A multifactorial lens on risk factors promoting the progression of Alzheimer's disease.

The prevalence of Alzheimer's disease (AD) among adults has continued to increase over the last two decades, which has sparked a significant increase in research that focuses on the topic of "brain health." While AD is partially determined by a genetic predisposition, there are still numerous pathophysiological factors that require further research. This research requirement stems from the acknowledgment that AD is a multifactorial disease that to date, cannot be prevented. Therefore, addressing and understanding the potential AD risk factors is necessary to increase the quality of life of an aging population. To raise awareness of critical pathways that impact AD progression, this review manuscript describes AD etiologies, structural impairments, and biomolecular changes that can significantly increase the risk of AD. Among them, a special highlight is given to inflammasomes, which have been shown to bolster neuroinflammation. Alike, the role of brain-derived neurotrophic factor, an essential neuropeptide that promotes the preservation of cognition is presented. In addition, the functional role of neurovascular units to regulate brain health is highlighted and contrasted to inflammatory conditions, such as cellular senescence, vascular damage, and increased visceral adiposity, who all increase the risk of neuroinflammation. Altogether, a multifactorial interventional approach is warranted to reduce the risk of AD.

Why graph theory deserves more focus. Comment on "Connectivity analyses for task-based fMRI" by Huang et al.

Huang et al. have conducted a thorough examination of methodologies used for identifying and analyzing functional connectivity using task-based fMRI. Their review adeptly describes current approaches without bias or preference. In this commentary, we explain why we believe that graph theory is the optimal approach for studying neural mechanisms associated with complex behaviors and cognitive processes that are engaged during task-based fMRI.

The doc versus the bot: A pilot study to assess the quality and accuracy of physician and chatbot responses to clinical questions in gynecologic oncology.

Artificial intelligence (AI) applications to medical care are currently under investigation. We aimed to evaluate and compare the quality and accuracy of physician and chatbot responses to common clinical questions in gynecologic oncology. In this cross-sectional pilot study, ten questions about the knowledge and management of gynecologic cancers were selected. Each question was answered by a recruited gynecologic oncologist, ChatGPT (Generative Pretreated Transformer) AI platform, and Bard by Google AI platform. Five recruited gynecologic oncologists who were blinded to the study design were allowed 15 min to respond to each of two questions. Chatbot responses were generated by inserting the question into a fresh session in September 2023. Qualifiers and language identifying the response source were removed. Three gynecologic oncology providers who were blinded to the response source independently reviewed and rated response quality using a 5-point Likert scale, evaluated each response for accuracy, and selected the best response for each question. Overall, physician responses were judged to be best in 76.7 % of evaluations versus ChatGPT (10.0 %) and Bard (13.3 %; p < 0.001). The average quality of responses was 4.2/5.0 for physicians, 3.0/5.0 for ChatGPT and 2.8/5.0 for Bard (t-test for both and ANOVA p < 0.001). Physicians provided a higher proportion of accurate responses (86.7 %) compared to ChatGPT (60 %) and Bard (43 %; p < 0.001 for both). Physicians provided higher quality responses to gynecologic oncology clinical questions compared to chatbots. Patients should be cautioned against non-validated AI platforms for medical advice; larger studies on the use of AI for medical advice are needed.

Thr4 phosphorylation on RNA Pol II occurs at early transcription regulating 3'-end processing.

RNA polymerase II relies on a repetitive sequence domain (YSPTSPS) within its largest subunit to orchestrate transcription. While phosphorylation on serine-2/serine-5 of the carboxyl-terminal heptad repeats is well established, threonine-4's role remains enigmatic. Paradoxically, threonine-4 phosphorylation was only detected after transcription end sites despite functionally implicated in pausing, elongation, termination, and messenger RNA processing. Our investigation revealed that threonine-4 phosphorylation detection was obstructed by flanking serine-5 phosphorylation at the onset of transcription, which can be removed selectively. Subsequent proteomic analyses identified many proteins recruited to transcription via threonine-4 phosphorylation, which previously were attributed to serine-2. Loss of threonine-4 phosphorylation greatly reduces serine-2 phosphorylation, revealing a cross-talk between the two marks. Last, the function analysis of the threonine-4 phosphorylation highlighted its role in alternative 3'-end processing within pro-proliferative genes. Our findings unveil the true genomic location of this evolutionarily conserved phosphorylation mark and prompt a reassessment of functional assignments of the carboxyl-terminal domain.

Abstinence from cocaine self-administration promotes microglia pruning of astrocytes which drives cocaine-seeking behavior.

Rodent drug self-administration leads to compromised ability of astrocytes to maintain glutamate homeostasis within the brain's reward circuitry, as well as reductions in surface area, volume, and synaptic colocalization of astrocyte membranes. However, the mechanisms driving astrocyte responses to cocaine are unknown. Here, we report that long-access cocaine self-administration followed by prolonged home cage abstinence results in decreased branching complexity of nucleus accumbens astrocytes, characterized by the loss of peripheral processes. Using a combination of confocal fluorescence microcopy and immuno-gold electron microscopy, we show that alterations in astrocyte structural features are driven by microglia phagocytosis, as labeled astrocyte membranes are found within microglia phagolysosomes. Inhibition of complement C3-mediated phagocytosis using the neutrophil inhibitory peptide (NIF) rescued astrocyte structure and decreased cocaine seeking behavior following cocaine self-administration and abstinence. Collectively, these results provide evidence for microglia pruning of accumbens astrocytes across cocaine abstinence which mediates cocaine craving.

Geographic and racial disparities in the quality of surgical care among patients with nonmetastatic uterine cancer.

BACKGROUND: Although the rates of minimally invasive surgery and sentinel lymph node biopsy have increased considerably over time in the surgical management of early-stage uterine cancer, practice varies significantly in the United States, and there are disparities among low-volume centers and patients of Black race. A significant number of counties in the United States are without a gynecologic oncologist, and almost half of the counties with the highest gynecologic cancer rates lack a local gynecologic oncologist. OBJECTIVE: This study aimed to evaluate the relationships of distance traveled and proximity to gynecologic oncologists with the receipt of and racial disparities in the quality of surgical care among patients who underwent a hysterectomy for nonmetastatic uterine cancer. STUDY DESIGN: Patients who underwent a hysterectomy for nonmetastatic uterine cancer in Kentucky, Maryland, Florida, and North Carolina were identified in the 2012 to 2018 State Inpatient Database and the State Ambulatory Surgery Services Database files. County-to-county distances were used as the distances traveled to the nearest gynecologic oncologist. Factors associated with the receipt of minimally invasive surgery and lymph node dissection were analyzed using multivariable logistic regression models, as was the assessment of the interaction between travel for surgery and patient race. RESULTS: Among 21,837 cases, 45.5% lived in a county without a gynecologic oncologist; overall, 55.5% traveled to another county for surgery, including 88% of those who lacked a local gynecologic oncologist. Patients who lacked access to a local gynecologic oncologist in their county who did not travel for surgery were more likely to receive open surgery and no lymph node dissection, and those in counties without access in any surrounding county were affected even more. Among patients in counties without a gynecologic oncologist, those who traveled for surgery had a similar likelihood of undergoing minimally invasive surgery (71%) but had a greater likelihood of undergoing lymph node dissection (64.7% vs 57.2%) than nontravelers. Among those in counties without a gynecologic oncologist, a longer distance traveled was associated with receipt of a lymph node assessment. When compared with non-Black patients, Black patients were less likely to undergo minimally invasive surgery (57.0% vs 74.1%). In adjusted regression models that controlled for a diagnosis of fibroids, Black race was an independent risk factor for the receipt of open surgery. There was a significant interaction between Black race and travel for surgery, and Black patients who lived in counties without a gynecologic oncologist who did not travel faced an incrementally lower likelihood of receiving minimally invasive surgery (odds ratio, 0.57 when compared with non-Black patients who traveled for surgery; odds ratio, 0.60 as interaction term; P<.001 for both). Similar disparities in surgical quality by race were noted for Black patients who lived in counties with a gynecologic oncologist who traveled out of county for surgery. CONCLUSION: Patients, particularly those of Black race, who lacked local access to gynecologic oncologist specialty care benefitted from traveling to specialty centers to ensure access to high-quality surgery for nonmetastatic uterine cancer. Further work is needed to ensure equitable and universal access to high-quality care through patient travel or specialist outreach.

Heterogeneity of Salmonella enterica lipopolysaccharide counteracts macrophage and antimicrobial peptide defenses.

Salmonella enterica is comprised of over 2,500 serovars, in which non-typhoidal serovars (NTS), Enteritidis (SE), and Typhimurium (STM) are the most clinically associated with human infections. Although NTS have similar genetic elements to cause disease, phenotypic variation including differences in lipopolysaccharide (LPS) composition may control immune evasion. Here, we demonstrate that macrophage host defenses and LL-37 antimicrobial efficacy against SE and STM are substantially altered by LPS heterogeneity. We found that SE evades macrophage killing by inhibiting phagocytosis while STM survives better intracellularly post-phagocytosis. SE-infected macrophages failed to activate the inflammasomes and subsequently produced less interleukin-1ß (IL-1ß), IL-18, and interferon λ. Inactivation of LPS biosynthesis genes altered LPS composition, and the SE LPS-altered mutants could no longer inhibit phagocytosis, inflammasome activation, and type II interferon signaling. In addition, SE and STM showed differential susceptibility to the antimicrobials LL-37 and colistin, and alteration of LPS structure substantially increased susceptibility to these molecules. Collectively, our findings highlight that modification of LPS composition by Salmonella increases resistance to host defenses and antibiotics.

Synapse Regulation.

Microglia are the resident immune cells of the brain. As such, they rapidly detect changes in normal brain homeostasis and accurately respond by fine-tuning in a tightly regulated manner their morphology, gene expression, and functional behavior. Depending on the nature of these changes, microglia can thicken and retract their processes, proliferate and migrate, release numerous signaling factors and compounds influencing neuronal physiology (e.g., cytokines and trophic factors), in addition to secreting proteases able to transform the extracellular matrix, and phagocytosing various types of cellular debris, etc. Because microglia also transform rapidly (on a time scale of minutes) during experimental procedures, studying these very special cells requires methods that are specifically non-invasive. The development of such methods has provided unprecedented insights into the roles of microglia during normal physiological conditions. In particular, transcranial two-photon in vivo imaging revealed that presumably "resting" microglia continuously survey the brain parenchyma with their highly motile processes, in addition to modulating their structural and functional interactions with neuronal circuits along the changes in neuronal activity and behavioral experience occurring throughout the lifespan. In this chapter, we will describe how surveillant microglia interact with synaptic elements and modulate the number, maturation, function, and plasticity of synapses in the healthy developing, mature, and aging brain, with consequences on neuronal activity, learning and memory, and the behavioral outcome.

Adult Neurogenesis, Learning and Memory.

Neural plasticity can be defined as the ability of neural circuits to be shaped by external and internal factors. It provides the brain with a capacity for functional and morphological remodelling, with many lines of evidence indicating that these changes are vital for learning and memory formation. The basis of this brain plasticity resides in activity- and experience-driven modifications of synaptic strength, including synaptic formation, elimination or weakening, as well as of modulation of neuronal population, which drive the structural reorganization of neural networks. Recent evidence indicates that brain-resident glial cells actively participate in these processes, suggesting that mechanisms underlying plasticity in the brain are multifaceted. Establishing the 'tripartite' synapse, the role of astrocytes in modulating synaptic transmission in response to neuronal activity was recognized first. Further redefinition of the synapse as 'quad-partite' followed to acknowledge the contribution of microglia which were revealed to affect numerous brain functions via dynamic interactions with synapses, acting as 'synaptic sensors' that respond to neuronal activity and neurotransmitter release, as well as crosstalk with astrocytes. Early studies identified microglial ability to dynamically survey their local brain environment and established their integral role in the active interfacing of environmental stimuli (both internal and external), with brain plasticity and remodelling. Following the introduction to neurogenesis, this chapter details the role that microglia play in regulating neurogenesis in adulthood, specifically as it relates to learning and memory, as well as factors involved in modulation of microglia. Further, a microglial perspective is introduced for the context of environmental enrichment impact on neurogenesis, learning and memory across states of stress, ageing, disease and injury.

High thermal quality rookeries facilitate high thermoregulatory accuracy in pregnant female rattlesnakes.

Temperature is a primary factor influencing organismal development, and the fluctuating daily and seasonal thermal regimes of temperate climates may challenge the ability of viviparous reptiles to optimize body temperatures during gestation. Testing how viviparous reptiles navigate highly variable thermal conditions (e.g., relatively cold nights and/or highly fluctuating temperatures) is a powerful way to understand how they use microhabitats for thermoregulatory benefits. We assessed the thermal ecology of pregnant and non-pregnant female Prairie Rattlesnakes (Crotalus viridis) inhabiting a high-elevation, montane shrubland in northwest Colorado throughout their short summer active season, addressing the thermal consequences of microhabitat selection with a focus on thermoregulation of pregnant females at communal rookery sites. We deployed operative temperature models to collect data on the thermal quality of microhabitats used by the snakes, and calculated thermoregulatory accuracy of the snakes by comparing their field-active body temperatures with preferred body temperatures of snakes placed in a thermal gradient. Pregnant females inhabited rocky, hilltop rookeries that had higher thermal quality due to higher and less variable nighttime temperatures compared to microhabitats in the surrounding prairie. Pregnant females therefore thermoregulated more accurately than non-pregnant females. The difference was most pronounced during the night, when pregnant females at rookeries maintained higher body temperatures than non-pregnant snakes in the prairie. Our results support the hypothesis that one major reason female rattlesnakes at high latitudes and/or high elevations forgo migration and gestate at communal, rocky, hilltop rookeries is that, relative to prairie microhabitats, they provide better conditions for thermoregulation during pregnancy.

The value of long-term ecological research for evolutionary insights.

Scientists must have an integrative understanding of ecology and evolution across spatial and temporal scales to predict how species will respond to global change. Although comprehensively investigating these processes in nature is challenging, the infrastructure and data from long-term ecological research networks can support cross-disciplinary investigations. We propose using these networks to advance our understanding of fundamental evolutionary processes and responses to global change. For ecologists, we outline how long-term ecological experiments can be expanded for evolutionary inquiry, and for evolutionary biologists, we illustrate how observed long-term ecological patterns may motivate new evolutionary questions. We advocate for collaborative, multi-site investigations and discuss barriers to conducting evolutionary work at network sites. Ultimately, these networks offer valuable information and opportunities to improve predictions of species' responses to global change.

Protocol for the in vitro reconstruction of site-specifically phosphorylated RNA Pol II to identify the recruitment of novel transcription regulators.

The repetitive C-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAPII) becomes differentially phosphorylated throughout the transcription cycle. Here, we present a protocol to site-specifically phosphorylate the CTD of RNAPII by leveraging the specificity of well-characterized CTD kinases. We describe the steps for optimal phosphorylation of the CTD and the preparation of nuclear protein extract. This protocol can be used to identify the interactome of a phospho-CTD and has the potential to identify novel RNAPII-binding proteins. For complete details on the use and execution of this protocol, please refer to Moreno et al.1.

Spatial memory encoding is associated with the anterior and posterior hippocampus: An fMRI activation likelihood estimation meta-analysis.

It has been hypothesized that differential processing occurs along the longitudinal (anterior-posterior) axis of the hippocampus. One hypothesis is that spatial memory (during both encoding and retrieval) is associated with the posterior hippocampus. An alternative hypothesis is that memory encoding (either spatial or nonspatial) is associated with the anterior hippocampus and memory retrieval is associated with the posterior hippocampus. Of importance, during spatial memory encoding, the spatial-posterior hypothesis predicts posterior hippocampal involvement, whereas the encoding-retrieval hypothesis predicts anterior hippocampal involvement. To distinguish between these hypotheses, we conducted a coordinate-based fMRI activation likelihood estimation (ALE) meta-analysis of 26 studies (with a total of 435 participants) that reported hippocampal activity during spatial memory encoding and/or spatial memory retrieval. Both spatial memory encoding and spatial memory retrieval produced extensive activity along the longitudinal axis of the hippocampus as well as the entorhinal cortex, the perirhinal cortex, and the parahippocampal cortex. Critically, the contrast of spatial memory encoding and spatial memory retrieval produced activations in both the anterior hippocampus and the posterior hippocampus. That spatial memory encoding produced activity in both the anterior and posterior hippocampus can be taken to reject strict forms of the spatial-posterior hypothesis, which stipulates that all forms of spatial memory produce activity in the posterior hippocampus, and the encoding-retrieval hypothesis, which stipulates that all forms of encoding versus retrieval produce activity in only the anterior hippocampus. Our results indicate that spatial memory encoding can involve the anterior hippocampus and the posterior hippocampus.

Developing a mouse model of human coronavirus NL63 infection: comparison with rhinovirus-A1B and effects of prior rhinovirus infection.

Human coronavirus (HCoV)-NL63 causes respiratory tract infections in humans and uses angiotensin-converting enzyme 2 (ACE2) as a receptor. We sought to establish a mouse model of HCoV-NL63 and determine whether prior rhinovirus (RV)-A1B infection affected HCoV-NL63 replication. HCoV-NL63 was propagated in LLC-MK2 cells expressing human ACE2. RV-A1B was grown in HeLa-H1 cells. C57BL6/J or transgenic mice expressing human ACE2 were infected intranasally with sham LLC-MK2 cell supernatant or 1 × 105 tissue culture infectious dose (TCID50) units HCoV-NL63. Wild-type mice were infected with 1 × 106 plaque-forming units (PFU) RV-A1B. Lungs were assessed for vRNA, bronchoalveolar lavage (BAL) cells, histology, HCoV-NL63 nonstructural protein 3 (nsp3), and host gene expression by next-generation sequencing and qPCR. To evaluate sequential infections, mice were infected with RV-A1B followed by HCoV-NL63 infection 4 days later. We report that hACE2 mice infected with HCoV-NL63 showed evidence of replicative infection with increased levels of vRNA, BAL neutrophils and lymphocytes, peribronchial and perivascular infiltrates, and expression of nsp3. Viral replication peaked 3 days after infection and inflammation persisted 6 days after infection. HCoV-NL63-infected hACE2 mice showed increased mRNA expression of IFNs, IFN-stimulated proteins, and proinflammatory cytokines. Infection with RV-A1B 4 days before HCoV-NL63 significantly decreased both HCoV-NL63 vRNA levels and airway inflammation. Mice infected with RV-A1B prior to HCoV-NL63 showed increased expression of antiviral proteins compared with sham-treated mice. In conclusion, we established a mouse model of HCoV-NL63 replicative infection characterized by relatively persistent viral replication and inflammation. Prior infection with RV-A1B reduced HCoV-NL63 replication and airway inflammation, indicative of viral interference.NEW & NOTEWORTHY We describe a mouse model of human coronavirus (HCoV) infection. Infection of transgenic mice expressing human angiotensin-converting enzyme 2 (ACE2) with HCoV-NL63 produced a replicative infection with peribronchial inflammation and nonstructural protein 3 expression. Mice infected with RV-A1B 4 days before HCoV-NL63 showed decreased HCoV-NL63 replication and airway inflammation and increased expression of antiviral proteins compared with sham-treated mice. This research may shed light on human coronavirus infections, viral interference, and viral-induced asthma exacerbations.

Itaconate suppresses house dust mite-induced allergic airways disease and Th2 cell differentiation.

Itaconate was initially identified as an antimicrobial compound produced by myeloid cells. Beyond its antimicrobial role, itaconate may also serve as a crucial metabolic and immune modulator. We therefore examined the roles of aconitate decarboxylase 1 (Acod1) and itaconate in house dust mite (HDM)-sensitized and -challenged mice, a model of T helper 2 (Th2)-driven allergic airways disease. HDM treatment induced lung Acod1 mRNA expression and bronchoalveolar lavage (BAL) itaconate levels in wild-type C57BL/6 mice. Acod1 knockout mice (Acod1-KO) with negligible BAL itaconate showed heightened HDM-induced type 2 cytokine expression, increased serum IgE, and enhanced recruitment of Th2 cells in the lung, indicating a shift towards a more pronounced Th2 immune response. Acod1-KO mice also showed increased eosinophilic airway inflammation and hyperresponsiveness. Experiments in chimeric mice demonstrated that bone marrow from Acod1-KO mice is sufficient to increase type 2 cytokine expression in wild-type mice, and that restitution of bone marrow from wild type mice attenuates mRNA expression of Th2 cytokines in Acod1-KO mice. Specific deletion of Acod1 in lysozyme-secreting macrophages (LysM-cre+Acod1flox/flox) recapitulated the exaggerated phenotype observed in whole-body Acod1-KO mice. Adoptive transfer of Acod1-KO bone marrow-derived macrophages also increased lung mRNA expression of Th2 cytokines. In addition, treatment of Th2-polarized CD4 cells with itaconate impeded Th2 cell differentiation, as shown by reduced expression of Gata3 and decreased release of IL-5 and IL-13. Finally, public datasets of human samples show lower Acod1 expression in subjects with allergic asthma, consistent with a protective role of itaconate in asthma pathogenesis. Together, these data suggest that itaconate plays a protective, immunomodulatory role in limiting airway type 2 inflammation after allergen challenge by attenuating T cell responses.

Evaluation of the Veterinary IDEXX SNAP 4Dx Plus Test for the Diagnosis of Lyme Disease in Humans.

Background: Lyme disease, caused by infection with Borrelia burgdorferi, is the most common vector-borne disease in the United States. The standard two-tier testing (STTT) algorithm suffers from low sensitivity, misinterpretation, and long turnaround time, preventing timely detection and treatment. To address these challenges, we hypothesized that the canine point-of-care (PoC) SNAP 4Dx Plus test used to detect Borrelia burgdorferi antibodies could be employed for human diagnosis. Materials and Methods: The SNAP 4Dx Plus testing was conducted in accordance with the manufacturer's instructions, with results read by manual inspection. All analyses were conducted using R version 4.3.1, and agreement between the PoC assay and the STTT was assessed using kappa statistics with GraphPad software. Results: We included 102 previously-tested human serum samples, of which 19 samples (18.6%) were STTT positive. Compared to the STTT, the SNAP 4Dx Plus test demonstrated a low sensitivity of 0.16 (95% CI 0.03 to 0.40). Conclusion: Overall, our results do not support the use of the SNAP 4Dx Plus LD assay for the diagnosis of human Lyme disease. Differences in antibody concentrations between human and canine samples may partly explain our findings.

Bone marrow-derived myeloid cells transiently colonize the brain during postnatal development and interact with glutamatergic synapses.

Although the roles of embryonic yolk sac-derived, resident microglia in neurodevelopment were extensively studied, the possible involvement of bone marrow-derived cells remains elusive. In this work, we used a fate-mapping strategy to selectively label bone marrow-derived cells and their progeny in the brain (FLT3+IBA1+). FLT3+IBA1+ cells were confirmed to be transiently present in the healthy brain during early postnatal development. FLT3+IBA1+ cells have a distinct morphology index at postnatal day(P)0, P7, and P14 compared with neighboring microglia. FLT3+IBA1+ cells also express the microglial markers P2RY12 and TMEM119 and interact with VGLUT1 synapses at P14. Scanning electron microscopy indeed showed that FLT3+ cells contact and engulf pre-synaptic elements. Our findings suggest FLT3+IBA1+ cells might assist microglia in their physiological functions in the developing brain including synaptic pruning which is performed using their purinergic sensors. Our findings stimulate further investigation on the involvement of peripheral macrophages during homeostatic and pathological development.

First Response to Opioids Survey Tool (FROST): Pilot study of a brief screening tool to assess opioid use disorder risk.

OBJECTIVE: Early work suggests the type of subjective experiences upon first opioid use may predict opioid use disorder (OUD) risk. This study developed and pilot-tested a brief survey to evaluate the "first response" to opioids. DESIGN: A cross-sectional survey research study. The survey was administered to a subsample for the second time to assess test-retest reliability. SETTING: Outpatient. PARTICIPANTS: Convenience sample of adults treated for OUD at an opioid treatment program. MAIN OUTCOME MEASURES: A seven-question First Response to Opioids Survey Tool (FROST), developed based on the existing questionnaires and stakeholder-advisor feedback, was evaluated. RESULTS: Participants (N = 157) were 36.8 (standard deviation [SD] = 9.4) years old, with 79.6 percent identifying as Caucasian and 56.7 percent male. They reported opioid initiation at 20.6 (SD = 8.8) years old, with a prescription-based (78.3 percent), orally administered (66.2 percent), and illicitly procured (51.0 percent) opioids. Upon opioid initiation, positive-valence, euphoria-like subjective experiences of feeling "comfortable" (65.0 percent), "happy" (61.1 percent), "euphoria" (58.6 percent), and "energized" (44.6 percent) were common, and different (p < 0.05) from other types of subjective experiences. Among 64 individuals who answered a question about "drug-liking," 50 (78.1 percent) reported drug-liking. Among 31 respondents who completed the survey a second time, the test-retest consistency was 78.2 percent for subjective experience characteristics and 72 percent for drug-liking responses. Qualitative results corroborated quantitative findings. CONCLUSION: These results suggest that euphoria-type experiences and drug-liking upon opioid initiation are common among adults with OUD and FROST's promising psychometric properties. Future research should assess clinical utility of this brief survey, which could be applied at bedside and help identify those at risk for OUD, guide safer opioid prescribing, and reduce opioid-related harm.

A functional aged human iPSC-cortical neuron model recapitulates Alzheimer's disease, senescence, and the response to therapeutics.

INTRODUCTION: The degeneration of cortical layers is associated with cognitive decline in Alzheimer's disease (AD). Current therapies for AD are not disease-modifying, and, despite substantial efforts, research and development for AD has faced formidable challenges. In addition, cellular senescence has emerged as a significant contributor to therapy resistance. METHODS: Human iPSC-derived cortical neurons were cultured on microelectrode arrays to measure long-term potentiation (LTP) noninvasively. Neurons were treated with pathogenic amyloid-ß (Aß) to analyze senescence and response to therapeutic molecules. RESULTS: Microphysiological recordings revealed Aß dampened cortical LTP activity and accelerated neuronal senescence. Aging neurons secreted inflammatory factors previously detected in brain, plasma, and cerebral spinal fluid of AD patients, in which drugs modulated senescence-related factors. DISCUSSION: This platform measures and records neuronal LTP activity in response to Aß and therapeutic molecules in real-time. Efficacy data from similar platforms have been accepted by the FDA for neurodegenerative diseases, expediting regulatory submissions. HIGHLIGHTS: This work developed a progerontic model of amyloid-ß (Aß)-driven cortical degeneration. This work measured neuronal LTP and correlated function with aging biomarkers. Aß is a driver of neuronal senescence and cortical degeneration. Molecules rescued neuronal function but did not halt Aß-driven senescence. Therapeutic molecules modulated secretion of inflammatory factors by aging neurons.

Regional differences in leaf evolution facilitate photosynthesis following severe drought.

Characterizing physiological and anatomical changes that underlie rapid evolution following climatic perturbation can broaden our understanding of how climate change is affecting biodiversity. It can also provide evidence of cryptic adaptation despite stasis at higher levels of biological organization. Here, we compared evolutionary changes in populations of Mimulus cardinalis from historically different climates in the north and south of the species' range following an exceptional drought. We grew seeds produced from predrought ancestral plants alongside peak-drought descendants in a common glasshouse and exposed them to wet and dry conditions. Before the drought, northern ancestral populations expressed traits contributing to drought escape, while southern ancestral populations expressed drought avoidance. Following the drought, both regions evolved to reduce water loss and maintain photosynthesis in dry treatments (drought avoidance), but via different anatomical alterations in stomata, trichomes, and palisade mesophyll. Additionally, southern populations lost the ability to take advantage of wet conditions. These results reveal rapid evolution towards drought avoidance at an anatomical level following an exceptional drought, but suggest that differences in the mechanisms between regions incur different trade-offs. This sheds light on the importance of characterizing underlying mechanisms for downstream life-history and macromorphological traits.