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.

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.

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.

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.

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.

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.

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.

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.

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 functional role of meningeal lymphatics in sex difference of stress susceptibility in mice.

Major depressive disorder is one of the most common mental health conditions. Meningeal lymphatics are essential for drainage of molecules in the cerebrospinal fluid to the peripheral immune system. Their potential role in depression-like behaviour has not been investigated. Here, we show in mice, sub-chronic variable stress as a model of depression-like behaviour impairs meningeal lymphatics in females but not in males. Manipulations of meningeal lymphatics regulate the sex difference in the susceptibility to stress-induced depression- and anxiety-like behaviors in mice, as well as alterations of the medial prefrontal cortex and the ventral tegmental area, brain regions critical for emotional regulation. Together, our findings suggest meningeal lymphatic impairment contributes to susceptibility to stress in mice, and that restoration of the meningeal lymphatics might have potential for modulation of depression-like behaviour.

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.

Sex-Specific Transcriptomic Signatures in Brain Regions Critical for Neuropathic Pain-Induced Depression.

Neuropathic pain is a chronic debilitating condition with a high comorbidity with depression. Clinical reports and animal studies have suggested that both the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC) are critically implicated in regulating the affective symptoms of neuropathic pain. Neuropathic pain induces differential long-term structural, functional, and biochemical changes in both regions, which are thought to be regulated by multiple waves of gene transcription. However, the differences in the transcriptomic profiles changed by neuropathic pain between these regions are largely unknown. Furthermore, women are more susceptible to pain and depression than men. The molecular mechanisms underlying this sexual dimorphism remain to be explored. Here, we performed RNA sequencing and analyzed the transcriptomic profiles of the mPFC and ACC of female and male mice at 2 weeks after spared nerve injury (SNI), an early time point when the mice began to show mild depressive symptoms. Our results showed that the SNI-induced transcriptomic changes in female and male mice were largely distinct. Interestingly, the female mice exhibited more robust transcriptomic changes in the ACC than male, whereas the opposite pattern occurred in the mPFC. Cell type enrichment analyses revealed that the differentially expressed genes involved genes enriched in neurons, various types of glia and endothelial cells. We further performed gene set enrichment analysis (GSEA), which revealed significant de-enrichment of myelin sheath development in both female and male mPFC after SNI. In the female ACC, gene sets for synaptic organization were enriched, and gene sets for extracellular matrix were de-enriched after SNI, while such signatures were absent in male ACC. Collectively, these findings revealed region-specific and sexual dimorphism at the transcriptional levels induced by neuropathic pain, and provided novel therapeutic targets for chronic pain and its associated affective disorders.

An optimal control framework for joint-channel parallel MRI reconstruction without coil sensitivities.

GOAL: This work aims at developing a novel calibration-free fast parallel MRI (pMRI) reconstruction method incorporate with discrete-time optimal control framework. The reconstruction model is designed to learn a regularization that combines channels and extracts features by leveraging the information sharing among channels of multi-coil images. We propose to recover both magnitude and phase information by taking advantage of structured convolutional networks in image and Fourier spaces. METHODS: We develop a novel variational model with a learnable objective function that integrates an adaptive multi-coil image combination operator and effective image regularization in the image and Fourier spaces. We cast the reconstruction network as a structured discrete-time optimal control system, resulting in an optimal control formulation of parameter training where the parameters of the objective function play the role of control variables. We demonstrate that the Lagrangian method for solving the control problem is equivalent to back-propagation, ensuring the local convergence of the training algorithm. RESULTS: We conduct a large number of numerical experiments of the proposed method with comparisons to several state-of-the-art pMRI reconstruction networks on real pMRI datasets. The numerical results demonstrate the promising performance of the proposed method evidently. CONCLUSION: The proposed method provides a general deep network design and training framework for efficient joint-channel pMRI reconstruction. SIGNIFICANCE: By learning multi-coil image combination operator and performing regularizations in both image domain and k-space domain, the proposed method achieves a highly efficient image reconstruction network for pMRI.

Plexin-A1 expression in the inhibitory neurons of infralimbic cortex regulates the specificity of fear memory in male mice.

Maintaining appropriate levels of fear memory specificity is crucial for individual's survival and mental health, whereas overgeneralized fear commonly occurs in neuropsychiatric disorders, including posttraumatic stress disorder and generalized anxiety disorder. However, the molecular mechanisms regulating fear memory specificity remain poorly understood. The medial prefrontal cortex (mPFC) is considered as a key brain region in fear memory regulation. Previous transcriptomic studies have identified that plexin-A1, a transmembrane receptor critical for axon development, was downregulated in the mPFC after fear memory training. In this study, we identified that learning-induced downregulation of the mRNA and protein levels of plexin-A1 specifically occurred in the inhibitory but not excitatory neurons in the infralimbic cortex (IL) of mPFC. Further studies of plexin-A1 by virus-mediated over-expression of functional mutants selectively in the IL inhibitory neurons revealed the critical roles of plexin-A1 for regulating memory specificity and anxiety. Moreover, our findings revealed that plexin-A1 regulated the distribution of glutamic acid decarboxylase 67, a GABA synthetase, which in turn modulated the activity of IL and its downstream brain regions. Collectively, our findings elucidate the molecular modifier of IL inhibitory neurons in regulating memory specificity and anxiety, and provide candidates for developing therapeutic strategies for the prevention or treatment of a series of fear generalization-related neuropsychiatric disorders.

An Optimization-Based Meta-Learning Model for MRI Reconstruction with Diverse Dataset.

This work aims at developing a generalizable Magnetic Resonance Imaging (MRI) reconstruction method in the meta-learning framework. Specifically, we develop a deep reconstruction network induced by a learnable optimization algorithm (LOA) to solve the nonconvex nonsmooth variational model of MRI image reconstruction. In this model, the nonconvex nonsmooth regularization term is parameterized as a structured deep network where the network parameters can be learned from data. We partition these network parameters into two parts: a task-invariant part for the common feature encoder component of the regularization, and a task-specific part to account for the variations in the heterogeneous training and testing data. We train the regularization parameters in a bilevel optimization framework which significantly improves the robustness of the training process and the generalization ability of the network. We conduct a series of numerical experiments using heterogeneous MRI data sets with various undersampling patterns, ratios, and acquisition settings. The experimental results show that our network yields greatly improved reconstruction quality over existing methods and can generalize well to new reconstruction problems whose undersampling patterns/trajectories are not present during training.

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.

An increase in VGF expression through a rapid, transcription-independent, autofeedback mechanism improves cognitive function.

The release of neuropeptides from dense core vesicles (DCVs) modulates neuronal activity and plays a critical role in cognitive function and emotion. The granin family is considered a master regulator of DCV biogenesis and the release of DCV cargo molecules. The expression of the VGF protein (nonacronymic), a secreted neuropeptide precursor that also belongs to the extended granin family, has been previously shown to be induced in the brain by hippocampus-dependent learning, and its downregulation is mechanistically linked to neurodegenerative diseases such as Alzheimer's disease and other mood disorders. Currently, whether changes in translational efficiency of Vgf and other granin mRNAs may be associated and regulated with learning associated neural activity remains largely unknown. Here, we show that either contextual fear memory training or the administration of TLQP-62, a peptide derived from the C-terminal region of the VGF precursor, acutely increases the translation of VGF and other granin proteins, such as CgB and Scg2, via an mTOR-dependent signaling pathway in the absence of measurable increases in mRNA expression. Luciferase-based reporter assays confirmed that the 3'-untranslated region (3'UTR) of the Vgf mRNA represses VGF translation. Consistently, the truncation of the endogenous Vgf mRNA 3'UTR results in substantial increases in VGF protein expression both in cultured primary neurons and in brain tissues from knock in mice expressing a 3'UTR-truncation mutant encoded by the modified Vgf gene. Importantly, Vgf 3'UTR-truncated mice exhibit enhanced memory performance and reduced anxiety- and depression-like behaviors. Our results therefore reveal a rapid, transcription-independent induction of VGF and other granin proteins after learning that are triggered by the VGF-derived peptide TLQP-62. Our findings suggest that the rapid, positive feedforward increase in the synthesis of granin family proteins might be a general mechanism to replenish DCV cargo molecules that have been released in response to neuronal activation and is crucial for memory function and mood stability.

Repetitive transcranial magnetic stimulation increases the brain's drainage efficiency in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with high prevalence rate among the elderly population. A large number of clinical studies have suggested repetitive transcranial magnetic stimulation (rTMS) as a promising non-invasive treatment for patients with mild to moderate AD. However, the underlying cellular and molecular mechanisms remain largely uninvestigated. In the current study, we examined the effect of high frequency rTMS treatment on the cognitive functions and pathological changes in the brains of 4- to 5-month old 5xFAD mice, an early pathological stage with pronounced amyloidopathy and cognitive deficit. Our results showed that rTMS treatment effectively prevented the decline of long-term memories of the 5xFAD mice for novel objects and locations. Importantly, rTMS treatment significantly increased the drainage efficiency of brain clearance pathways, including the glymphatic system in brain parenchyma and the meningeal lymphatics, in the 5xFAD mouse model. Significant reduction of Aß deposits, suppression of microglia and astrocyte activation, and prevention of decline of neuronal activity as indicated by the elevated c-FOS expression, were observed in the prefrontal cortex and hippocampus of the rTMS-treated 5xFAD mice. Collectively, these findings provide a novel mechanistic insight of rTMS in regulating brain drainage system and ß-amyloid clearance in the 5xFAD mouse model, and suggest the potential use of the clearance rate of contrast tracer in cerebrospinal fluid as a prognostic biomarker for the effectiveness of rTMS treatment in AD patients.