprinidae: Schizothorax). However, parallel patterns of differential introgression during secondary contact are a viable alternative hypothesis. Here, we used ddRADseq (N = 35 319 de novo and N = 10 884 transcriptome-aligned SNPs), as derived from Nepali/Bhutanese samples (N = 48 each), to test these competing hypotheses. We first employed genome-wide allelic depths to derive appropriate ploidy models, then a Bayesian approach to yield genotypes statistically consistent under the inferred expectations. Elevational ‘ecotypes’ were consistent in geometric morphometric space, but with phylogenetic relationships at the drainage level, sustaining a hypothesis of independent emergence. However, partitioned analyses of phylogeny and admixture identified subsets of loci under selection that retained genealogical concordance with morphology, suggesting instead that apparent patterns of morphological/phylogenetic discordance are driven by widespread genomic homogenization. Here, admixture occurring in secondary contact effectively ‘masks’ previous isolation. Our results underscore two salient factors: (i) morphological adaptations are retained despite hybridization and (ii) the degree of admixture varies across tributaries, presumably concomitant with underlying environmental or anthropogenic factors.

In the central nervous system (CNS), glial cells, such as microglia and astrocytes, are normally associated with support roles including contributions to energy metabolism, synaptic plasticity, and ion homeostasis. In addition to providing support for neurons, microglia and astrocytes function as the resident immune cells in the brain. The glial function is impacted by multiple aspects including aging and local CNS changes caused by neurodegeneration. During aging, microglia and astrocytes display alterations in their homeostatic functions. For example, aged microglia and astrocytes exhibit impairments in the lysosome and mitochondrial function as well as in their regulation of synaptic plasticity. Recent evidence suggests that glia can also alter the pathology associated with many neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Shifts in the microbiome can impact glial function as well. Disruptions in the microbiome can lead to aberrant microglial and astrocytic reactivity, which can contribute to an exacerbation of disease and neuronal dysfunction. In this review, we will discuss the normal physiological functions of microglia and astrocytes, summarize novel findings highlighting the role of glia in aging and neurodegenerative diseases, and examine the contribution of microglia and astrocytes to disease progression.

Abstract Over a million people in Peru may be exposed to lead (Pb) due to past or present mining‐related activities; however, neither soil Pb nor blood Pb are routinely monitored throughout the country. Because little is known about Pb contamination in smaller mining‐impacted towns, soil Pb was mapped in four such towns with a portable X‐ray fluorescence analyzer in 2015. The roadside mapping delineated hotspots of highly contaminated soil (1,000–6,000 mg/kg Pb) in two of the towns. The local health department, provided with a LeadCare II analyzer, then measured blood‐Pb levels >5 in 65% and >10 μg/dL in 15% of children (n = 200) up to 6 years of age in these same four communities. There were no clear relations between child blood‐Pb levels and Pb levels in soil samples collected inside (n = 50) or outside the home (n = 50). Increased child blood Pb was associated with decreased level of cleanliness of parent clothing (n = 136) and shoes (n = 138), linking a possible behavioral factor for transferring contaminated soil and dust to children. In order to explore individual exposure and variations in soil Pb, 10 parents of children with blood Pb >10 μg/dL and 10 parents of children with blood Pb

Filoviruses, such as the Ebola virus (EBOV) and Marburg virus (MARV), are causative agents of sporadic outbreaks of hemorrhagic fevers in humans. To infect cells, filoviruses are internalized via macropinocytosis and traffic through the endosomal pathway where host cathepsin-dependent cleavage of the viral glycoproteins occurs. Subsequently, the cleaved viral glycoprotein interacts with the late endosome/lysosome resident host protein, Niemann-Pick C1 (NPC1). This interaction is hypothesized to trigger viral and host membrane fusion, which results in the delivery of the viral genome into the cytoplasm and subsequent initiation of replication. Some studies suggest that EBOV viral particles activate signaling cascades and host-trafficking factors to promote their localization with host factors that are essential for entry. However, the mechanism through which these activating signals are initiated remains unknown. By screening a kinase inhibitor library, we found that receptor tyrosine kinase inhibitors potently block EBOV and MARV GP-dependent viral entry. Inhibitors of epidermal growth factor receptor (EGFR), tyrosine protein kinase Met (c-Met), and the insulin receptor (InsR)/insulin like growth factor 1 receptor (IGF1R) blocked filoviral GP-mediated entry and prevented growth of replicative EBOV in Vero cells. Furthermore, inhibitors of c-Met and InsR/IGF1R also blocked viral entry in macrophages, the primary targets of EBOV infection. Interestingly, while the c-Met and InsR/IGF1R inhibitors interfered with EBOV trafficking to NPC1, virus delivery to the receptor was not impaired in the presence of the EGFR inhibitor. Instead, we observed that the NPC1 positive compartments were phenotypically altered and rendered incompetent to permit viral entry. Despite their different mechanisms of action, all three RTK inhibitors tested inhibited virus-induced Akt activation, providing a possible explanation for how EBOV may activate signaling pathways during entry. In sum, these studies strongly suggest that receptor tyrosine kinases initiate signaling cascades essential for efficient post-internalization entry steps.

Ecological restoration can promote biodiversity conservation in anthropogenically fragmented habitats, but effectiveness of these management efforts need to be statistically validated to determine ’success.’ One such approach is to gauge the extent of recolonization as a measure of landscape permeability and, in turn, population connectivity. In this context, we estimated dispersal and population connectivity in prairie vole (Microtus ochrogaster; N = 231) and meadow vole (M. pennsylvanicus; N = 83) within five tall-grass prairie restoration sites embedded within the agricultural matrix of midwestern North America. We predicted that vole dispersal would be constrained by the extent of agricultural land surrounding restored habitat patches, spatially isolating vole populations and resulting in significant genetic structure. We first employed genetic assignment tests based on 15 microsatellite DNA loci to validate field-derived species-designations, then tested reclassified samples with multivariate and Bayesian clustering to assay for spatial and temporal genetic structure. Population connectivity was further evaluated by calculating pairwise FST, then potential demographic effects explored by computing migration rates, effective population size (Ne), and average relatedness (r). Genetic species assignments reclassified 25% of initial field identifications (N = 11 M. ochrogaster; N = 67 M. pennsylvanicus). In M. ochrogaster population connectivity was high across the study area, reflected in little to no spatial or temporal genetic structure. In M. pennsylvanicus genetic structure was detected, but relatedness estimates identified it as kin-clustering instead, underscoring social behavior among populations rather than spatial isolation as the cause. Estimates of Ne and r were stable across years, reflecting high dispersal and demographic resilience. Combined, these metrics suggest the agricultural matrix is highly permeable for voles and does not impede dispersal. High connectivity observed confirms that the restored landscape is productive and permeable for specific management targets such as voles and also demonstrates population genetic assays as a tool to statistically evaluate effectiveness of conservation initiatives.

Alzheimer's disease (AD) is the most prevalent form of late-onset dementia. AD affects the health of millions of people in the United States and worldwide. Currently, there are no approved therapies that can halt or reverse the clinical progression of AD. Traditionally, AD is characterized first by the appearance of amyloid-β (Aβ) plaques followed by the formation of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (p-tau). These lesions are linked to synapse loss and eventual cognitive impairment. Additionally, microgliosis is consistently found in regions of the brain with AD pathology. The role of microglia in AD onset and progression remains unclear. Several recent reports indicate that the assembly of the multi-protein complex known as the NOD, LRR, and pyrin-domain containing 3 (Nlrp3) inflammasome by microglia results in apoptosis spec-like protein containing a CARD (Asc) spec formation, which then nucleates new Aβ plaques, thus amplifying Aβ-associated pathology. NFTs can also activate the Nlrp3 inflammasome leading to enhanced tau-associated pathology. Here, we will review the role of microglia and the activation of the inflammasome in the innate immune response to AD.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. In response to Aβ and tau aggregates, microglia, the primary innate immune cells of the central nervous system (CNS), facilitate Aβ and tau clearance and contribute to neuroinflammation that damages neurons. Microglia also perform a wide range of other functions, e.g., synaptic pruning, within the CNS that require a large amount of energy. Glucose appears to be the primary energy source, but microglia can utilize several other substrates for energy production including other sugars and ketone bodies. Recent studies have demonstrated that changes in the metabolic profiles of immune cells, including macrophages, are important in controlling their activation and effector functions. Additional studies have focused on the role of metabolism in neuron and astrocyte function while until recently microglia metabolism has been considerably less well understood. Considering many neurological disorders, such as neurodegeneration associated with AD, are associated with chronic inflammation and alterations in brain energy metabolism, it is hypothesized that microglial metabolism plays a significant role in the inflammatory responses of microglia during neurodegeneration. Here, we review the role of microglial immunometabolism in AD.

Staphylococcus aureus (S. aureus) causes a range of diseases ranging from superficial skin and soft-tissue infections to invasive and life-threatening conditions (Klevens et al., 2007; Kobayashi et al., 2015). S. aureus utilizes the Sae sensory system to adapt to neutrophil challenge. Although the roles of the SaeR response regulator and its cognate sensor kinase SaeS have been demonstrated to be critical for surviving neutrophil interaction and for causing infection, the roles for the accessory proteins SaeP and SaeQ remain incompletely defined. To characterize the functional role of these proteins during innate immune interaction, we generated isogenic deletion mutants lacking these accessory genes in USA300 (USA300ΔsaeP and USA300ΔsaeQ). S. aureus survival was increased following phagocytosis of USA300ΔsaeP compared to USA300 by neutrophils. Additionally, secreted extracellular proteins produced by USA300ΔsaeP cells caused significantly more plasma membrane damage to human neutrophils than extracellular proteins produced by USA300 cells. Deletion of saeQ resulted in a similar phenotype, but effects did not reach significance during neutrophil interaction. The enhanced cytotoxicity of USA300ΔsaeP cells toward human neutrophils correlated with an increased expression of bi-component leukocidins known to target these immune cells. A saeP and saeQ double mutant (USA300ΔsaePQ) showed a significant increase in survival following neutrophil phagocytosis that was comparable to the USA300ΔsaeP single mutant and increased the virulence of USA300 during murine bacteremia. These data provide evidence that SaeP modulates the Sae-mediated response of S. aureus against human neutrophils and suggest that saeP and saeQ together impact pathogenesis in vivo.

There are few reports that describe crystal structures of compounds containing cobalt complexed to either dimethyl sulfoxide (Me2SO) or quinoline (C9H7N). The title compound, [Co(C2H6OS)6][CoCl3(C9H7N)]2, is a cobalt salt in which the metal ion is complexed to both Me2SO and quinoline. In particular, we observed that anhydrous cobalt(II) chloride reacts with quinoline in Me2SO to form a salt that is to be formulated as [CoII(Me2SO)6]2+{[CoIICl3quinoline]2−}. The CoII atom in the cation portion of this molecule lies on a inversion center and is bound to the O atoms of six Me2SO moieties in an octahedral configuration, while the CoII atom in the anion is attached to three chloride ligands and one quinoline moiety in a tetrahedral arrangement.

Monomer sequence is an emerging tool to precisely encode information (and thus structure and function) into polymer systems. Here the authors use sequence-control in complex coacervates to understand how monomer sequence translates to physical material properties.

Sleep Disordered Breathing (SDB) and Alzheimer’s Disease (AD) are strongly associated clinically, but it is unknown if they are mechanistically associated. Here, we review data covering both the cellular and molecular responses in SDB and AD with an emphasis on the overlapping neuroimmune responses in both diseases. We extensively discuss the use of animal models of both diseases and their relative utilities in modeling human disease. Data presented here from mice exposed to intermittent hypoxia indicate that microglia become more activated following exposure to hypoxia. This also supports the idea that intermittent hypoxia can activate the neuroimmune system in a manner like that seen in AD. Finally, we highlight similarities in the cellular and neuroimmune responses between SDB and AD and propose that these similarities may lead to a pathological synergy between SDB and AD.

ILC2 and ILC3 are generally thought to require IL-7. Here the authors use IL-7 ko mice and provide side-by-side comparison of ILCs from different tissues to show that IL-7 signalling is not required for intestinal ILC maintenance or function and that IL-15 can compensate for absence of IL-7.

Exciton diffusion plays a role in many optoelectronic devices. In some materials, this migration cannot be detected using photoluminescence. Mullenbachet al. use photovoltage measurements to extract the diffusion length in organic photovoltaic cells, and examine a series of non-luminescent materials.

Staphylococcus aureus is a common Gram-positive bacteria that is a major cause of human morbidity and mortality. The SaeR/S two-component sensory system of S. aureus is important for virulence gene transcription and pathogenesis. However, the influence of SaeR phosphorylation on virulence gene transcription is not clear. To determine the importance of potential SaeR phosphorylation sites for S. aureus virulence, we generated genomic alanine substitutions at conserved aspartic acid residues in the receiver domain of the SaeR response regulator in clinically significant S. aureus pulsed-field gel electrophoresis (PFGE) type USA300. Transcriptional analysis demonstrated a dramatic reduction in the transcript abundance of various toxins, adhesins, and immunomodulatory proteins for SaeR with an aspartic acid to alanine substitution at residue 51. These findings corresponded to a significant decrease in cytotoxicity against human erythrocytes and polymorphonuclear leukocytes, the ability to block human myeloperoxidase activity, and pathogenesis during murine soft-tissue infection. Analysis of SaeR sequences from over 8,000 draft S. aureus genomes revealed that aspartic acid residue 51 is 100% conserved. Collectively, these results demonstrate that aspartic acid residue 51 of SaeR is essential for S. aureus virulence and underscore a conserved target for novel antimicrobial strategies that treat infection caused by this pathogen.

Since the onset of hydraulic gold mining in California’s Sierra Nevada foothills in 1852, the environmental damage caused by displacement and storage of hydraulic mining sediment (HMS) has been a significant ecological problem downstream. Large volumes of mercury-laden HMS from the Yuba River watershed were deposited within the river corridor, creating the anthropogenic Yuba Fan. However, there are outstanding uncertainties about how much HMS is still contained within this fan. To quantify the deep storage of HMS in the Yuba Fan, we analyzed mercury concentrations of sediment samples collected from borings and outcrops at multiple depths. The mercury concentrations served as chemostratigraphic markers to identify the contacts between the HMS and underlying pre-mining deposits. The HMS had mercury concentrations at least ten-fold higher than pre-mining deposits. Analysis of the lower Yuba Fan’s volume suggests that approximately 8.1. 107 m3 of HMS was deposited within the study area between 1852 and 1999, representing ~32% of the original Yuba Fan delivered by 19th Century hydraulic gold mining. Our estimate of the mercury mass contained within this region is 6.7. 103 kg, which is several orders of magnitude smaller than what was estimated to have been lost to the mining process. We suggest that this discrepancy is likely due to a combination of missing (yet to be found) mercury masses stored upstream, overestimated losses during mining, and high delivery of mercury to the lowland Sacramento Valley and to the San Francisco Bay-Delta system, where it poses a great risk to sensitive ecosystems.