Although single-cell RNA sequencing studies have begun to provide compendia of cell expression profiles
, it has been difficult to systematically identify and localize all molecular cell types in ...individual organs to create a full molecular cell atlas. Here, using droplet- and plate-based single-cell RNA sequencing of approximately 75,000 human cells across all lung tissue compartments and circulating blood, combined with a multi-pronged cell annotation approach, we create an extensive cell atlas of the human lung. We define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 out of 45 previously known cell types and 14 previously unknown ones. This comprehensive molecular atlas identifies the biochemical functions of lung cells and the transcription factors and markers for making and monitoring them; defines the cell targets of circulating hormones and predicts local signalling interactions and immune cell homing; and identifies cell types that are directly affected by lung disease genes and respiratory viruses. By comparing human and mouse data, we identified 17 molecular cell types that have been gained or lost during lung evolution and others with substantially altered expression profiles, revealing extensive plasticity of cell types and cell-type-specific gene expression during organ evolution including expression switches between cell types. This atlas provides the molecular foundation for investigating how lung cell identities, functions and interactions are achieved in development and tissue engineering and altered in disease and evolution.
Microglia regulate synaptic circuit remodeling and phagocytose synaptic material in the healthy brain; however, the mechanisms directing microglia to engulf specific synapses and avoid others remain ...unknown. Here, we demonstrate that an innate immune signaling pathway protects synapses from inappropriate removal. The expression patterns of CD47 and its receptor, SIRPα, correlated with peak pruning in the developing retinogeniculate system, and mice lacking these proteins exhibited increased microglial engulfment of retinogeniculate inputs and reduced synapse numbers in the dorsal lateral geniculate nucleus. CD47-deficient mice also displayed increased functional pruning, as measured by electrophysiology. In addition, CD47 was found to be required for neuronal activity-mediated changes in engulfment, as microglia in CD47 knockout mice failed to display preferential engulfment of less active inputs. Taken together, these results demonstrate that CD47-SIRPα signaling prevents excess microglial phagocytosis and show that molecular brakes can be regulated by activity to protect specific inputs.
•“Don’t eat me” signals are developmentally regulated in the dLGN during peak pruning•CD47KO and SIRPαKO mice exhibit increased microglial engulfment•CD47KOs show increased functional pruning and sustained reductions in synapse number•CD47 is localized to more active inputs and required for activity-dependent engulfment
Lehrman et al. discover that CD47-SIRPα signaling prevents excess microglial phagocytosis during developmental synaptic pruning. They find that CD47 is required for neuronal activity-mediated changes in microglial engulfment and that mice lacking CD47 display increased structural and functional pruning.
This Note offers an efficiency-effectiveness framework for evaluating the success of school finance and teacher tenure court-ordered legislative reforms. In June 2014, Los Angeles Superior Court ...Judge Rolf Treu struck down California's teacher tenure laws as unconstitutional in the landmark case Vergara v. State. While the California Court of Appeal reversed the trial court's order and the California Supreme Court declined to review the decision, I argue that lessons from the Vergara case remain relevant to explain the complex relationship between the legislature and courts in teacher tenure and school finance reform. Political factors such as disunited political leadership and interest groups, lack of political priming, and inability to use a court-created policy window suggested that any hypothetical Vergara legislative remedy was likely to be a low-efficiency/no-effectiveness paradigm similar to the New York Campaign for Fiscal Equity, with such a remedy languishing in years of endless litigation. In contrast, a better path forward would have relied on a Williams model of high-efficiency/moderate-effectiveness to seek moderate reform and resolve the Vergara litigation through settlement. Consequently, even though the Vergara case has been resolved, the efficiency-effectiveness framework remains relevant as a method of analyzing the success of future California teacher tenure lawsuits as well as teacher tenure lawsuits in other states.
Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a ...role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2–inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869.
•Ibrutinib induced a high rate of sustained responses for patients with cGVHD and inadequate response to corticosteroid-containing therapy.•This trial supported the approval of ibrutinib for treatment of adult patients with cGVHD after failure of ≥1 lines of systemic therapy.
•Orbitofrontal cortex lesions had no effect on initial acquisition of sign-tracking.•Orbitofrontal cortex lesions impaired sign-tracking during reversal learning.•Orbitofrontal cortex is critical for ...modifying previously learned behaviors.
A cue associated with a rewarding event can trigger behavior towards the cue itself due to the cue acquiring incentive value through its pairing with the rewarding outcome (i.e., sign-tracking). For example, rats will approach, press, and attempt to “consume” a retractable lever conditioned stimulus (CS) that signals delivery of a food unconditioned stimulus (US). Attending to food-predictive CSs is important when seeking out food, and it is just as important to be able to modify one's behavior when the relationships between CSs and USs are changed. Using a discriminative autoshaping procedure with lever CSs, the present study investigated the effects of orbitofrontal cortex (OFC) lesions on sign-tracking and reversal learning. Insertion of one lever was followed by sucrose delivery upon retraction, and insertion of another lever was followed by nothing. After the acquisition phase, the contingencies between the levers and outcomes were reversed. Bilateral OFC lesions had no effect on the acquisition of sign-tracking. However, OFC-lesioned rats showed substantial deficits in acquiring sign-tracking compared to sham-lesioned rats once the stimulus-outcome contingencies were reversed. Over the course of reversal learning, OFC-lesioned rats were able to reach comparable levels of sign-tracking as sham-lesioned rats. These findings suggest that OFC is not necessary for the ability of a CS to acquire incentive value and provide more evidence that OFC is critical for modifying behavior appropriately following a change in stimulus-outcome contingencies.
Rationale
Understanding the behavioral and neurobiological factors that render some individuals more susceptible than others to opioid addiction will be critical in combatting the opioid crisis.
...Objective
The purpose of the current study was to determine if behavioral traits associated with an increased likelihood to take and seek cocaine are the same traits that render one more susceptible to opioid-taking and opioid-seeking behavior. Individual differences in the acquisition of remifentanil self-administration and subsequent cue-induced reinstatement of remifentanil-seeking behavior were investigated using two animal models: the high-responder (HR)/low-responder (LR) and sign-tracker (ST)/goal-tracker (GT) models. Relative to LR rats, HR rats show increased novelty-induced locomotion or “sensation-seeking” behavior, and are more likely to acquire cocaine-taking behavior and do so at a faster rate. Relative to GT rats, ST rats attribute greater incentive motivational value to reward cues and are more likely to exhibit reinstatement of cocaine-seeking behavior.
Results
In contrast to previous work using cocaine, we did not observe individual differences with respect to the acquisition of remifentanil self-administration- or cue-induced reinstatement of remifentanil-seeking behavior within the context of either the HR/LR or ST/GT model. Thus, neither the sensation-seeking trait nor the propensity to attribute incentive motivational value to reward cues predicts remifentanil-taking or remifentanil-seeking behavior.
Conclusions
These findings suggest that different traits may confer the initiation of opioid- vs. cocaine-taking behavior, and the propensity to relapse to opioid- vs. cocaine-seeking. Additional studies are needed to identify which neurobehavioral constructs confer liability to opioid use and relapse.
Total waste from human activities, including waste plastics, is huge in Hong Kong. In particular, as a result of the prevention and control measures implemented during the COVID-19 pandemic, ...take-away meals increased tremendously in Hong Kong, generating disposable plastic tableware (DPT). Although Hong Kong has a charging scheme for plastic bags, it does not have a scheme for plastic tableware. Therefore, this study aimed to understand the attitudes and behavior of people in Hong Kong toward DPT. Our study focused on undergraduate students in Hong Kong, given that they will play a significant role in the future of environmental sustainability. The attitudes and behavior of Hong Kong undergraduate students toward DPT were examined through an online survey with 385 respondents. A multiple stepwise regression was conducted to investigate whether cognitive attitude formation factors could explain the sustainable attitudes formed by undergraduate students in Hong Kong. The survey results revealed that most undergraduates considered DPT to be one of the major causes of environmental damage in Hong Kong; however, many of them, particularly those who strongly agreed with this statement, said that the problem of DPT did not affect their quality of life. The regression analysis showed that imposing a DPT charge would be the most significant driver to reduce its use. The research findings identified gaps between attitudes and behavior regarding the use of DPT and the factors influencing sustainable DPT consumption.
The azide anion (N
3
-) is highly toxic. It exists most commonly as sodium azide, which is used widely and is readily available, raising the potential for occupational incidents and use as a weapon ...of mass destruction. Azide-poisoned patients present with vomiting, seizures, hypotension, metabolic acidosis, and coma; death can occur. No specific azide antidote exists, with treatment being solely supportive. Azide inhibits mitochondrial cytochrome c oxidase and is likely oxidized to nitric oxide in vivo. Cytochrome c oxidase inhibition depletes intracellular adenosine triphosphate and increases oxidative stress, while increased nitric oxide causes hypotension and exacerbates oxidative damage. Here, we tested whether the cobalamin (vitamin B
12
) analog cobinamide, a strong and versatile antioxidant that also neutralizes nitric oxide, can reverse azide toxicity in mammalian cells, Drosophila melanogaster, and mice.
We found cobinamide bound azide with a moderate affinity (K
a
2.87 × 10
5
M
−1
). Yet, cobinamide improved growth, increased intracellular adenosine triphosphate, and reduced apoptosis and malondialdehyde, a marker of oxidative stress, in azide-exposed cells. Cobinamide rescued Drosophila melanogaster and mice from lethal exposure to azide and was more effective than hydroxocobalamin. Azide likely generated nitric oxide in the mice, as evidenced by increased serum nitrite and nitrate, and reduced blood pressure and peripheral body temperature in the animals; the reduced temperature was likely due to reflex vasoconstriction in response to the hypotension. Cobinamide improved recovery of both blood pressure and body temperature.
We conclude cobinamide likely acted by neutralizing both oxidative stress and nitric oxide, and that it should be given further consideration as an azide antidote.
Cues associated with rewarding events acquire value themselves as a result of the incentive value of the reward being transferred to the cue. Consequently, presentation of a reward‐paired cue can ...trigger reward‐seeking behaviours towards the cue itself (i.e. sign‐tracking). The ventral pallidum (VP) has been demonstrated to be involved in a number of motivated behaviours, both conditioned and unconditioned. However, its contribution to the acquisition of incentive value is unknown. Using a discriminative autoshaping procedure with levers, the effects of disrupting VP activity in rats on the emergence of sign‐tracking was investigated using chemogenetics, i.e. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Transient disruption of VP neurons activation of the inhibitory hM4D(Gi) DREADD through systemic injections of clozapine N‐oxide (CNO) prior to each autoshaping session impaired acquisition of sign‐tracking (lever press rate) without having any effect on approach to the site of reward delivery (i.e. goal‐tracking) or on the expression of sign‐tracking after it was acquired. In addition, electrophysiological recordings were conducted in freely behaving rats following VP DREADD activation. The majority of VP units that were responsive to CNO injections exhibited rapid inhibition relative to baseline, a subset of CNO‐responsive units showed delayed excitation, and a smaller subset displayed a mixed response of inhibition and excitation following CNO injections. It is argued that disruption of VP during autoshaping specifically disrupted the transfer of incentive value that was attributed to the lever cue, suggesting a surprisingly fundamental role for the VP in acquiring, compared with expressing, Pavlovian incentive values.
We show that chemogenetic disruption of VP activity using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) impaired the acquisition of sign‐tracking and provide the first characterization of changes in neural activity following activation of inhibitory DREADDs in freely behaving rats.
Appetitive sign-tracking, in which reward-paired cues elicit approach that can result in cue interaction, demonstrates how cues acquire motivational value. For example, rats will approach and ...subsequently interact with a lever insertion cue that signals food delivery upon its retraction. However, lever deflections are rapidly reduced once rats are trained on an omission schedule in which lever interactions cancel food delivery. Here we evaluated the change in sign-tracking response topography in rats exposed to such an omission procedure. Lever deflections dropped precipitously when they canceled reward. However, rats that were on an omission schedule continued to approach, sniff, and contact the lever without pressing it, and did so at comparable rates to rats that were not under an omission schedule. Thus, sign-tracking was maintained, albeit in a different manner, following omission. Such findings show that the motivational attraction to reward cues can be expressed with remarkable persistence and flexibility.
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