Integrated analysis of lncRNA, miRNA and mRNA expression profiles reveals regulatory pathways associated with pig testis function.

Long noncoding RNA (lncRNA) and microRNA (miRNA) are known to play pivotal roles in mammalian testicular function and spermatogenesis. However, their impact on porcine male reproduction has yet to be well unraveled. Here, we sequenced and identified lncRNA and miRNA expressed in the testes of Chinese indigenous Banna mini-pig inbred line (BMI) and introduced Western Duroc (DU) and Large White (LW) pigs. By pairwise comparison (BMI vs DU, BMI vs LW, and DU vs LW), we found the gene expression differences in the testes between Chinese local pigs and introduced Western commercial breeds were more striking than those between introduced commercial breeds. Furthermore, we found 1622 co-differentially expressed genes (co-DEGs), 122 co-differentially expressed lncRNAs (co-DELs), 39 co-differentially expressed miRNAs (co-DEMs) in BMI vs introduced commercial breeds (DU and LW). Functional analysis revealed that these co-DEGs and co-DELs/co-DEMs target genes were enriched in male sexual function pathways, including MAPK, AMPK, TGF-ß/Smad, Hippo, NF-kappa B, and PI3K/Akt signaling pathways. Additionally, we established 10,536 lncRNA-mRNA, 11,248 miRNA-mRNA pairs, and 62 ceRNA (lncRNA-miRNA-mRNA) networks. The ssc-miR-1343 had the most interactive factors in the ceRNA network, including 20 mRNAs and 3 lncRNAs, consisting of 56 ceRNA pairs. These factors played extremely important roles in the regulation of testis function as key nodes in the interactive regulatory network. Our results provide insight into the functional roles of lncRNAs and miRNAs in porcine testis and offer a valuable resource for understanding the differences between Chinese indigenous and introduced Western pigs.

Deficiency of Cullin 3, a Protein Encoded by a Schizophrenia and Autism Risk Gene, Impairs Behaviors by Enhancing the Excitability of Ventral Tegmental Area (VTA) DA Neurons.

The dopaminergic neuromodulator system is fundamental to brain functions. Abnormal dopamine (DA) pathway is implicated in psychiatric disorders, including schizophrenia (SZ) and autism spectrum disorder (ASD). Mutations in Cullin 3 (CUL3), a core component of the Cullin-RING ubiquitin E3 ligase complex, have been associated with SZ and ASD. However, little is known about the function and mechanism of CUL3 in the DA system. Here, we show that CUL3 is critical for the function of DA neurons and DA-relevant behaviors in male mice. CUL3-deficient mice exhibited hyperactive locomotion, deficits in working memory and sensorimotor gating, and increased sensitivity to psychostimulants. In addition, enhanced DA signaling and elevated excitability of the VTA DA neurons were observed in CUL3-deficient animals. Behavioral impairments were attenuated by dopamine D2 receptor antagonist haloperidol and chemogenetic inhibition of DA neurons. Furthermore, we identified HCN2, a hyperpolarization-activated and cyclic nucleotide-gated channel, as a potential target of CUL3 in DA neurons. Our study indicates that CUL3 controls DA neuronal activity by maintaining ion channel homeostasis and provides insight into the role of CUL3 in the pathogenesis of psychiatric disorders.SIGNIFICANCE STATEMENT This study provides evidence that Cullin 3 (CUL3), a core component of the Cullin-RING ubiquitin E3 ligase complex that has been associated with autism spectrum disorder and schizophrenia, controls the excitability of dopamine (DA) neurons in mice. Its DA-specific heterozygous deficiency increased spontaneous locomotion, impaired working memory and sensorimotor gating, and elevated response to psychostimulants. We showed that CUL3 deficiency increased the excitability of VTA DA neurons, and inhibiting D2 receptor or DA neuronal activity attenuated behavioral deficits of CUL3-deficient mice. We found HCN2, a hyperpolarization-activated channel, as a target of CUL3 in DA neurons. Our findings reveal CUL3's role in DA neurons and offer insights into the pathogenic mechanisms of autism spectrum disorder and schizophrenia.

circUSP13 facilitates the fast-to-slow myofiber shift via the MAPK/ERK signaling pathway in goat skeletal muscles.

Understanding how skeletal muscle fiber proportions are regulated is essential for understanding muscle function and improving the quality of mutton. While circular RNA (circRNA) has a critical function in myofiber type transformation, the specific mechanisms are not yet fully understood. Prior evidence indicates that circular ubiquitin-specific peptidase 13 (circUSP13) can promote myoblast differentiation by acting as a ceRNA, but its potential role in myofiber switching is still unknown. Herein, we found that circUSP13 enhanced slow myosin heavy chain (MyHC-slow) and suppressed MyHC-fast expression in goat primary myoblasts (GPMs). Meanwhile, circUSP13 evidently enhanced the remodeling of the mitochondrial network while inhibiting the autophagy of GPMs. We obtained fast-dominated myofibers, via treatment with rotenone, and further demonstrated the positive role of circUSP13 in the fast-to-slow transition. Mechanistically, activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway significantly impaired the slow-to-fast shift in fully differentiated myotubes, which was restored by circUSP13 or IGF1 overexpression. In conclusion, circUSP13 promoted the fast-to-slow myofiber type transition through MAPK/ERK signaling in goat skeletal muscle. These findings provide novel insights into the role of circUSP13 in myofiber type transition and contribute to a better understanding of the genetic mechanisms underlying meat quality.

Genome-wide identification of JAZ gene family members in autotetraploid cultivated alfalfa (Medicago sativa subsp. sativa) and expression analysis under salt stress.

BACKGROUND: Jasmonate ZIM-domain (JAZ) proteins, which act as negative regulators in the jasmonic acid (JA) signalling pathway, have significant implications for plant development and response to abiotic stress. RESULTS: Through a comprehensive genome-wide analysis, a total of 20 members of the JAZ gene family specific to alfalfa were identified in its genome. Phylogenetic analysis divided these 20 MsJAZ genes into five subgroups. Gene structure analysis, protein motif analysis, and 3D protein structure analysis revealed that alfalfa JAZ genes in the same evolutionary branch share similar exon‒intron, motif, and 3D structure compositions. Eight segmental duplication events were identified among these 20 MsJAZ genes through collinearity analysis. Among the 32 chromosomes of the autotetraploid cultivated alfalfa, there were 20 MsJAZ genes distributed on 17 chromosomes. Extensive stress-related cis-acting elements were detected in the upstream sequences of MsJAZ genes, suggesting that their response to stress has an underlying function. Furthermore, the expression levels of MsJAZ genes were examined across various tissues and under the influence of salt stress conditions, revealing tissue-specific expression and regulation by salt stress. Through RT‒qPCR experiments, it was discovered that the relative expression levels of these six MsJAZ genes increased under salt stress. CONCLUSIONS: In summary, our study represents the first comprehensive identification and analysis of the JAZ gene family in alfalfa. These results provide important information for exploring the mechanism of JAZ genes in alfalfa salt tolerance and identifying candidate genes for improving the salt tolerance of autotetraploid cultivated alfalfa via genetic engineering in the future.

Glycosyltransferase Slr1064 regulates carbon metabolism by modulating the levels of UDP-GlcNAc in Synechocystis sp. PCC 6803.

Glycosyltransferases (GTs) are enzymes that transfer sugars to various targets. They play important roles in diverse biological processes, including photosynthesis, cell motility, exopolysaccharide biosynthesis, and lipid metabolism; however, their involvement in regulating carbon metabolism in Synechocystis sp. PCC 6803 has not been reported. We identified a novel GT protein, Slr1064, involved in carbon metabolism. The effect of slr1064 deletion on the growth of Synechocystis cells and functional mechanisms of Slr1064 on carbon metabolism were thoroughly investigated through physiological, biochemistry, proteomic, and metabolic analyses. We found that this GT, which is mainly distributed in the membrane compartment, is essential for the growth of Synechocystis under heterotrophic and mixotrophic conditions, but not under autotrophic conditions. The deletion of slr1064 hampers the turnover rate of Gap2 under mixotrophic conditions and disrupts the assembly of the PRK/GAPDH/CP12 complex under dark culture conditions. Additionally, UDP-GlcNAc, the pivotal metabolite responsible for the O-GlcNAc modification of GAPDH, is downregulated in the Δslr1064. Our work provides new insights into the role of GTs in carbon metabolism in Synechocystis and elucidate the mechanism by which carbon metabolism is regulated in this important model organism.

Lateral GeSn p-i-n photodetectors on insulator prepared by the rapid melting growth method.

In this work, GeSn lateral p-i-n photodetectors (PDs) on insulator were fabricated with an active GeSn layer grown by the rapid melting growth (RMG) method. Taking advantages of the defect-free GeSn strips, GeSn PDs with 5.3% Sn content have low dark current and high responsivities, which are about 0.48, 0.47, and 0.24 A/W for wavelengths of 1550, 1630, and 2000 nm, respectively. The radio frequency of the lateral GeSn PDs was also studied and a 3 dB bandwidth of about 3.8 GHz was achieved. These results indicate that the GeSn grown by the rapid melting growth method is capable of fabricating high-performance Si-based optoelectronic devices.

RUNX1T1 modulates myogenic differentiation by regulating the calcium signaling pathway and the alternative splicing of ROCK2.

RUNX1T1 (Runt-related transcription factor 1, translocated to 1) plays a wide-ranging and diverse role in cellular development, including hematopoiesis and adipogenesis. However, little is known about the function of RUNX1T1 in the skeletal muscle development. Here, we assessed the impact of RUNX1T1 on the proliferation and myogenic differentiation of goat primary myoblasts (GPMs). It was observed that RUNX1T1 is highly expressed during the early stages of myogenic differentiation and the fetal stage. Moreover, the knockdown of RUNX1T1 promotes the proliferation and inhibits myogenic differentiation and mitochondrial biogenesis of GPMs. RNA sequencing analysis revealed that significantly differentially expressed genes in RUNX1T1 knockdown cells were enriched in the calcium signaling pathway. Additionally, we discovered that RUNX1T1 regulates alternative splicing (AS) events involved in myogenesis. We also show that silencing RUNX1T1 blocked the Ca2+ -CAMK signaling pathway and reduced the expression levels of muscle-specific isoforms of recombinant rho associated coiled coil containing crotein kinase 2 (ROCK2) during myogenic differentiation, partially explaining why RUNX1T1 deficiency leads to the impairment of myotube formation. These findings suggest that RUNX1T1 is a novel regulator of myogenic differentiation that regulates the calcium signaling pathway and AS of ROCK2. Overall, our results highlight the critical role of RUNX1T1 in myogenesis and broaden our understanding of myogenic differentiation.

The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons.

Dopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.

Global burden of acute hepatitis E between 1990 and 2019 and projections until 2030.

BACKGROUND AND AIMS: Acute hepatitis E (AHE) is still a public health issue worldwide. Here, we report the global burden of AHE in 204 countries and territories from 1990 to 2019 by age, sex and socio-demographic index (SDI), and predict the future trends to 2030. METHODS: Data on AHE were collected from the Global Burden of Diseases, Injuries and Risk Factors Study 2019. The average annual percentage change (AAPC) and joinpoint analysis were used to determine the burden trend. RESULTS: In 2019, there were 19.47 million (95% UI, 16.04 to 23.37 million) incident cases of AHE globally, with a 19% increase since 1990. Age-standardized rate (ASR) of disability-adjusted life years (DALYs), prevalent and incident cases declined from 1990 to 2019. In 2019, the ASR of incidence, prevalence and DALYs due to HEV infection were highest in the same regions of South Asia for both sexes. Southern Sub-Saharan Africa presented the highest increases in the ASR for incidence of HEV infection in both males (AAPC = .25) and females (AAPC = .24) from 1990 to 2019. Incident cases are higher in males than females before 55-59 years old. The SDI values were negatively correlated with the age-standardized DALYs. Between 2019 and 2030, the ASR for incidence and prevalence of HEV for both sexes showed an increasing trend. CONCLUSIONS: Although the overall ASR of AHE decreased, the burden of AHE remains an underappreciated problem for society. The findings may provide useful information for policymakers to develop appropriate strategies aimed at reducing the burden of AHE.

Spatially Resolved Metabolites in Stable and Unstable Human Atherosclerotic Plaques Identified by Mass Spectrometry Imaging.

BACKGROUND: Impairments in carbohydrate, lipid, and amino acid metabolism drive features of plaque instability. However, where these impairments occur within the atheroma remains largely unknown. Therefore, we sought to characterize the spatial distribution of metabolites within stable and unstable atherosclerosis in both the fibrous cap and necrotic core. METHODS: Atherosclerotic tissue specimens from 9 unmatched individuals were scored based on the Stary classification scale and subdivided into stable and unstable atheromas. After performing mass spectrometry imaging on these samples, we identified over 850 metabolite-related peaks. Using MetaboScape, METASPACE, and Human Metabolome Database, we confidently annotated 170 of these metabolites and found over 60 of these were different between stable and unstable atheromas. We then integrated these results with an RNA-sequencing data set comparing stable and unstable human atherosclerosis. RESULTS: Upon integrating our mass spectrometry imaging results with the RNA-sequencing data set, we discovered that pathways related to lipid metabolism and long-chain fatty acids were enriched in stable plaques, whereas reactive oxygen species, aromatic amino acid, and tryptophan metabolism were increased in unstable plaques. In addition, acylcarnitines and acylglycines were increased in stable plaques whereas tryptophan metabolites were enriched in unstable plaques. Evaluating spatial differences in stable plaques revealed lactic acid in the necrotic core, whereas pyruvic acid was elevated in the fibrous cap. In unstable plaques, 5-hydroxyindoleacetic acid was enriched in the fibrous cap. CONCLUSIONS: Our work here represents the first step to defining an atlas of metabolic pathways involved in plaque destabilization in human atherosclerosis. We anticipate this will be a valuable resource and open new avenues of research in cardiovascular disease.

Interictal interleukin-6 and tumor necrosis factor α levels are associated with seizure recurrence in adults with epilepsy.

BACKGROUND: Although there are models predicting epilepsy recurrence under different clinical conditions, few studies have examined blood biomarkers. Inflammation plays a crucial role in the occurrence and development of epilepsy. We analyzed inflammatory mediators in a regional hospital-based epilepsy cohort and investigated their relationship with subsequent epilepsy recurrence. METHODS: Interictal inflammatory mediators were measured in 128 patients diagnosed with epilepsy participating in a prospective study. Inflammatory mediators were compared during the follow-up period between patients who experienced epilepsy recurrence and those who did not. We also assessed the correlation between inflammatory mediators and the time interval until the next recurrence. RESULTS: Over a median 4-month follow-up period, 41 patients experienced seizure recurrence. Differences in interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) levels were observed between seizure recurrence and non-recurrence groups. After adjusting for covariates through multivariate Cox regression analysis, the patients in the third IL-6 tertile (>2.31 pg/mL; HR: 2.49; 95 % CI: 1.00-6.16; P = 0.049) and in the third TNF-α tertile (>0.74 pg/mL; HR: 2.80; 95 % CI: 1.13-6.92; P = 0.026) had higher risk of seizure recurrence. The time until the next recurrence was negatively correlated with IL-6 level (ρ =  - 0.392, P = 0.011). CONCLUSION: High levels of IL-6 and TNF-α are associated with a higher possibility of seizure recurrence. Future predictive models should also include inflammatory mediators in addition to clinical variables.

Effect of bacteria-algae ratio on treatment of anaerobic digested wastewater by symbiotic coupling of bacteria and algae under the background of carbon neutralization.

Environmental pollution is a growing concern, particularly the impact of sewage treatment gas on the atmosphere's greenhouse effect. Efficient sewage resource recycling is crucial to achieving carbon neutrality. The bacteria-algae symbiotic sewage treatment system combines wastewater treatment, carbon dioxide fixation, and biomass energy recovery to achieve the goal of carbon neutrality, environmental protection, and the transformation of high-value added products. This paper presents the construction of a sequencing batch photobiological reaction system that utilizes a microbial-algae symbiotic relationship. The system was used to analyze the degradation effects of sCOD, TN, AN, and TP in anaerobic digestion wastewater by varying the microbial-algae ratios. Additionally, changes in the microbial community were analyzed to explore the system's potential for reducing carbon emissions. The study's findings indicate that: 1)When the ratio of bacteria to algae was 2:3, the removal rates of TN, AN, sCOD, and TP were 81.38%, 94.28%, 75.33%, and 96.56%. 2)Changing the ratio of bacteria to algae would affect the bacterial concentration in the mixed system, but not the bacterial community structure. The results indicate that a ratio of 2:3 enhances the removal of pollutants by bacteria and algae symbionts.3) Under the context of carbon neutralization, this paper investigates the reduction of carbon emissions in ADE treated by bacteria-algae symbiosis at the optimal bacteria to algae ratio. The experimental process can reduce 177.03 mg CO2 compared to complete nutrient consumption treatment, which is equivalent to a reduction of 355.08 g CO2 per 1 m3 of ADE. For full anaerobic treatment, this experimental process can reduce 228.35 mg of CO2 equivalent CH4, which translates to a reduction of 456.71 g of CO2 equivalent CH4 per 1 m3 of ADE.

Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response.

Epilepsy, a common neurological disorder, is featured with recurrent seizures. Its underlying pathological mechanisms remain elusive. Here, we provide evidence for loss of neogenin (NEO1), a coreceptor for multiple ligands, including netrins and bone morphological proteins, in the development of epilepsy. NEO1 is reduced in hippocampi from patients with epilepsy based on transcriptome and proteomic analyses. Neo1 knocking out (KO) in mouse brains displays elevated epileptiform spikes and seizure susceptibility. These phenotypes were undetectable in mice, with selectively depleted NEO1 in excitatory (NeuroD6-Cre+) or inhibitory (parvalbumin+) neurons, but present in mice with specific hippocampal astrocytic Neo1 KO. Additionally, neurons in hippocampal dentate gyrus, a vulnerable region in epilepsy, in mice with astrocyte-specific Neo1 KO show reductions in inhibitory synaptic vesicles and the frequency of miniature inhibitory postsynaptic current(mIPSC), but increase of the duration of miniature excitatory postsynaptic current and tonic NMDA receptor currents, suggesting impairments in both GABAergic transmission and extracellular glutamate clearance. Further proteomic and cell biological analyses of cell-surface proteins identified GLAST, a glutamate-aspartate transporter that is marked reduced in Neo1 KO astrocytes and the hippocampus. NEO1 interacts with GLAST and promotes GLAST surface distribution in astrocytes. Expressing NEO1 or GLAST in Neo1 KO astrocytes in the hippocampus abolishes the epileptic phenotype. Taken together, these results uncover an unrecognized pathway of NEO1-GLAST in hippocampal GFAP+ astrocytes, which is critical for GLAST surface distribution and function, and GABAergic transmission, unveiling NEO1 as a valuable therapeutic target to protect the brain from epilepsy.

C15:0 and C17:0 partially mediate the association of milk and dairy products with bladder cancer risk.

The relationship between saturated fatty acids (SFA) and bladder cancer (BC) risk has been conflicting. Our aim was to investigate the relationship between erythrocyte membrane SFA and BC risk. A total of 404 participants were enrolled in the study (including 112 cases and 292 controls). A validated food frequency questionnaire was used to assess the food intake. The constitutive composition of fatty acids in the erythrocyte membrane was measured by gas chromatography. After adjustment for BC risk factors, SFA had no significant association with BC risk. However, C18:0 was positively linked with BC risk with an odds ratio (OR; 95% CI) of 2.99 (1.37-6.53). In contrast, very-long-chain saturated fatty acids (VLCSFA), especially C24:0, were negatively related to BC risk with an OR (95% CI) of 0.28 (0.12-0.65) for VLCSFA and 0.33 (0.15-0.75) for C24:0. Higher total odd-chain SFA (C15:0 and C17:0) were associated with a lower risk of BC with OR (95% CI) of 0.18 (0.076-0.44), 0.18 (0.068-0.47), 0.34 (0.14-0.81), respectively. After subgroup analysis, the protective effects C15:0 and C17:0 were still remained. Receiver operating characteristic analysis displayed that the combination of C15:0 and C17:0 indexes increased the accurate predictive rate of BC risk. Further mediation effect analysis showed that C15:0 and C17:0 could be used as partial mediation effectors for milk and dairy products and bladder carcinogenesis. Overall, the combination of odd-chain SFA (C15:0 and C17:0) in the erythrocyte membrane could serve as a reliable mediator and predictor, indicating a relationship between a high intake of milk and dairy products and a lower risk of BC.

Comprehensive beam delivery latency evaluation for gated proton therapy system using customized multi-channel signal acquisition platform.

PURPOSE: Beam delivery latency in respiratory-gated particle therapy systems is a crucial issue to dose delivery accuracy. The aim of this study is to develop a multi-channel signal acquisition platform for investigating gating latencies occurring within RPM respiratory gating system (Varian, USA) and ProBeam proton treatment system (Varian, USA) individually. METHODS: The multi-channel signal acquisition platform consisted of several electronic components, including a string position sensor for target motion detection, a photodiode for proton beam sensing, an interfacing board for accessing the trigger signal between the respiratory gating system and the proton treatment system, a signal acquisition device for sampling and synchronizing signals from the aforementioned components, and a laptop for controlling the signal acquisition device and data storage. RPM system latencies were determined by comparing the expected gating phases extracted from the motion signal with the trigger signal's state turning points. ProBeam system latencies were assessed by comparing the state turning points of the trigger signal with the beam signal. The total beam delivery latencies were calculated as the sum of delays in the respiratory gating system and the cyclotron proton treatment system. During latency measurements, simulated sinusoidal motion were applied at different amplitudes and periods for complete beam delivery latency evaluation under different breathing patterns. Each breathing pattern was repeated 30 times for statistical analysis. RESULTS: The measured gating ON/OFF latencies in the RPM system were found to be 104.20 ± 13.64 ms and 113.60 ± 14.98 ms, respectively. The measured gating ON/OFF delays in the ProBeam system were 108.29 ± 0.85 ms and 1.20 ± 0.04 ms, respectively. The total beam ON/OFF latencies were determined to be 212.50 ± 13.64 ms and 114.80 ± 14.98 ms. CONCLUSION: With the developed multi-channel signal acquisition platform, it was able to investigate the gating lags happened in both the respiratory gating system and the proton treatment system. The resolution of the platform is enough to distinguish the delays at the millisecond time level. Both the respiratory gating system and the proton treatment system made contributions to gating latency. Both systems contributed nearly equally to the total beam ON latency, with approximately 100 ms. In contrast, the respiratory gating system was the dominant contributor to the total beam OFF latency.

Transcranial Magneto-Acoustic Stimulation Protects Synaptic Rehabilitation from Amyloid-Beta Plaques via Regulation of Microglial Functions.

Transcranial magneto-acoustic stimulation (TMAS), which is characterized by high spatiotemporal resolution and high penetrability, is a non-invasive neuromodulation technology based on the magnetic-acoustic coupling effect. To reveal the effects of TMAS treatment on amyloid-beta (Aß) plaque and synaptic plasticity in Alzheimer's disease, we conducted a comparative analysis of TMAS and transcranial ultrasound stimulation (TUS) based on acoustic effects in 5xFAD mice and BV2 microglia cells. We found that the TMAS-TUS treatment effectively reduced amyloid plaque loads and plaque-associated neurotoxicity. Additionally, TMAS-TUS treatment ameliorated impairments in long-term memory formation and long-term potentiation. Moreover, TMAS-TUS treatment stimulated microglial proliferation and migration while enhancing the phagocytosis and clearance of Aß. In 5xFAD mice with induced microglial exhaustion, TMAS-TUS treatment-mediated Aß plaque reduction, synaptic rehabilitation improvement, and the increase in phospho-AKT levels were diminished. Overall, our study highlights that stimulation of hippocampal microglia by TMAS treatment can induce anti-cognitive impairment effects via PI3K-AKT signaling, providing hope for the development of new strategies for an adjuvant therapy for Alzheimer's disease.

A Small-Molecule Ratiometric Photoacoustic Probe for the High-Spatiotemporal-Resolution Imaging of Copper(II) Dynamics in the Mouse Brain.

Copper dysmetabolism is associated with various neurodegenerative disorders, making high-spatiotemporal-resolution imaging of Cu2+ in the brain essential for understanding the underlying pathophysiological processes. Nevertheless, the current probes encounter obstacles in crossing the blood-brain barrier (BBB) and providing high-spatial-resolution in deep tissues. Herein, we present a photoacoustic probe capable of imaging Cu2+ dynamics in the mouse brain with high-spatiotemporal-resolution. The probe demonstrates selective ratiometric and reversible responses to Cu2+ , while also efficiently crossing the BBB. Using the probe as the imaging agent, we successfully visualized Cu2+ in the brain of Parkinson's disease (PD) model mouse with a remarkable micron-level resolution. The imaging results revealed a significant increase in Cu2+ levels in the cerebral cortex as PD progresses, highlighting the close association between Cu2+ alternations in the region and the disease. We also demonstrated that the probe can be used to monitor changes in Cu2+ distribution in the PD model mouse brain during L-dopa intervention. Mechanism studies suggest that the copper dyshomeostasis in the PD mouse brain was dominated by the expression levels of divalent metal transporter 1. The application of our probe in imaging Cu2+ dynamics in the mouse brain offers valuable insights into the copper-related molecular mechanisms underlying neurodegenerative diseases.

A NIR-II Photoacoustic Probe for High Spatial Quantitative Imaging of Tumor Nitric Oxide in Vivo.

Nitric oxide (NO) exhibits both pro- and anti-tumor effects. Therefore, real-time in vivo imaging and quantification of tumor NO dynamics are essential for understanding the conflicting roles of NO played in pathophysiology. The current molecular probes, however, cannot provide high-resolution imaging in deep tissues, making them unsuitable for these purposes. Herein, we designed a photoacoustic probe with an absorption maximum beyond 1000 nm for high spatial quantitative imaging of in vivo tumor NO dynamics. The probe exhibits remarkable sensitivity, selective ratiometric response behavior, and good tumor-targeting abilities, facilitating ratiometric imaging of tumor NO throughout tumor progression in a micron-resolution level. Using the probe as the imaging agent, we successfully quantified NO dynamics in tumor, liver and kidney. We have pinpointed an essential concentration threshold of around 80 nmol/cm3 for NO, which plays a crucial role in the "double-edged-sword" function of NO in tumors. Furthermore, we revealed a reciprocal relationship between the NO concentration in tumors and that in the liver, providing initial insights into the possible NO-mediated communication between tumor and the liver. We believe that the probe will help resolve conflicting aspects of NO biology and guide the design of imaging agents for tumor diagnosis and anti-cancer drug screening.

An ErbB4-Positive Neuronal Network in the Olfactory Bulb for Olfaction.

Olfactory information is relayed and processed in the olfactory bulb (OB). Mitral cells (MCs), the principal output excitatory neurons of the OB, are controlled by multiple types of interneurons. However, mechanisms that regulate the activity of OB interneurons are not well understood. We provide evidence that the transmembrane tyrosine kinase ErbB4 is selectively expressed in subsets of OB inhibitory neurons in both male and female mice. ErbB4-positive (ErbB4+) neurons are mainly located in the glomerular layer (GL) and granule cell layer (GCL) and do not express previously defined markers. Optogenetic activation of GL-ErbB4+ neurons promotes theta oscillation, whereas activation of those in the GCL generates gamma oscillations. Stimulation of OB slices with NRG1, a ligand that activates ErbB4, increases GABA transmission onto MCs, suggesting a role of OB NRG1-ErbB4 signaling in olfaction. In accord, ErbB4 mutant mice or acute inhibition of ErbB4 by a chemical genetic approach diminishes GABA transmission, reduces bulbar local field potential (LFP) power, increases the threshold of olfactory sensitivity, and impairs odor discrimination. Together these results identified a bulbar inhibitory network of ErbB4+ neurons for olfaction. Considering both NRG1 and ErbB4 are susceptibility genes for neuropsychiatric disorders, our study provides insight into pathological mechanisms of olfactory malfunctions in these disorders.Significance Statement:This study demonstrates ErbB4+ neurons are a new subset of OB inhibitory neurons in the GL and GCL that innervate MCs and ErbB4- cells. They regulate olfaction by controlling local synchrony and distinct oscillations. ErbB4 inhibition diminishes GABA transmission, reduces bulbar local field potential (LFP) power, increases the threshold of olfactory sensitivity, and impairs odor discrimination. Our results provide insight into pathophysiological mechanism of olfaction deficits in brain disorders associated with NRG1 or ErbB4 mutations.

NUCLEAR TRANSPORT FACTOR 2-LIKE improves drought tolerance by modulating leaf water loss in alfalfa (Medicago sativa L.).

Drought is a major environmental factor that limits the production of alfalfa (Medicago sativa). In the present study, M. sativa NUCLEAR TRANSPORT FACTOR 2-LIKE (MsNTF2L) was identified as a nucleus-, cytoplasm-, and plasma membrane-localized protein. Its transcriptional expression was highly induced by ABA and drought stress. Overexpression of MsNTF2L in Arabidopsis resulted in hypersensitivity to ABA during both the seed germination and seedling growth stages. However, transgenic Arabidopsis plants exhibited enhanced tolerance to drought stress by reducing the levels of reactive oxygen species (ROS) and increasing the expression of stress/ABA-inducible genes. Consistently, analysis of MsNTF2L overexpression (OE) and RNA interference (RNAi) alfalfa plants revealed that MsNTF2L confers drought tolerance through promoting ROS scavenging, a decrease in stomatal density, ABA-induced stomatal closure, and epicuticular wax crystal accumulation. MsNTF2L highly affected epicuticular wax deposition, as a large group of wax biosynthesis and transport genes were influenced in the alfalfa OE and RNAi lines. Furthermore, transcript profiling of drought-treated alfalfa WT, OE, and RNAi plants showed a differential drought response for genes related to stress/ABA signaling, antioxidant defense, and photosynthesis. Taken together, these results reveal that MsNTF2L confers drought tolerance in alfalfa via modulation of leaf water loss (by regulating both stomata and wax deposition), antioxidant defense, and photosynthesis.