Comprehensive review and comparison on pretreatment of spent lithium-ion battery.

Pretreatment, the initial step in recycling spent lithium-ion batteries (LIBs), efficiently separates cathode and anode materials to facilitate key element recovery. Despite brief introductions in existing research, a comprehensive evaluation and comparison of processing methods is lacking. This study reviews 346 references on LIBs recycling, analyzing pretreatment stages, treatment conditions, and method effects. Our analysis highlights insufficient attention to discharge voltage safety and environmental impact. Mechanical disassembly, while suitable for industrial production, overlooks electrolyte recovery and complicates LIBs separation. High temperature pyrolysis flotation offers efficient separation of mixed electrode materials, enhancing mineral recovery. We propose four primary pretreatment processes: discharge, electrolyte recovery, crushing and separation, and electrode material recovery, offering simplified, efficient, green, low-cost, and high-purity raw materials for subsequent recovery processes.

A Prelimbic Cortex-Thalamus Circuit Bidirectionally Regulates Innate and Stress-induced Anxiety-like Behavior.

Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggest that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.Significance statement This study provides insight into PL downstream pathways for regulating innate and stress-induced anxiety-like behavior. We reported that PL-mediodorsal thalamic nucleus (MD) projection and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, this study provides definite evidence that MD-projecting PL neurons bidirectionally regulated remote fear memory retrieval and concordant with a role for the PL-MD in anxiety. Moreover, this study is the first demonstration that restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety.

Mature astrocytes as source for astrocyte repopulation after deletion in the medial prefrontal cortex: Implications for depression.

The adult brain retains a high repopulation capacity of astrocytes after deletion, and both mature astrocytes in the neocortex and neural stem cells in neurogenic regions possess the potential to generate astrocytes. However, the origin and the repopulation dynamics of the repopulating astrocytes after deletion remain largely unclear. The number of astrocytes is reduced in the medial prefrontal cortex (mPFC) of patients with depression, and selective elimination of mPFC astrocytes is sufficient to induce depression-like behaviors in rodents. However, whether astrocyte repopulation capacity is impaired in depression is unknown. In this study, we used different transgenic mouse lines to genetically label different cell types and demonstrated that in the mPFC of normal adult mice of both sexes, mature astrocytes were a major source of the repopulating astrocytes after acute deletion induced by an astrocyte-specific toxin, L-alpha-aminoadipic acid (L-AAA), and astrocyte regeneration was accomplished within two weeks accompanied by reversal of depression-like behaviors. Furthermore, re-ablation of mPFC astrocytes post repopulation led to reappearance of depression-like behaviors. In adult male mice subjected to 14-day chronic restraint stress, a well-validated mouse model of depression, the number of mPFC astrocytes was reduced; however, the ability of mPFC astrocytes to repopulate after L-AAA-induced deletion was largely unaltered. Our study highlights a potentially beneficial role for repopulating astrocytes in depression and provides novel therapeutic insights into enhancing local mature astrocyte generation in depression.

Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice.

Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients' blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.

Extracellular ATP Is a Homeostatic Messenger That Mediates Cell-Cell Communication in Physiological Processes and Psychiatric Diseases.

Neuronal activity is the basis of information encoding and processing in the brain. During neuronal activation, intracellular ATP (adenosine triphosphate) is generated to meet the high-energy demands. Simultaneously, ATP is secreted, increasing the extracellular ATP concentration and acting as a homeostatic messenger that mediates cell-cell communication to prevent aberrant hyperexcitability of the nervous system. In addition to the confined release and fast synaptic signaling of classic neurotransmitters within synaptic clefts, ATP can be released by all brain cells, diffuses widely, and targets different types of purinergic receptors on neurons and glial cells, making it possible to orchestrate brain neuronal activity and participate in various physiological processes, such as sleep and wakefulness, learning and memory, and feeding. Dysregulation of extracellular ATP leads to a destabilizing effect on the neural network, as found in the etiopathology of many psychiatric diseases, including depression, anxiety, schizophrenia, and autism spectrum disorder. In this review, we summarize advances in the understanding of the mechanisms by which extracellular ATP serves as an intercellular signaling molecule to regulate neural activity, with a focus on how it maintains the homeostasis of neural networks. In particular, we also focus on neural activity issues that result from dysregulation of extracellular ATP and propose that aberrant levels of extracellular ATP may play a role in the etiopathology of some psychiatric diseases, highlighting the potential therapeutic targets of ATP signaling in the treatment of these psychiatric diseases. Finally, we suggest potential avenues to further elucidate the role of extracellular ATP in intercellular communication and psychiatric diseases.

Preparation of Healthy Single Neuron or Astrocyte Suspension from Adult Mouse Brain for RNA-seq.

Single-cell RNA sequencing (scRNA-seq) has been widely applied in neuroscience research, enabling the investigation of cellular heterogeneity at the transcriptional level, the characterization of rare cell types, and the detailed analysis of the stochastic nature of gene expression. Isolation of single nerve cells in good health, especially from the adult rodent brain, is the most difficult and critical process for scRNA-seq. Here, we describe methods to optimize protease digestion of brain slices, which enable yield of millions of cells in good health from the adult brain.

Dyskinesia and Pain in Advanced Parkinson's Disease: Post Hoc Analysis from the Phase 3b, Open-Label, Randomized DYSCOVER Study.

INTRODUCTION: The DYSCOVER study was a phase 3b, open-label, randomized trial (NCT02799381) that evaluated levodopa-carbidopa intestinal gel (LCIG) versus optimized medical treatment (OMT) in patients with Parkinson's disease (PD) and a high burden of dyskinesia at baseline (defined as Unified Dyskinesia Rating Scale [UDysRS] total score ≥ 30). At week 12, patients receiving LCIG versus OMT experienced significant improvements in dyskinesia, pain, and health-related outcomes. The objective of this analysis was to examine correlations between dyskinesia, pain, and health-related outcomes in PD. METHODS: This post hoc analysis assessed correlations between UDysRS, King's Parkinson's Disease Pain Scale (KPPS), 8-item Parkinson's Disease Questionnaire (PDQ-8), Unified Parkinson's Disease Rating Scale part II, Clinical Global Impression of Severity (CGI-S) or Change (CGI-C), and "On" time without troublesome dyskinesia at baseline and after 12 weeks of LCIG or OMT. Correlations were assessed by Pearson correlation coefficients (categorization: weak, r = 0.20-0.39; moderate, r = 0.40-0.59; strong, r ≥ 0.60). RESULTS: Among 61 patients, moderate-to-strong positive and significant correlations were observed between UDysRS and KPPS scores (baseline, r = 0.47; week 12 change from baseline [CFB], r = 0.63; all p < 0.001). UDysRS and KPPS scores had moderate-to-strong positive and highly significant correlations with PDQ-8 scores (baseline, r = 0.45 and 0.46, respectively; CFB, r = 0.54 and 0.64, respectively; all p < 0.001). Moderate positive and significant correlations were observed between UDysRS and CGI-S/CGI-C scores (baseline, r = 0.41; CFB, r = 0.47; all p < 0.001). CONCLUSIONS: In patients with high dyskinesia burden, positive correlations were observed between dyskinesia, pain, and health-related quality of life (HRQoL) at baseline. Improvements in dyskinesia and pain were associated with improvements in HRQoL, demonstrating the clinical burden of troublesome dyskinesia. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov identifier NCT02799381.

Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy.

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Effects of upadacitinib on enthesitis in patients with psoriatic arthritis: a post hoc analysis of SELECT-PsA 1 and 2.

OBJECTIVES: To characterize the effect of upadacitinib 15 mg once daily (UPA15) on enthesitis in patients with psoriatic arthritis from the SELECT-PsA Phase 3 trials. METHODS: Patients with an inadequate response/intolerance to ≥ 1 non-biologic DMARD (SELECT-PsA 1) or ≥ 1 biologic DMARD (SELECT-PsA 2) received UPA15, adalimumab 40 mg every other week or placebo (weeks 0-24) switched to UPA15 (week 24 onward). The Leeds Enthesitis Index (LEI) and Spondyloarthritis Research Consortium of Canada (SPARCC) index were used to assess improvement in enthesitis, enthesitis resolution, maintenance of enthesitis resolution, and protection from enthesitis development through week 56. RESULTS: Data from 639 patients receiving UPA15 and 635 patients receiving placebo (including 317 patients who switched from placebo to UPA15) were analysed. UPA15 led to higher rates of enthesitis resolution vs placebo at week 24 (LEI: 59.8% vs 38.0%; SPARCC index: 50.6% vs 31.5%, respectively) and greater improvements in the LEI (-1.7 vs -1.0) and SPARCC index (-3.4 vs -1.9); improvements were maintained through week 56. Improvements were observed after 12 weeks of UPA15 treatment. Over 90% of patients without enthesitis (LEI = 0) at baseline receiving UPA15 were enthesitis-free at week 56, and UPA15 prevented recurrence of enthesitis at week 56 in > 80% of patients with enthesitis at baseline who achieved resolution (LEI = 0) at week 24. CONCLUSIONS: UPA15 is associated with a comprehensive improvement in enthesitis, with improvements observed after 12 weeks of treatment. Additionally, treatment with UPA15 was associated with maintaining an enthesitis-free state after resolution and protection against new-onset enthesitis. CLINICALTRIALS.GOV IDENTIFIERS: NCT03104400 (SELECT-PsA 1) and NCT03104374 (SELECT-PsA 2).

The mechanism of China's renewable energy utilization impact on carbon emission intensity: Evidence from the perspective of intermediary transmission.

Renewable energy (RE) plays a crucial role in global energy transformation, and a thorough study of the potential impact of RE on regional carbon emissions is of great significance. This is particularly relevant to China, which needs to clarify its path to carbon reduction. Using the sample data of 30 provinces in China from 2000 to 2021, this paper uses the Granger causality test to verify the causal relationship between carbon emission intensity (CEI) and other factors. It builds a mediation effect model on this basis to explore the direct impact effect and indirect transmission path of renewable energy utilization (REU) on CEI. The results show that REU has a one-way causal relationship with CEI. REU can directly and indirectly reduce CEI by improving social wealth and changing the direction of energy investment. In addition, REU indirectly increases CEI through the transmission paths of investment in the energy industry - social affluence and industrial level-social affluence. The CEI is indirectly reduced through the conduction paths of (social affluence-Urbanization rate), (Investment in the energy industry-Urbanization rate), (Industrial level-Urbanization rate), and (Industrial level-Investment in the energy industry). These conclusions will assist policymakers in exploring targeted pathways for low-carbon power development, providing a reference for strategic and sustainable carbon reduction policies.

Dopamine D2 receptors in pyramidal neurons in the medial prefrontal cortex regulate social behavior.

Drugs acting on dopamine D2 receptors are widely used for the treatment of several neuropsychiatric disorders, including schizophrenia and depression. Social deficits are a core symptom of these disorders. Pharmacological manipulation of dopamine D2 receptors (Drd2), a Gi-coupled subtype of dopamine receptors, in the medial prefrontal cortex (mPFC) has shown that Drd2 is implicated in social behaviors. However, the type of neurons expressing Drd2 in the mPFC and the underlying circuit mechanism regulating social behaviors remain largely unknown. Here, we show that Drd2 were mainly expressed in pyramidal neurons in the mPFC and that the activation of the Gi-pathway in Drd2+ pyramidal neurons impaired social behavior in male mice. In contrast, the knockdown of D2R in pyramidal neurons in the mPFC enhanced social approach behaviors in male mice and selectively facilitated the activation of mPFC neurons projecting to the nucleus accumbens (NAc) during social interaction. Remarkably, optogenetic activation of mPFC-to-NAc-projecting neurons mimicked the effects of conditional D2R knockdown on social behaviors. Altogether, these results demonstrate a cell type-specific role for Drd2 in the mPFC in regulating social behavior, which may be mediated by the mPFC-to-NAc pathway.

The decreased risk of hepatocellular carcinoma in hepatitis B virus-related cirrhotic portal hypertension patients after laparoscopic splenectomy and azygoportal disconnection.

BACKGROUND: Posthepatitic cirrhosis is one of the leading risk factors for hepatocellular carcinoma (HCC) worldwide, among which hepatitis B cirrhosis is the dominant one. This study explored whether laparoscopic splenectomy and azygoportal disconnection (LSD) can reduce the risk of HCC among patients with hepatitis B virus (HBV)-related cirrhotic portal hypertension (CPH). METHODS: A total of 383 patients with HBV-related CPH diagnosed as gastroesophageal variceal bleeding and secondary hypersplenism were identified in our hepatobiliary pancreatic center between April 2012 and April 2022, and conducted an 11-year retrospective follow-up. We used inverse probability of treatment weighting (IPTW) to correct for potential confounders, weighted Kaplan-Meier curves, and logistic regression to estimate survival and risk differences. RESULTS: Patients were divided into two groups based on treatment method: LSD (n = 230) and endoscopic therapy (ET; n = 153) groups. Whether it was processed through IPTW or not, LSD group showed a higher survival benefit than ET group according to Kaplan-Meier analysis (P < 0.001). The incidence density of HCC was higher in the ET group compared to LSD group at the end of follow-up [32.1/1000 vs 8.0/1000 person-years; Rate ratio: 3.998, 95% confidence intervals (CI) 1.928-8.293]. Additionally, in logistic regression analyses weighted by IPTW, LSD was an independent protective predictor of HCC incidence compared to ET (odds ratio 0.516, 95% CI 0.343-0.776; P = 0.002). CONCLUSION: Considering the ability of LSD to improve postoperative survival and prevent HCC in HBV-related CPH patients with gastroesophageal variceal bleeding and secondary hypersplenism, it is worth promoting in the context of the shortage of liver donors.

Increased NMDARs in neurons and glutamine synthetase in astrocytes underlying autistic-like behaviors of Gabrb1-/- mice.

Mutations of the GABA-A receptor subunit ß1 (GABRB1) gene are found in autism patients. However, it remains unclear how mutations in Gabrb1 may lead to autism. We generated Gabrb1-/- mouse model, which showed autistic-like behaviors. We carried out RNA-seq on the hippocampus and found glutamatergic pathway may be involved. We further carried out single-cell RNA sequencing on the whole brain followed by qRT-PCR, immunofluorescence, electrophysiology, and metabolite detection on specific cell types. We identified the up-regulated Glul/Slc38a3 in astrocytes, Grin1/Grin2b in neurons, glutamate, and the ratio of Glu/GABA in the hippocampus. Consistent with these results, increased NMDAR-currents and reduced GABAAR-currents in the CA1 neurons were detected in Gabrb1-/- mice. NMDAR antagonist memantine or Glul inhibitor methionine sulfoximine could rescue the abnormal behaviors in Gabrb1-/- mice. Our data reveal that upregulation of the glutamatergic synapse pathway, including NMDARs at neuronal synapses and glutamine exported by astrocytes, may lead to autistic-like behaviors.

A comparison of the impact on neuronal transcriptome and cognition of rAAV5 transduction with three different doses in the mouse hippocampus.

Introduction: Recombinant adeno-associated viruses (rAAVs) are widely used in genetic therapeutics. AAV5 has shown superior transduction efficiency, targeting neurons and glial cells in primate brains. Nonetheless, the comprehensive impact of AAV5 transduction on molecular and behavioral alterations remains unexplored. This study focuses on evaluating the effects of AAV5 transduction in the hippocampus, a critical region for memory formation and emotional processes. Methods: In this experiment, fluorescence-activated cell sorting (FACS) was utilized to isolate the mCherry-labeled pyramidal neurons in the hippocampus of CaMkIIα-cre mice following three different doses rAAV5-mCherry infusion after 3 weeks, which were then subjected to RNA sequencing (RNA-seq) to assess gene expression profiles. The cytokines concentration, mRNA expression, and glial response in hippocampi were confirmed by ELASA, digital droplet PCR and immunohistochemistry respectively. Locomotion and anxiety-like behaviors were elevated by Open Field Test and Elevated Plus Maze Test, while the Y-Maze were used to assessed spatial working memory. Recognition memory and fear responses were examined by the Novel Object Recognition Test and Fear Conditioning Test, respectively. Results: We found that 2.88 × 1010 v.g rAAV5 transduction significantly upregulated genes related to the immune response and apoptosis, and downregulated genes associated with mitochondrial function and synaptic plasticity in hippocampal pyramidal neurons, while did not induce neuronal loss and gliosis compared with 2.88 × 109 v.g and 2.88 × 108 v.g. Furthermore, the same doses impaired working memory and contextual fear memory, without effects on locomotion and anxiety-related behaviors. Discussion: Our findings highlight the detrimental impact of high-dose administration compared to median-dose or low-dose, resulting in increased neural vulnerability and impaired memory. Therefore, when considering the expression effectiveness of exogenous genes, it is crucial to also take potential side effects into account in clinical settings. However, the precise molecular mechanisms underlying these drawbacks of high-dose rAAV5-mCherry still require further investigation in future studies.

EphB6 deficiency in intestinal neurons promotes tumor growth in colorectal cancer by neurotransmitter GABA signaling.

EphB6 belongs to the receptor tyrosine kinase, whose low expression is associated with shorter survival of colorectal cancer (CRC) patients. But the role and mechanism of EphB6 in the progression of CRC need further study. In addition, EphB6 was mainly expressed in intestinal neurons. But how EphB6 is involved in functions of intestinal neurons has not been known. In our study, we constructed a mouse xenograft model of CRC by injecting CMT93 cells into the rectum of EphB6-deficient mice. We found that the deletion of EphB6 in mice promoted tumor growth of CMT93 cells in a xenograft model of CRC, which was independent of changes in the gut microbiota. Interestingly, inhibition of intestinal neurons by injecting botulinum toxin A into rectum of EphB6-deficient mice could eliminate the promotive effect of EphB6 deficiency on tumor growth in the xenograft model of CRC. Mechanically, the deletion of EphB6 in mice promoted the tumor growth in CRC by increasing GABA in the tumor microenvironment. Furthermore, EphB6 deficiency in mice increased the expression of synaptosomal-associated protein 25 in the intestinal myenteric plexus, which mediated the release of GABA. Our study concluded that EphB6 knockout in mice promotes tumor growth of CMT93 cells in a xenograft model of CRC by modulating GABA release. Our study found a new regulating mechanism of EphB6 on the tumor progression in CRC that is dependent on intestinal neurons.

Regional differences and driving factors of carbon emission intensity in China's electricity generation sector.

As an industry with immense decarbonization potential, the low-carbon transformation of the power sector is crucial to China's carbon emission (CE) reduction commitment. Based on panel data of 30 provinces in China from 2000 to 2019, this research calculates and analyzes the provincial CE intensity in electricity generation (CEIE) and its spatial distribution characteristics. Additionally, the GTWR model based on the construction explains the regional heterogeneity and dynamic development trend of each driving factor's influence on CEIE from time and space. The main results are as follows: CEIE showed a gradual downward trend in time and a spatial distribution pattern of high in the northeast and low in the southwest. The contribution of driving factors to CEIE has regional differences, and the power structure contributes most to the CEIE of the power sector, which promotes regional CE. Concurrently, most provinces with similar economic development, technological level, geographic location, or resource endowment characteristics show similar spatial and temporal trends. These detections will furnish broader insights into implementing CE reduction policies for the regional power sector.