Learning spiking neuronal networks with artificial neural networks: neural oscillations.

First-principles-based modelings have been extremely successful in providing crucial insights and predictions for complex biological functions and phenomena. However, they can be hard to build and expensive to simulate for complex living systems. On the other hand, modern data-driven methods thrive at modeling many types of high-dimensional and noisy data. Still, the training and interpretation of these data-driven models remain challenging. Here, we combine the two types of methods to model stochastic neuronal network oscillations. Specifically, we develop a class of artificial neural networks to provide faithful surrogates to the high-dimensional, nonlinear oscillatory dynamics produced by a spiking neuronal network model. Furthermore, when the training data set is enlarged within a range of parameter choices, the artificial neural networks become generalizable to these parameters, covering cases in distinctly different dynamical regimes. In all, our work opens a new avenue for modeling complex neuronal network dynamics with artificial neural networks.

Relationship between cognitive function and weight-adjusted waist index in people ≥ 60 years old in NHANES 2011-2014.

BACKGROUND: Widespread attention has been given to the detrimental effects of obesity on cognitive function. However, there is no evidence on the connection between low cognitive performance and the WWI (weight-adjusted waist index). This study looked into the connection between poor cognitive performance and the WWI in senior Americans. METHODS: A cross-sectional research study was carried out with information from the NHANES 2011-2014. With multivariate linear regression models, the pertinence between the WWI and low cognitive function in persons older than 60 years was examined. The nonlinear link was described using threshold effect analyses and fitted smoothed curves. Interaction tests and subgroup analysis were also conducted. RESULTS: The study had 2762 individuals in all, and subjects with higher WWI values were at greater risk for low cognitive function. In the completely adjusted model, the WWI was positively connected with low cognitive performance assessed by CERAD W-L (OR = 1.22, 95% CI 1.03-1.45, p = 0.0239), AFT (OR = 1.30, 95% CI 1.09-1.54, p = 0.0029), and DSST (OR = 1.59, 95% CI 1.30-1.94, p < 0.0001). The effect of each subgroup on the positive correlation between the WWI and low cognitive performance was not significant. The WWI and low cognitive performance as determined by CERAD W-L and AFT had a nonlinear connection (log-likelihood ratio < 0.05). CONCLUSION: Among older adults in the United States, the risk of low cognitive performance may be positively related to the WWI.

Automatic planning for head and neck seed implant brachytherapy based on deep convolutional neural network dose engine.

BACKGROUND: Seed implant brachytherapy (SIBT) is an effective treatment modality for head and neck (H&N) cancers; however, current clinical planning requires manual setting of needle paths and utilizes inaccurate dose calculation algorithms. PURPOSE: This study aims to develop an accurate and efficient deep convolutional neural network dose engine (DCNN-DE) and an automatic SIBT planning method for H&N SIBT. METHODS: A cohort of 25 H&N patients who received SIBT was utilized to develop and validate the methods. The DCNN-DE was developed based on 3D-unet model. It takes single seed dose distribution from a modified TG-43 method, the CT image and a novel inter-seed shadow map (ISSM) as inputs, and predicts the dose map of accuracy close to the one from Monte Carlo simulations (MCS). The ISSM was proposed to better handle inter-seed attenuation. The accuracy and efficacy of the DCNN-DE were validated by comparing with other methods taking MCS dose as reference. For SIBT planning, a novel strategy inspired by clinical practice was proposed to automatically generate parallel or non-parallel potential needle paths that avoid puncturing bone and critical organs. A heuristic-based optimization method was developed to optimize the seed positions to meet clinical prescription requirements. The proposed planning method was validated by re-planning the 25 cases and comparing with clinical plans. RESULTS: The absolute percentage error in the TG-43 calculation for CTV V100 and D90 was reduced from 5.4% and 13.2% to 0.4% and 1.1% with DCNN-DE, an accuracy improvement of 93% and 92%, respectively. The proposed planning method could automatically obtain a plan in 2.5 ± 1.5 min. The generated plans were judged clinically acceptable with dose distribution comparable with those of the clinical plans. CONCLUSIONS: The proposed method can generate clinically acceptable plans quickly with high accuracy in dose evaluation, and thus has a high potential for clinical use in SIBT.

Rapid and accurate detection of SARS-CoV-2 using the RHAM technology.

Rapid and sensitive detection of pathogens is of utmost importance in interrupting the transmission chain of infectious diseases. In recent years, this has proven to be vital during the coronavirus disease (COVID-19) global pandemic that put countless lives at risk. Numerous molecular diagnostic methods were used, including RT-PCR, NASBA, E-SDA, E-RCA, LAMP, and RPA. However, these technologies potentially require primer optimization and complex instruments. Here, we propose the RHAM (RNase Hybridization-Assisted amplification) system as a rapid, specific, and sensitive molecular diagnosis platform. Combining the LAMP and RNase HII-mediated fluorescent reporter, the RHAM system can amplify and visualize the target in one isothermal system with high sensitivity (5 × 102 copies/mL). There was no cross-reactivity with other common respiratory viruses. Analysis of clinical samples revealed the RHAM system to generate positive signals within 15 min without false positive or negative results. The present study shows that RHAM is not only an ideal platform for detecting pathogens, such as SARS-CoV-2 but can be potentially applied in POCT settings.

Correlation between Spectral CT Parameters and Ki67 Expression in Hepatocellular Carcinoma.

OBJECTIVE: The objective of this study was to analyze the relationship between quantitative parameters of spectral CT and the Ki67 expression index of tumor cells in hepatocellular carcinoma (HCC). METHODS: A total of 19 patients who underwent preoperative spectral CT dual-phase enhancement and who were diagnosed with HCC by postoperative pathology were prospectively selected. Patients with ≥10% Ki67-positive tumor cells formed a high-Ki67 group, and those with <10% Ki67- positive cells formed a low-Ki67 group. The iodine concentrations (ICs) of the lesion and the descending aorta were measured during the arterial and venous phases. Relative iodine concentration (RIC) was calculated thus: RIC=IClesion/ICdescending aorta. CT values of the lesions at 40 and 70 keV were measured during the enhanced arterial and venous phases. The slope of the spectral curve (λ) was calculated thus: λ = (40 keV-70 keV) /(70-30). To compare the differences in quantitative parameters between the high- and low-Ki67 groups, either an independent samples t-test (normal distribution) or a Mann-Whitney U test (non-normal distribution) was used. Receiver operating characteristic curves were used to evaluate the effectiveness of spectral CT parameters in distinguishing between high-Ki67 and low-Ki67 groups. Pearson correlation analysis was used to evaluate the correlation between spectral CT quantitative parameters and Ki67 expression. RESULTS: IC, RIC and λ values for the high-Ki67 group in arterial and venous phases were higher than those for the low-Ki67 group, P < 0.05. IC, RIC, and λ values in the arterial phase were 0.83, 0.89, and 0.75, respectively; in the venous phase, the values of these three parameters were 0.76, 0.77, and 0.69, respectively. IC, RIC, and λ were positively correlated with Ki67 expression in both arterial and venous phases, with a highest correlation of 0.82 for arterial-phase RIC. CONCLUSION: The quantitative parameters of spectral CT in HCC were correlated with Ki67 expression. This finding may make it easier for clinicians to determine whether a tumor is high or low in Ki67 before surgery.

Glycine Decarboxylase (GLDC) Plays a Crucial Role in Regulating Energy Metabolism, Invasion, Metastasis and Immune Escape for Prostate Cancer.

Glycine decarboxylase (GLDC) is one of the core enzymes for glycine metabolism, and its biological roles in prostate cancer (PCa) are unclear. First, we found that GLDC plays a central role in glycolysis in 540 TCGA PCa patients. Subsequently, a metabolomic microarray showed that GLDC enhanced aerobic glycolysis in PCa cells, and GLDC and its enzyme activity enhanced glucose uptake, lactate production and lactate dehydrogenase (LDH) activity in PCa cells. Next, we found that GLDC was highly expressed in PCa, was directly regulated by hypoxia-inducible factor (HIF1-α) and regulated downstream LDHA expression. In addition, GLDC and its enzyme activity showed a strong ability to promote the migration and invasion of PCa both in vivo and in vitro. Furthermore, we found that the GLDC-high group had a higher TP53 mutation frequency, lower CD8+ T-cell infiltration, higher immune checkpoint expression, and higher immune exclusion scores than the GLDC-low group. Finally, the GLDC-based prognostic risk model by applying LASSO Cox regression also showed good predictive power for the clinical characteristics and survival in PCa patients. This evidence indicates that GLDC plays crucial roles in glycolytic metabolism, invasion and metastasis, and immune escape in PCa, and it is a potential therapeutic target for prostate cancer.

Stress relief as a natural resilience mechanism against depression-like behaviors.

Relief, the appetitive state after the termination of aversive stimuli, is evolutionarily conserved. Understanding the behavioral role of this well-conserved phenomenon and its underlying neurobiological mechanisms are open and important questions. Here, we discover that the magnitude of relief from physical stress strongly correlates with individual resilience to depression-like behaviors in chronic stressed mice. Notably, blocking stress relief causes vulnerability to depression-like behaviors, whereas natural rewards supplied shortly after stress promotes resilience. Stress relief is mediated by reward-related mesolimbic dopamine neurons, which show minute-long, persistent activation after stress termination. Circuitry-wise, activation or inhibition of circuits downstream of the ventral tegmental area during the transient relief period bi-directionally regulates depression resilience. These results reveal an evolutionary function of stress relief in depression resilience and identify the neural substrate mediating this effect. Importantly, our data suggest a behavioral strategy of augmenting positive valence of stress relief with natural rewards to prevent depression.

Rapid and Selective Uptake of Radioactive Cesium from Water by a Microporous Zeolitic-like Sulfide.

The fast and efficient removal of 137Cs+ ions from water is of great significance for the further treatment and disposal of highly active nuclear waste. Hitherto, although many layered metal sulfides have been proven to be very effective in capturing aqueous cesium, three-dimensional (3D) microporous examples have rarely been explored, especially compounds that are systematically used to study cesium ion exchange behaviors. In this paper, we present detailed Cs+ ion exchange properties of a 3D, microporous, zeolitic-like sulfide, namely K@GaSnS-1, in different conditions. Isotherm studies indicate that K@GaSnS-1 has a high cesium saturation capacity of 249.3 mg/g. In addition, it exhibits rapid sorption kinetics, with an equilibrium time of only 2 min. Further studies show that K@GaSnS-1 also displays a strong preference and good selectivity for cesium, with the highest distribution coefficient Kd value up to 3.53 × 104 mL/g. Also noteworthy is that the excellent cesium ion exchange properties are well-maintained despite acidic, basic, and competitive multiple-component environments. More importantly, the Cs+-exchanged products can be easily eluted and regenerated by a low-cost and eco-friendly method. These merits demonstrated by K@GaSnS-1 render it very promising in the effective and efficient separation of radioactive cesium from nuclear waste.

Effects of new hypoglycemic drugs on cardiac remodeling: a systematic review and network meta-analysis.

BACKGROUND: In recent years, the incidence of diabetes mellitus has been increasing annually, and cardiovascular complications secondary to diabetes mellitus have become the leading cause of death in diabetic patients. Considering the high incidence of type 2 diabetes (T2DM) combined with cardiovascular disease (CVD), some new hypoglycemic agents with cardiovascular protective effects have attracted extensive attention. However, the specific role of these regimens in ventricular remodeling remains unknown. The purpose of this network meta-analysis was to compare the effects of sodium glucose cotransporter type 2 inhibitor (SGLT-2i), glucagon-like peptide 1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 inhibitor (DPP-4i) on ventricular remodeling in patients with T2DM and/or CVD. METHODS: Articles published prior to 24 August 2022 were retrieved in four electronic databases: the Cochrane Library, Embase, PubMed, and Web of Science. This meta-analysis included randomized controlled trials (RCTs) and a small number of cohort studies. The differences in mean changes of left ventricular ultrasonic parameters between the treatment and control groups were compared. RESULTS: A total of 31 RCTs and 4 cohort studies involving 4322 patients were analyzed. GLP-1RA was more significantly associated with improvement in left ventricular end-systolic diameter (LVESD) [MD = -0.38 mm, 95% CI (-0.66, -0.10)] and LV mass index (LVMI) [MD = -1.07 g/m2, 95% CI (-1.71, -0.42)], but significantly decreased e' [MD = -0.43 cm/s 95% CI (-0.81, -0.04)]. DPP-4i was more strongly associated with improvement in e' [MD = 3.82 cm/s, 95% CI (2.92,4.7)] and E/e'[MD = -5.97 95% CI (-10.35, -1.59)], but significantly inhibited LV ejection fraction (LVEF) [MD = -0.89% 95% CI (-1.76, -0.03)]. SGLT-2i significantly improved LVMI [MD = -0.28 g/m2, 95% CI (-0.43, -0.12)] and LV end-diastolic diameter (LVEDD) [MD = -0.72 ml, 95% CI (-1.30, -0.14)] in the overall population, as well as E/e' and SBP in T2DM patients combined with CVD, without showing any negative effect on left ventricular function. CONCLUSION: The results of the network meta-analysis provided high certainty to suggest that SGLT-2i may be more effective in cardiac remodeling compared to GLP-1RA and DPP-4i. While GLP-1RA and DPP-4i may have a tendency to improve cardiac systolic and diastolic function respectively. SGLT-2i is the most recommended drug for reversing ventricular remodeling in this meta-analysis.

Identification of key genes in sepsis by WGCNA.

When the body damages its own tissues in response to an infection, sepsis develops. Medical treatments are limited. It's important to understand the molecular mechanism behind sepsis pathogenesis and identify potential molecular treatment targets. We made two modules based on how genes work together by using WGCNA analysis. The light-green GSE131761 module and the blue GSE137342 module had the strongest links to sepsis. A gene ontology (GO) analysis showed that most of the genes in the lightgreen module were involved in the inflammatory response, specific granule, and immune receptor activity. Most of the genes in the blue module were significantly more likely to have the GO terms proteasomal protein catabolic process, ubiquitin ligase complex, and ubiquitin-like protein transferase activity. The KEGG analysis showed that the genes in module lightgreen were mostly involved in the TNF signaling pathway, while the genes in module blue were mostly involved in the Prion disease pathway. There were two hub genes that were found. In the end, ANKRD22 and VNN1 were singled out as crucial genes. This study used WGCNA to investigate sepsis-associated susceptibility modules and genes. Our study identified two modules and two key genes as essential components in sepsis etiology, which may improve our understanding of its molecular mechanisms.

Multi-band oscillations emerge from a simple spiking network.

In the brain, coherent neuronal activities often appear simultaneously in multiple frequency bands, e.g., as combinations of alpha (8-12 Hz), beta (12.5-30 Hz), and gamma (30-120 Hz) oscillations, among others. These rhythms are believed to underlie information processing and cognitive functions and have been subjected to intense experimental and theoretical scrutiny. Computational modeling has provided a framework for the emergence of network-level oscillatory behavior from the interaction of spiking neurons. However, due to the strong nonlinear interactions between highly recurrent spiking populations, the interplay between cortical rhythms in multiple frequency bands has rarely been theoretically investigated. Many studies invoke multiple physiological timescales (e.g., various ion channels or multiple types of inhibitory neurons) or oscillatory inputs to produce rhythms in multi-bands. Here, we demonstrate the emergence of multi-band oscillations in a simple network consisting of one excitatory and one inhibitory neuronal population driven by constant input. First, we construct a data-driven, Poincaré section theory for robust numerical observations of single-frequency oscillations bifurcating into multiple bands. Then, we develop model reductions of the stochastic, nonlinear, high-dimensional neuronal network to capture the appearance of multi-band dynamics and the underlying bifurcations theoretically. Furthermore, when viewed within the reduced state space, our analysis reveals conserved geometrical features of the bifurcations on low-dimensional dynamical manifolds. These results suggest a simple geometric mechanism behind the emergence of multi-band oscillations without appealing to oscillatory inputs or multiple synaptic or neuronal timescales. Thus, our work points to unexplored regimes of stochastic competition between excitation and inhibition behind the generation of dynamic, patterned neuronal activities.

FACI is a novel clathrin adaptor protein 2-binding protein that facilitates low-density lipoprotein endocytosis.

BACKGROUND: Cholesterol plays a vital role in multiple physiological processes. Cellular uptake of cholesterol is mediated primarily through endocytosis of low-density lipoprotein (LDL) receptor. New modifiers of this process remain to be characterized. Particularly, the role of fasting- and CREB-H-induced (FACI) protein in cholesterol homeostasis merits further investigation. METHODS: Interactome profiling by proximity labeling and affinity purification - mass spectrometry was performed. Total internal reflection fluorescence microscopy and confocal immunofluorescence microscopy were used to analyze protein co-localization and interaction. Mutational analysis was carried out to define the domain and residues required for FACI localization and function. Endocytosis was traced by fluorescent cargos. LDL uptake in cultured cells and diet-induced hypercholesterolemia in mice were assessed. RESULTS: FACI interacted with proteins critically involved in clathrin-mediated endocytosis, vesicle trafficking, and membrane cytoskeleton. FACI localized to clathrin-coated pits (CCP) on plasma membranes. FACI contains a conserved DxxxLI motif, which mediates its binding with the adaptor protein 2 (AP2) complex. Disruption of this motif of FACI abolished its CCP localization but didn't affect its association with plasma membrane. Cholesterol was found to facilitate FACI transport from plasma membrane to endocytic recycling compartment in a clathrin- and cytoskeleton-dependent manner. LDL endocytosis was enhanced in FACI-overexpressed AML12 cells but impaired in FACI-depleted HeLa cells. In vivo study indicated that hepatic FACI overexpression alleviated diet-induced hypercholesterolemia in mice. CONCLUSIONS: FACI facilitates LDL endocytosis through its interaction with the AP2 complex.

Ultrathin quantum light source with van der Waals NbOCl2 crystal.

Interlayer electronic coupling in two-dimensional materials enables tunable and emergent properties by stacking engineering. However, it also results in significant evolution of electronic structures and attenuation of excitonic effects in two-dimensional semiconductors as exemplified by quickly degrading excitonic photoluminescence and optical nonlinearities in transition metal dichalcogenides when monolayers are stacked into van der Waals structures. Here we report a van der Waals crystal, niobium oxide dichloride (NbOCl2), featuring vanishing interlayer electronic coupling and monolayer-like excitonic behaviour in the bulk form, along with a scalable second-harmonic generation intensity of up to three orders higher than that in monolayer WS2. Notably, the strong second-order nonlinearity enables correlated parametric photon pair generation, through a spontaneous parametric down-conversion (SPDC) process, in flakes as thin as about 46 nm. To our knowledge, this is the first SPDC source unambiguously demonstrated in two-dimensional layered materials, and the thinnest SPDC source ever reported. Our work opens an avenue towards developing van der Waals material-based ultracompact on-chip SPDC sources as well as high-performance photon modulators in both classical and quantum optical technologies1-4.

Aberrant splicing events caused by insertion of genes of interest into expression vectors.

Background: Expression of genes of interest from plasmids or lentiviral vectors is one of the most common tools in molecular and gene therapy. Aberrant splicing between the inserted gene of interest and downstream vector sequence has not been systematically analyzed. Methods: Formation of aberrant fusion transcripts and proteins was detected by RT-PCR, sequencing, Western blotting and mass spectrometry. Bioinformatic analysis was performed to identify all human and mouse genes prone to vector-dependent aberrant splicing. Selected genes were experimentally validated. Results: When we expressed human FACI in cultured cells, an aberrant splicing event was found to occur between FACI transcript and downstream plasmid sequence through one exon-exon junction in FACI that accidentally contributes a splice donor site. To explore whether this could be a general phenomenon, we searched the whole human and mouse genomes for protein-coding genes that harbor an exon-exon junction resembling a splice donor site. Almost all genes prone to this type of aberrant splicing were identified. A total of 17 genes among the hits were randomly selected for experimental validation. RT-PCR and sequencing results verified that 13 genes were aberrantly spliced on the identified exon-exon junctions. In addition, all 17 genes were aberrantly spliced on their V5 tag sequence. Aberrant fusion protein expression from all 17 genes was validated by immunoblotting. Aberrant splicing was prevented by recoding the V5 tag or the splice sites. Conclusions: Our study revealed an unexpectedly high frequency of vector-dependent aberrant splicing events. Aberrant formation of the resulting fusion proteins could undermine the accuracy of gain-of-function studies and might cause potential side effects when the therapeutic gene is expressed in vivo. Our work has implications in improving vector construction and epitope tagging for gene expression and therapy.

Deletion of ACLY Disrupts Histone Acetylation and IL-10 Secretion in Trophoblasts, Which Inhibits M2 Polarization of Macrophages: A Possible Role in Recurrent Spontaneous Abortion.

Changes to macrophage polarization affect the local microenvironment of the placenta, resulting in pathological pregnancy diseases such as recurrent spontaneous abortion (RSA). Macrophages are in close contact with trophoblasts during placental development, and trophoblast-derived cytokines are important regulators of macrophage polarization and function. Histone acetylation can affect the expression and secretion of cytokines, and ATP citrate lyase (ACLY) is an important factor that regulates histone acetylation. The aim of this study was to investigate the effect of ACLY expression differences in trophoblast on macrophage polarization and its mechanism. Our data demonstrate that ACLY level in placental villi of patients with RSA is decreased, which may lead to the inhibition of histone acetylation in trophoblasts, thereby reducing the secretion of IL-10. Reduced IL-10 secretion activates endoplasmic reticulum stress in macrophages, thus inhibiting their M2 polarization.

Hypoxia-induced polarization of M2 macrophages and C-C motif chemokine ligand 5 secretion promotes the migration and invasion of trophoblasts†.

In the early stage of pregnancy, hypoxia in the placenta is of great significance to the migration and invasion of trophoblasts. In addition, changes to the polarity and activity of macrophages can affect embryo implantation, trophoblast migration and invasion, and vascular remodeling by affecting cytokine secretion. However, the mechanism of the effects of hypoxic conditions in the placenta on trophoblasts remains unknown. We used gene knockdown on macrophages, and drug treatment on trophoblasts, and cultured them under hypoxic and normoxic conditions. The cells were then subjected to wound-healing assays, Transwell cell invasion experiments, quantitative real-time reverse transcription Polymerase Chain Reaction (PCR), western blotting, and immunofluorescence. The polarization of macrophages in each group, the migration and invasion ability of trophoblasts, and changes to the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway were detected. Hypoxic conditions induce M2 polarization of macrophages. The conditioned medium from macrophages under hypoxic conditions increased the migration and invasion of trophoblasts and enhanced the levels of phosphorylated (p)-PI3K and p-AKT in trophoblasts. After C-C motif chemokine ligand 5 knockdown in macrophages, the ability of conditioned medium from macrophages cultured under hypoxic conditions to promote the migration and invasion of trophoblasts was weakened significantly. The use of PI3K/AKT signaling pathway agonists could reverse the attenuation effect caused by C-C motif chemokine ligand 5 knockdown.

Near-Field Modulation of Differently Oriented Single Photon Emitters with A Plasmonic Probe.

Single photon emitters (SPEs) are critical components of photon-based quantum technology. Recently, the interaction between surface plasmons and emitters has attracted increasing attention because of its potential to improve the quality of single-photon sources through stronger light-matter interactions. In this work, we use a hybrid plasmonic probe composed of a fiber taper and silver nanowire to controllably modulate the radiation properties of SPEs with differently oriented polarization. For out-of-plane oriented SPEs such as single CdSe quantum dots, the radiation lifetime could be reduced by a factor as large as seven; for in-plane oriented SPEs such as hBN defect SPEs, the average modulation amplitude varied from 0.69 to 1.23, depending on the position of the probe. The experimental results were highly consistent with the simulations and theory. This work provides an efficient approach for optimizing the properties of SPEs for quantum photonic integration.

Transverse Mode-Encoded Quantum Gate on a Silicon Photonic Chip.

As an important degree of freedom (d.o.f.) in photonic integrated circuits, the orthogonal transverse mode provides a promising and flexible way to increase communication capability, for both classical and quantum information processing. To construct large-scale on-chip multimode multi-d.o.f.s quantum systems, a transverse mode-encoded controlled-NOT (CNOT) gate is necessary. Here, with the help of our new transverse mode-dependent directional coupler and attenuator, we demonstrate the first multimode implementation of a 2-qubit quantum gate. The ability of the gate is demonstrated by entangling two separated transverse mode qubits with an average fidelity of 0.89±0.02 and the achievement of 10 standard deviations of violations in the quantum nonlocality verification. In addition, a fidelity of 0.82±0.01 is obtained from quantum process tomography used to completely characterize the CNOT gate. Our work paves the way for universal transverse mode-encoded quantum operations and large-scale multimode multi-d.o.f.s quantum systems.

Multilevel monte carlo for cortical circuit models.

Multilevel Monte Carlo (MLMC) methods aim to speed up computation of statistics from dynamical simulations. MLMC is easy to implement and is sometimes very effective, but its efficacy may depend on the underlying dynamics. We apply MLMC to networks of spiking neurons and assess its effectiveness on prototypical models of cortical circuitry under different conditions. We find that MLMC can be very efficient for computing reliable features, i.e., features of network dynamics that are reproducible upon repeated presentation of the same external forcing. In contrast, MLMC is less effective for complex, internally generated activity. Qualitative explanations are given using concepts from random dynamical systems theory.

FACI Is a Novel CREB-H-Induced Protein That Inhibits Intestinal Lipid Absorption and Reverses Diet-Induced Obesity.

BACKGROUND & AIMS: CREB-H is a key liver-enriched transcription factor governing lipid metabolism. Additional targets of CREB-H remain to be identified and characterized. Here, we identified a novel fasting- and CREB-H-induced (FACI) protein that inhibits intestinal lipid absorption and alleviates diet-induced obesity in mice. METHODS: FACI was identified by reanalysis of existing transcriptomic data. Faci-/- mice were generated by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9)-mediated genome engineering. RNA sequencing was performed to identify differentially expressed genes in Faci-/- mice. Lipid accumulation in the villi was assessed by triglyceride measurement and Oil red O staining. In vitro fatty acid uptake assay was performed to verify in vivo findings. RESULTS: FACI expression was enriched in liver and intestine. FACI is a phospholipid-binding protein that localizes to plasma membrane and recycling endosomes. Hepatic transcription of Faci was regulated by not only CREB-H, but also nutrient-responsive transcription factors sterol regulatory element-binding protein 1 (SREBP1), hepatocyte nuclear factor 4α (HNF4α), peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α), and CREB, as well as fasting-related cyclic adenosine monophosphate (cAMP) signaling. Genetic knockout of Faci in mice showed an increase in intestinal fat absorption. In accordance with this, Faci deficiency aggravated high-fat diet-induced obesity, hyperlipidemia, steatosis, and other obesity-related metabolic dysfunction in mice. CONCLUSIONS: FACI is a novel CREB-H-induced protein. Genetic disruption of Faci in mice showed its inhibitory effect on fat absorption and obesity. Our findings shed light on a new target of CREB-H implicated in lipid homeostasis.