Hyperactive lateral habenula mediates the comorbidity between rheumatoid arthritis and depression-like behaviors.

Rheumatoid arthritis (RA) patients have a high prevalence for depression. On the other hand, comorbid with depression is associated with worse prognosis for RA. However, little is known about the underlying mechanisms for the comorbidity between RA and depression. It remains to be elucidated which brain region is critically involved in the development of depression in RA, and whether alterations in the brain may affect pathological development of RA symptoms. Here, by combining clinical and animal model studies, we show that in RA patients, the level of depression is significantly correlated with the severity of RA disease activity and affects patients' quality of life. The collagen antibody-induced arthritis (CAIA) mouse model of RA also develops depression-like behaviors, accompanied by hyperactivity and alterations in gene expression reflecting cerebrovascular disruption in the lateral habenula (LHb), a brain region critical for processing negative valence. Importantly, inhibition of the LHb not only alleviates depression-like behaviors, but also results in rapid remission of RA symptoms and amelioration of RA-related pathological changes. Together, our study highlights a critical but previously overlooked contribution of hyperactive LHb to the comorbidity between RA and depression, suggesting that targeting LHb in conjunction with RA treatments may be a promising strategy for RA patients comorbid with depression.

Optimal design of a 4 × 4 MMI thermal optical switch with trapezoidal air trenches.

Optical switches are important in signal routing and switching. In this paper, a thermal optical switch with trapezoidal air trenches is proposed. The proposed structure consists of two cascaded 4×4 multimode interference (MMI) couplers. The beam propagation method is used to optimize the dimension and analyze the characteristics. Simulation results show excess loss (EL) and insertion loss (IL) are less than 0.14 dB and 0.22 dB at the wavelength of 1550 nm, respectively. Besides, the extinction ratio (ER) is higher than 21 dB. This design has the advantages of small size, low loss, and high flexibility, which is promising for application to all-optical network routing.

Distinct Transcriptomic Profiles in the Dorsal Hippocampus and Prelimbic Cortex Are Transiently Regulated following Episodic Learning.

A fundamental, evolutionarily conserved biological mechanism required for long-term memory formation is rapid induction of gene transcription upon learning in relevant brain areas. For episodic types of memories, two regions undergoing this transcription are the dorsal hippocampus (dHC) and prelimbic (PL) cortex. Whether and to what extent these regions regulate similar or distinct transcriptomic profiles upon learning remain to be understood. Here, we used RNA sequencing in the dHC and PL cortex of male rats to profile their transcriptomes in untrained conditions (baseline) and at 1 h and 6 d after inhibitory avoidance learning. We found that, of 33,713 transcripts, >14,000 were significantly expressed at baseline in both regions and ∼3000 were selectively enriched in each region. Gene Ontology biological pathway analyses indicated that commonly expressed pathways included synapse organization, regulation of membrane potential, and vesicle localization. The enriched pathways in the dHC were gliogenesis, axon development, and lipid modification, while in the PL cortex included vesicle localization and synaptic vesicle cycle. At 1 h after learning, 135 transcripts changed significantly in the dHC and 478 in the PL cortex; of these, only 34 were shared. Biological pathways most significantly regulated by learning in the dHC were protein dephosphorylation, glycogen and glucan metabolism, while in the PL cortex were axon development and axonogenesis. The transcriptome profiles returned to baseline by 6 d after training. Thus, a significant portion of dHC and PL cortex transcriptomic profiles is divergent, and their regulation upon learning is largely distinct and transient.SIGNIFICANCE STATEMENT Long-term episodic memory formation requires gene transcription in several brain regions, including the hippocampus and PFC. The comprehensive profiles of the dynamic mRNA changes that occur in these regions following learning are not well understood. Here, we performed RNA sequencing in the dorsal hippocampus and prelimbic cortex, a PFC subregion, at baseline, 1 h, and 6 d after episodic learning in rats. We found that, at baseline, dorsal hippocampus and prelimbic cortex differentially express a significant portion of mRNAs. Moreover, learning produces a transient regulation of region-specific profiles of mRNA, indicating that unique biological programs in different brain regions underlie memory formation.

NaOTs-promoted transition metal-free C-N bond cleavage to form C-X (X = N, O, S) bonds.

Multifunctional transformation of amide C-N bond cleavage is reported. The protocol applies to benzamide, thioamide, alcohols, and mercaptan under similar reaction conditions catalyzed by NaOTs. It is noteworthy that NaOTs can not only be recycled and reused for up to three cycles without significant loss in catalytic activity, but also catalyze gram-grade reactions. This study provides a novel solution with mild conditions and a simple procedure for transformation of multiple amides.

TLR4-induced B7-H1 on keratinocytes negatively regulates CD4+ T cells and CD8+ T cells responses in oral lichen planus.

Oral lichen planus (OLP) is a T-cell-mediated autoimmune mucocutaneous disease affected by the interactions among the keratinocytes, CD4+ T cells and CD8+ T cells. B7-H1 induced by Toll-like receptors (TLRs) can suppress T-cell immune reaction, thereby resulting in immune tolerance. However, the role of TLR-mediated B7-H1 on keratinocytes in the immune response of OLP is still unknown. The present study showed that TLR4 could induce time-coursed B7-H1 expression on oral keratinocytes, and blocking NF-κB or PI3K/mTOR pathway downregulated B7-H1 transcriptional expression. Moreover, TLR4-stimulated oral keratinocytes inhibited the proliferation of OLP CD4+ T cells and OLP CD8+ T cells, and simultaneously prompted their apoptosis. Blockade of keratinocyte-associated B7-H1 restored the declined proliferation of OLP CD4+ T cells and OLP CD8+ T cells, and prevented their increased apoptosis. Therefore, TLR4-upregulated B7-H1 on keratinocytes could decelerate immune responses of CD4+ T cells and CD8+ T cells in OLP.

Icaritin Reduces Oral Squamous Cell Carcinoma Progression via the Inhibition of STAT3 Signaling.

Icaritin, a traditional Chinese medicine, possesses antitumor activity. The current study aimed to investigate icaritin effect and potential mechanism on oral squamous cell carcinoma (OSCC) development. OSCC cells proliferation, apoptosis, and autophagy were analyzed after incubation with icaritin at different concentrations and incubation times. The expressions of proteins related to proliferation, apoptosis, and autophagy, as well as signal transducer and activator of transcription 3 (STAT3) signal network, were also evaluated by western blot. Furthermore, STAT3 was knocked down by siRNA transfection to determine STAT3 role in OSCC cell proliferation and apoptosis. An oral specific carcinogenesis mouse model was used to explore icaritin effect on OSCC in vivo. Icaritin significantly inhibited OSCC proliferation in vitro and reduced the expression of both the cell-cycle progression proteins cyclin A2 and cyclin D1. Besides, icaritin increased cleaved caspase 3 and cleaved poly-(ADP-ribose) polymerase expression leading to apoptosis, and it activated autophagy. Icaritin significantly inhibited the expression of phospho-STAT3 (p-STAT3) in a dose- and time-dependent manner. In the in vivo experiment, the number of malignant tumors in the icaritin-treated group was significantly lower than the control. Overall, icaritin suppressed proliferation, promoted apoptosis and autophagy, and inhibited STAT3 signaling in OSCC in vitro and in vivo. In conclusion, icaritin might be a potential therapeutic agent against OSCC development.

Home blood pressure monitor use in patients with chronic kidney disease.

Home blood pressure monitoring (HBPM) is recommended in patients with chronic kidney disease (CKD) and hypertension (HTN). However, little is known about the use and pattern of HBPM in CKD patients. A cross-sectional study was conducted in an out-patient nephrology clinic. A total of 285 patients participated in the study. Of all patients, 66% reported using HBPM. Self-reported compliance with BP medications (93.9% vs. 85.1%, p 0.03), exercise >3 days/week (45.9 vs. 26.3%, p <0.001) and dietary sodium restriction (85.6% vs. 71.6%, p < 0.001) were more common in HBPM users vs. non-HBPM users. Most patients with HBPM used upper arm cuff (82.3%), reported receiving education on correct use of HBPM (82.5%), had perception that home BP was controlled (75.4%) and believed that HBPM is helpful in managing hypertension (85.4%). Most common reason for not using HBPM was lack of advice by a physician (43.4%). HBPM use is common in patients with CKD and HTN. HBPM users are more likely to follow life-style and dietary modifications for blood pressure control.

Local synaptic integration of mitogen-activated protein kinase and protein kinase A signaling mediates intermediate-term synaptic facilitation in Aplysia.

It is widely appreciated that memory processing engages a wide range of molecular signaling cascades in neurons, but how these cascades are temporally and spatially integrated is not well understood. To explore this important question, we used Aplysia californica as a model system. We simultaneously examined the timing and subcellular location of two signaling molecules, MAPK (ERK1/2) and protein kinase A (PKA), both of which are critical for the formation of enduring memory for sensitization. We also explored their interaction during the formation of enduring synaptic facilitation, a cellular correlate of memory, at tail sensory-to-motor neuron synapses. We find that repeated tail nerve shock (TNS, an analog of sensitizing training) immediately and persistently activates MAPK in both sensory neuron somata and synaptic neuropil. In contrast, we observe immediate PKA activation only in the synaptic neuropil. It is followed by PKA activation in both compartments 1 h after TNS. Interestingly, blocking MAPK activation during, but not after, TNS impairs PKA activation in synaptic neuropil without affecting the delayed PKA activation in sensory neuron somata. Finally, by applying inhibitors restricted to the synaptic compartment, we show that synaptic MAPK activation during TNS is required for the induction of intermediate-term synaptic facilitation, which leads to the persistent synaptic PKA activation required to maintain this facilitation. Collectively, our results elucidate how MAPK and PKA signaling cascades are spatiotemporally integrated in a single neuron to support synaptic plasticity underlying memory formation.

MAPK establishes a molecular context that defines effective training patterns for long-term memory formation.

Although the importance of spaced training trials in the formation of long-term memory (LTM) is widely appreciated, surprisingly little is known about the molecular mechanisms that support interactions between individual trials. The intertrial dynamics of ERK/MAPK activation have recently been correlated with effective training patterns for LTM. However, whether and how MAPK is required to mediate intertrial interactions remains unknown. Using a novel two-trial training pattern which induces LTM in Aplysia, we show that the first of two training trials recruits delayed protein synthesis-dependent nuclear MAPK activity that establishes a unique molecular context involving the recruitment of CREB kinase and ApC/EBP and is an essential intertrial signaling mechanism for LTM induction. These findings provide the first demonstration of a requirement for MAPK in the intertrial interactions during memory formation and suggest that the kinetics of MAPK activation following individual experiences determines effective training intervals for LTM formation.

CCAAT enhancer binding protein δ plays an essential role in memory consolidation and reconsolidation.

A newly formed memory is temporarily fragile and becomes stable through a process known as consolidation. Stable memories may again become fragile if retrieved or reactivated, and undergo a process of reconsolidation to persist and strengthen. Both consolidation and reconsolidation require an initial phase of transcription and translation that lasts for several hours. The identification of the critical players of this gene expression is key for understanding long-term memory formation and persistence. In rats, the consolidation of inhibitory avoidance (IA) memory requires gene expression in both the hippocampus and amygdala, two brain regions that process contextual/spatial and emotional information, respectively; IA reconsolidation requires de novo gene expression in the amygdala. Here we report that, after IA learning, the levels of the transcription factor CCAAT enhancer binding protein δ (C/EBPδ) are significantly increased in both the hippocampus and amygdala. These increases are essential for long-term memory consolidation, as their blockade via antisense oligodeoxynucleotide-mediated knockdown leads to memory impairment. Furthermore, C/EBPδ is upregulated and required in the amygdala for IA memory reconsolidation. C/EBPδ is found in nuclear, somatic, and dendritic compartments, and a dendritic localization of C/EBPδ mRNA in hippocampal neuronal cultures suggests that this transcription factor may be translated at synapses. Finally, the induction of long-term potentiation at CA3-CA1 synapses by tetanic stimuli in acute slices, a cellular model of long-term memory, leads to an accumulation of C/EBPδ in the nucleus. We conclude that the transcription factor C/EBPδ plays a critical role in memory consolidation and reconsolidation.

On optimal control at the onset of a new viral outbreak.

We propose a versatile model with a flexible choice of control for an early-pandemic outbreak prevention when vaccine/drug is not yet available. At that stage, control is often limited to non-medical interventions like social distancing and other behavioral changes. For the SIR optimal control problem, we show that the running cost of control satisfying mild, practically justified conditions generates an optimal strategy, u(t), t ∈ [0, T], that is sustainable up until some moment τ ∈ [0, T). However, for any t ∈ [τ, T], the function u(t) will decline as t approaches T, which may cause the number of newly infected people to increase. So, the window from 0 to τ is the time for public health officials to prepare alternative mitigation measures, such as vaccines, testing, antiviral medications, and others. In addition to theoretical study, we develop a fast and stable computational method for solving the proposed optimal control problem. The efficiency of the new method is illustrated with numerical examples of optimal control trajectories for various cost functions and weights. Simulation results provide a comprehensive demonstration of the effects of control on the epidemic spread and mitigation expenses, which can serve as invaluable references for public health officials.

A new bufadienolide from Bufo gargarizans Cantor.

Bufo gargarizans Cantor (B. gargarizans) is the most widely distributed and abundant species of toad in China. Bufadienolides and indole alkaloids have cardiotonic and anti-tumor activities and are important pharmacological components of B. bufo gargarizans. In this experiment, a novel compound (1) and two known compounds (2 and 3) were isolated and identified from the dry skin of B. bufo gargarizans, both of which are bufadienolides. Various column chromatography methods were used to separate and purify the extract from the dried skin of B. bufo gargarizans. Accurate molecular weights were measured by HR-ESI-MS, and the chemical structure of the compounds was determined by NMR spectrometers. The structures were named as (2ß,5ß,16α)-2,5,16-trihydroxide bufa-14,20,22 dienolide (1), gamabufotalin (2) and desacetylbufotalin (3). In vitro cytotoxic activity assay indicated that compound 1 showed a moderate cytotoxicity against A549 cells with IC50 value of 12.65 µM.

Blockage of VEGF function by bevacizumab alleviates early-stage cerebrovascular dysfunction and improves cognitive function in a mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant type of dementia worldwide. It is characterized by the progressive and irreversible decline of cognitive functions. In addition to the pathological beta-amyloid (Aß) deposition, glial activation, and neuronal injury in the postmortem brains of AD patients, increasing evidence suggests that the often overlooked vascular dysfunction is an important early event in AD pathophysiology. Vascular endothelial growth factor (VEGF) plays a critical role in regulating physiological functions and pathological changes in blood vessels, but whether VEGF is involved in the early stage of vascular pathology in AD remains unclear. METHODS: We used an antiangiogenic agent for clinical cancer treatment, the humanized monoclonal anti-VEGF antibody bevacizumab, to block VEGF binding to its receptors in the 5×FAD mouse model at an early age. After treatment, memory performance was evaluated by a novel object recognition test, and cerebral vascular permeability and perfusion were examined by an Evans blue assay and blood flow scanning imaging analysis. Immunofluorescence staining was used to measure glial activation and Aß deposits. VEGF and its receptors were analyzed by enzyme-linked immunosorbent assay and immunoblotting. RNA sequencing was performed to elucidate bevacizumab-associated transcriptional signatures in the hippocampus of 5×FAD mice. RESULTS: Bevacizumab treatment administered from 4 months of age dramatically improved cerebrovascular functions, reduced glial activation, and restored long-term memory in both sexes of 5×FAD mice. Notably, a sex-specific change in different VEGF receptors was identified in the cortex and hippocampus of 5×FAD mice. Soluble VEGFR1 was decreased in female mice, while full-length VEGFR2 was increased in male mice. Bevacizumab treatment reversed the altered expression of receptors to be comparable to the level in the wild-type mice. Gene Set Enrichment Analysis of transcriptomic changes revealed that bevacizumab effectively reversed the changes in the gene sets associated with blood-brain barrier integrity and vascular smooth muscle contraction in 5×FAD mice. CONCLUSIONS: Our study demonstrated the mechanistic roles of VEGF at the early stage of amyloidopathy and the protective effects of bevacizumab on cerebrovascular function and memory performance in 5×FAD mice. These findings also suggest the therapeutic potential of bevacizumab for the early intervention of AD.

Distinct roles of excitatory and inhibitory neurons in the medial prefrontal cortex in the expression and reconsolidation of methamphetamine-associated memory in male mice.

Methamphetamine, a commonly abused drug, is known for its high relapse rate. The persistence of addictive memories associated with methamphetamine poses a significant challenge in preventing relapse. Memory retrieval and subsequent reconsolidation provide an opportunity to disrupt addictive memories. However, the key node in the brain network involved in methamphetamine-associated memory retrieval has not been clearly defined. In this study, using the conditioned place preference in male mice, whole brain c-FOS mapping and functional connectivity analysis, together with chemogenetic manipulations of neural circuits, we identified the medial prefrontal cortex (mPFC) as a critical hub that integrates inputs from the retrosplenial cortex and the ventral tegmental area to support both the expression and reconsolidation of methamphetamine-associated memory during its retrieval. Surprisingly, with further cell-type specific analysis and manipulation, we also observed that methamphetamine-associated memory retrieval activated inhibitory neurons in the mPFC to facilitate memory reconsolidation, while suppressing excitatory neurons to aid memory expression. These findings provide novel insights into the neural circuits and cellular mechanisms involved in the retrieval process of addictive memories. They suggest that targeting the balance between excitation and inhibition in the mPFC during memory retrieval could be a promising treatment strategy to prevent relapse in methamphetamine addiction.

Gambogic acid affects high glucose-induced apoptosis and inflammation of retinal endothelial cells through the NOX4/NLRP3 pathway.

Background: This study aimed to investigate the effect and mechanism of gambogic acid (GA) on the apoptosis and inflammation of human retinal endothelial cells (HRECs) under high glucose conditions. Methods: HRECs were cultured in a high glucose medium to simulate retinal endothelial cell injury induced by diabetic retinopathy. Flow cytometry was used to analyze the apoptosis level of HRECs. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Western blotting was applied to detect the intracellular apoptosis-related proteins and expression levels of NADPH oxidase 4 (NOX4), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), and interleukin (IL)-1ß. Enzyme linked immunosorbent assay (ELISA) was utilized to detect the expression of IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α) in the cell supernatants. The messenger RNA (mRNA) levels of IL-6, IL-8, IL-10, and TNF-α were detected by reverse transcription-polymerase chain reaction (RT-qPCR). Results: We observed that high glucose induced the apoptosis and inflammation of HRECs. In addition, the high glucose environment promoted NOX/NLRP3 pathway activation. The activity of HRECs was not significantly affected by the presence of 20 µM or less of GA, and 15 µM of GA could restore the diminished activity of HRECs induced by high glucose. The apoptosis of HRECs cultured under high glucose conditions was significantly inhibited (P<0.05), the levels of IL-6, IL-8, and TNF-α in the cell supernatant were significantly decreased (P<0.05), and the levels of IL-10 were significantly increased (P<0.05). Meanwhile, the relative mRNA expression levels of IL-6, IL-8, and TNF-α in HRECs were significantly decreased (P<0.05), while those of IL-10 were significantly increased (P<0.05). The activity of the high glucose-induced NOX4/NLRP3 pathway in HRECs was significantly inhibited after treatment with 15 µM of GA (P<0.05). Following activation of the NOX4/NLRP3 pathway in HRECs, the apoptosis level was significantly increased (P<0.05), and the inflammatory response was aggravated (P<0.05). Inhibiting the activity of the intracellular NOX4/NLRP3 pathway markedly inhibited cell apoptosis and the inflammatory response (P<0.05). Conclusions: GA can inhibit the apoptosis and inflammation of HRECs under high glucose conditions by inhibiting the activity of the NOX4/NLRP3 pathway. This has a significant inhibitory effect on diabetic retinopathy, which is worthy of further study.

Retraction: gambogic acid affects high glucose-induced apoptosis and inflammation of retinal endothelial cells through the NOX4/NLRP3 pathway.

[This retracts the article DOI: 10.21037/atm-22-6591.].

The impact of parental overprotection on the emotions and behaviors of pediatric hematologic cancer patients: a multicenter cross-sectional study.

Background: Parental overprotection may have an impact on children's emotional and behavioral problems (EBPs). As pediatric hematologic cancer patients have compromised immune systems, parents of such children often worry excessively, interfering with their daily lives. Therefore, avoiding overprotection is crucial for the overall physical and mental health of pediatric hematologic cancer patients. Aims: The aim of this study was to examine the current status of EBPs in pediatric hematologic cancer patients and analyze their associated risk factors. Design: This work was a multicenter cross-sectional observational and correlational study. We collected data anonymously through parental questionnaires from three pediatric hematologic oncology hospitals in China. The Strengths and Difficulties Questionnaire, the Parental Overprotection Measure (POM) scale, and a general information survey designed by the research team were employed to assess children's EBPs, the degree of parental overprotection, as well as basic demographic and disease-related information. Chi-square tests and generalized linear mixed-effects regression analysis were used to analyze the factors influencing EBPs among the pediatric hematologic cancer patients. Setting and participants: Using a convenience sampling method, a total of 202 participants' parents were selected. All participants were invited to complete the questionnaire through one-on-one guidance. Results: Emotional symptoms accounted for the highest proportion of abnormal EBPs in children (27.72%), followed by peer problems (26.24%), prosocial behavior (25.74%), behavioral problems (14.36%), and total difficulties (13.86%). A minority of children had abnormal hyperactivity scores (4.95%). The results of a generalized linear mixed regression analysis showed that age, duration of illness, and parental overprotection were significant factors influencing abnormal EBPs in children (p < 0.05). A POM score threshold of 37 exhibited good sensitivity (74%) and specificity (90%) in predicting abnormal EBPs in children. Conclusion: Pediatric hematologic cancer patients under excessive parental protection are more prone to experiencing EBPs. Healthcare professionals should guide parents to reduce this excessive protection, thus mitigating the occurrence of EBPs in children.

A phase 2 study of thalidomide for the treatment of radiation-induced blood-brain barrier injury.

Radiation-induced brain injury (RIBI) is a debilitating sequela after radiotherapy to treat head and neck cancer, and 20 to 30% of patients with RIBI fail to respond to or have contraindications to the first-line treatments of bevacizumab and corticosteroids. Here, we reported a Simon's minmax two-stage, single-arm, phase 2 clinical trial (NCT03208413) to assess the efficacy of thalidomide in patients with RIBI who were unresponsive to or had contraindications to bevacizumab and corticosteroid therapies. The trial met its primary endpoint, with 27 of 58 patients enrolled showing ≥25% reduction in the volume of cerebral edema on fluid-attenuated inversion recovery-magnetic resonance imaging (FLAIR-MRI) after treatment (overall response rate, 46.6%; 95% CI, 33.3 to 60.1%). Twenty-five (43.1%) patients demonstrated a clinical improvement based on the Late Effects Normal Tissues-Subjective, Objective, Management, Analytic (LENT/SOMA) scale, and 36 (62.1%) experienced cognitive improvement based on the Montreal Cognitive Assessment (MoCA) scores. In a mouse model of RIBI, thalidomide restored the blood-brain barrier and cerebral perfusion, which were attributed to the functional rescue of pericytes secondary to elevation of platelet-derived growth factor receptor ß (PDGFRß) expression by thalidomide. Our data thus demonstrate the therapeutic potential of thalidomide for the treatment of radiation-induced cerebral vasculature impairment.

Extra Proximal-Gradient Network with Learned Regularization for Image Compressive Sensing Reconstruction.

Learned optimization algorithms are promising approaches to inverse problems by leveraging advanced numerical optimization schemes and deep neural network techniques in machine learning. In this paper, we propose a novel deep neural network architecture imitating an extra proximal gradient algorithm to solve a general class of inverse problems with a focus on applications in image reconstruction. The proposed network features learned regularization that incorporates adaptive sparsification mappings, robust shrinkage selections, and nonlocal operators to improve solution quality. Numerical results demonstrate the improved efficiency and accuracy of the proposed network over several state-of-the-art methods on a variety of test problems.