Gain Of Function Research Articles

Selective Enhancer Gain of Function Deregulates MYC Expression in Multiple Myeloma

Abstract MYC deregulation occurs in the majority of multiple myeloma (MM) cases and is associated with progression and worse prognosis. Enhanced MYC expression occurs in about 70% of MM patients, but it is known to be driven by translocation or amplification events in only ~40% of myelomas. Here, we used CRISPR interference (CRISPRi) to uncover an epigenetic mechanism of MYC regulation whereby increased accessibility of a plasma cell-type specific enhancer leads to increased MYC expression. This native enhancer activity was not associated with enhancer hijacking events but led to specific binding of c-MAF, IRF4, and SPIB transcription factors that activated MYC expression in the absence of known genetic aberrations. In addition, focal amplification was another mechanism of activation of this enhancer in approximately 3.4% of MM patients. Together, these findings define an epigenetic mechanism of MYC deregulation in MM beyond known translocations or amplifications and point to the importance of non-coding regulatory elements and their associated transcription factor networks as drivers of MM progression.

Use of the Novel Site-Directed Enzyme Enhancement Therapy (SEE-Tx) Drug Discovery Platform to Identify Pharmacological Chaperones for Glutaric Acidemia Type 1.

Allosteric regulators acting as pharmacological chaperones hold promise for innovative therapeutics since they target noncatalytic sites and stabilize the folded protein without competing with the natural substrate, resulting in a net gain of function. Exogenous allosteric regulators are typically more selective than active site inhibitors and can be more potent than competitive inhibitors when the natural substrate levels are high. To identify novel structure-targeted allosteric regulators (STARs) that bind to and stabilize the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), the computational site-directed enzyme enhancement therapy (SEE-Tx) technology was applied. SEE-Tx is an innovative drug discovery platform with the potential to identify drugs for treating protein misfolding disorders, such as glutaric acidemia type 1 (GA1) disease. Putative allosteric regulators were discovered using structure- and ligand-based virtual screening methods and validated using orthogonal biophysical and biochemical assays. The computational approach presented here could be used to discover allosteric regulators of other protein misfolding disorders.

Increased cGMP improves microvascular exercise training adaptations independent of endothelial nitric oxide synthase.

Impaired microvascular function is a hallmark of pre-diabetes. With development of atherosclerosis this impaired microvascular function can result in diminished capacity for ambulation and is a risk factor for Type 2 Diabetes. Dynamic changes in vascular tone are determined, in large part, by the eNOS/NO/cGMP axis. We used gain of function of the eNOS/NO/cGMP axis in diet-induced obese (DIO) mice and reduced function in lean mice to test the hypothesis that functionality of this vascular control mechanism parallels the benefits of an exercise training regimen. DIO mice have lower exercise capacity than lean mice and were used for pharmacological gain of function. The PDE-5a inhibitor - sildenafil - increases cGMP and was administered to DIO mice daily. In sedentary mice, we find that sildenafil does not improve exercise capacity. In contrast, it amplifies the microcirculatory effects of exercise training. Sildenafil synergizes with exercise training to improve performance during an incremental exercise test. Improved exercise performance was accompanied by increased skeletal muscle capillary flow velocity and capillary density measured via intravital microscopy. Loss of function was tested in lean mice hemizygous for endothelial cell (EC) specific eNOS creating an EC-eNOS knockdown (KD). EC-eNOS KD decreases capillary density and exercise tolerance in sedentary mice; however, it did not prevent exercise-training induced improvements in endurance capacity. These data show that 1) increasing cGMP with sildenafil enhances microcirculatory function and exercise work tolerance that results from training; 2) eNOS KD does not prevent the microcirculatory or improvements in exercise tolerance with training. PDE-5a inhibitors combined with physical exercise are a potential mechanism for improving ambulation in patients with circulatory limitations.

Impact of Chromosomal Fusion and Transposable Elements on the Genomic Evolution and Genetic Diversity of Ilex Species.

The genus Ilex belongs to the sole family and is the single genus within the order Aquifoliales, exhibiting significant phenotypic diversity. However, the genetic differences underlying these phenotypic variations have rarely been studied. In this study, collinearity analyses of three Ilex genomes, Ilex latifolia Thunb., Ilex polyneura (Hand.-Mazz.) S. Y. Hu, and Ilex asprella Champ. ex Benth., indicated a recent fusion event contributing to the reduction of chromosomes in I. asprella. Comparative genome analyses showed slight differences in gene annotation among the three species, implying a minimal disruption of genes following chromosomal fusion in I. asprella. Comprehensive annotation of transposable elements (TEs) revealed that TEs constitute a significant portion of the Ilex genomes, with LTR transposons being predominant. TEs exhibited an inverse relationship with gene density, potentially influencing gene regulation and chromosomal architecture. TE insertions were shown to affect the conformation and binding sites of key genes such as 7-deoxyloganetin glucosyltransferase and transmembrane kinase (TMK) genes, highlighting potential functional impacts. The structural variations caused by TE insertions suggest significant roles in the evolutionary dynamics, leading to either loss or gain of gene function. This study underscores the importance of TEs in shaping the genomic landscape and evolutionary trajectories of Ilex species.

The Effect of Smoking on the Functional Gain After Inpatient Rehabilitation in People with Spinal Cord Injury

The Effect of Smoking on the Functional Gain After Inpatient Rehabilitation in People with Spinal Cord Injury

Cyclophilin D, regulator of the mitochondrial permeability transition, impacts bone development and fracture repair

Mitochondrial Permeability Transition Pore (MPTP) and its key positive regulator, Cyclophilin D (CypD), control activity of cell oxidative metabolism important for differentiation of stem cells of various lineages including osteogenic lineage. Our previous work (Sautchuk et al., 2022) showed that CypD gene, Ppif, is transcriptionally repressed during osteogenic differentiation by regulatory Smad transcription factors in BMP canonical pathway, a major driver of osteoblast (OB) differentiation. Such a repression favors closure of the MPTP, priming OBs to higher usage of mitochondrial oxidative metabolism. The physiological role of CypD/MPTP regulation was demonstrated by its inverse correlation with BMP signaling in aging and bone fracture healing in addition to the negative effect of CypD gain-of-function (GOF) on bone maintenance. Here we show evidence that CypD GOF also negatively affects bone development and growth as well as fracture healing in adult mice. Developing craniofacial and long bones presented with delayed ossification and decreased growth rate, respectively, whereas in fracture, bony callus volume was diminished. Given that Genome Wide Association Studies showed that PPIF locus is associated with both body height and bone mineral density, our new data provide functional evidence for the role of PPIF gene product, CypD, and thus MPTP in bone growth and repair.

Interval riccati equation-based and non-probabilistic dynamic reliability-constrained multi-objective optimal vibration control with multi-source uncertainties

Structural vibration control is used to ensure the safety of structures in service and has become an active research area in the past few years. In this study, uncertainties in structural dynamics are considered to propose an interval linear quadratic regulator (LQR) method based on an interval Riccati equation. Multi-objective optimization with non-probabilistic dynamic reliability as a constraint is performed to design an optimal uncertain vibration control system. To alleviate the difficulty of quantifying the probabilistic uncertainty and accurately characterize uncertainty information for small samples, multi-source uncertainties are regarded as interval parameters. The bounds on these uncertainties are determined, and the deterministic and uncertain parts of an interval state-space equation for vibration control are then formulated using an expanded-order matrix and the interval analysis method. Next, the interval perturbation method with a matrix series is used to develop a novel solution method for the linear inhomogeneous time-invariant equation in the interval state-space equation for the vibration control system and is used to accurately predict the interval bounds of the state responses. The conventional LQR method from modern control theory is used to propose a novel optimal control method based on a novel interval Riccati equation using the Lyapunov equation and interval uncertainty propagation. The proposed interval control method can be used to estimate the uncertain bounds of the controlled gain and cost function. A non-probabilistic dynamic reliability model is established to evaluate the reliability index of the system, which can overcome the limitations of the large computational cost of determining the probabilistic reliability. The deterministic controlled cost and uncertain states are considered as two optimization objectives with the proposed reliability constraint. The resulting constrained multi-objective optimal vibration control problem is designed and solved using c-DPEA. A flowchart is presented as a clear overview of the uncertain vibration control method, and the effectiveness of the proposed method is validated using two numerical examples. Different optimal control designs are obtained using different reliability constraints for quantitatively analyzing the safety of the control system.

Reduction of RAD23A extends lifespan and mitigates pathology in TDP-43 mice.

Protein misfolding and aggregation are cardinal features of neurodegenerative disease (NDD) and they contribute to pathophysiology by both loss-of-function (LOF) and gain-of-function (GOF) mechanisms. This is well exemplified by TDP-43 which aggregates and mislocalizes in several NDDs. The depletion of nuclear TDP-43 leads to reduction in its normal function in RNA metabolism and the cytoplasmic accumulation of TDP-43 leads to aberrant protein homeostasis. A modifier screen found that loss of rad23 suppressed TDP-43 pathology in invertebrate and tissue culture models. Here we show in a mouse model of TDP-43 pathology that genetic or antisense oligonucleotide (ASO)-mediated reduction in rad23a confers benefits on survival and behavior, histological hallmarks of disease and reduction of mislocalized and aggregated TDP-43. This results in improved function of the ubiquitin-proteasome system (UPS) and correction of transcriptomic alterations evoked by pathologic TDP-43. RAD23A-dependent remodeling of the insoluble proteome appears to be a key event driving pathology in this model. As TDP-43 pathology is prevalent in both familial and sporadic NDD, targeting RAD23A may have therapeutic potential.

Idiopathic Distal Sensory Polyneuropathy and Fibromyalgia Syndrome: A Comparative Phenotyping Study.

Painful idiopathic distal sensory polyneuropathy (IDSP) and fibromyalgia syndrome (FMS) are cryptogenic chronic pain syndromes. The contribution of small fibre pathology (SFP) in FMS remains controversial. This study aims to quantify small nerve pathology in participants with IDSP and FMS and identify relationships of SFP with sensory phenotypes. In this study, 73 individuals (FMS: 25, IDSP: 23, healthy volunteers: 25) underwent comprehensive assessment, including neurological exams, questionnaires, sensory tests, and corneal confocal microscopy. IDSP participants displayed lower wind-up ratio (WUR) relative to FMS (p<0.001), loss of function to thermal and mechanical stimuli and elevated neuropathy disability scores compared to FMS and healthy volunteers (all p<0.001). FMS participants demonstrated gain of function to heat and blunt pressure pain responses relative to IDSP, and healthy volunteers (heat: p=0.002 and p=0.003; pressure: both p<0.001) and WUR (both p<0.001). FMS participants exhibited reduced corneal nerve fibre density (p=0.02), while IDSP participants had lower global corneal nerve measures (density, branch density, and length) relative to healthy volunteers (all p<0.001). Utilising corneal nerve fibre length, SFP was demonstrated in 66.6% of participants (FMS: 13/25; IDSP: 22/23). Participants with SFP,in both FMS and IDSP, reported symptoms indicative of small nerve fibre disease. Although distinctions in pain distributions are evident between individuals with FMS and IDSP, over 50% of participants between the two conditions displayed both a loss and gain of thermal and mechanical function suggestive of shared mechanisms. However, sensory phenotypes were associated with the presence of SFP in IDSP but not in FMS.

ELUCIDATING THE DIFFERENTIAL IMPACTS OF EQUIVALENT GATING-CHARGE MUTATIONS IN VOLTAGE-GATED SODIUM CHANNELS.

Voltage-gated sodium (Nav) channels are pivotal for cellular signaling and mutations in Nav channels can lead to excitability disorders in cardiac, muscular, and neural tissues. A major cluster of pathological mutations localizes in the voltage-sensing domains (VSDs), resulting in either gain-of-function (GoF), loss-of-function (LoF) effects, or both. However, the mechanism behind this functional divergence of mutations at equivalent positions remains elusive. Through hotspot analysis, we identified three gating charges (R1, R2, and R3) as major mutational hotspots in VSDs. The same amino-acid substitutions at equivalent gating-charge positions in VSDI and VSDII of the cardiac sodium channel Nav1.5 show differential gating-property impacts in electrophysiology measurements. We conducted 120 μs molecular dynamics (MD) simulations on wild-type and six mutants to elucidate the structural basis of their differential impacts. Our μs-scale MD simulations with applied external electric fields captured VSD state transitions and revealed the differential structural dynamics between equivalent R-to-Q mutants. Notably, we observed transient leaky conformations in some mutants during structural transitions, offering a detailed structural explanation for gating-pore currents. Our salt-bridge network analysis uncovered VSD-specific and state-dependent interactions among gating charges, countercharges, and lipids. This detailed analysis elucidated how mutations disrupt critical electrostatic interactions, thereby altering VSD permeability and modulating gating properties. By demonstrating the crucial importance of considering the specific structural context of each mutation, our study represents a significant leap forward in understanding structure-function relationships in Nav channels. Our work establishes a robust framework for future investigations into the molecular basis of ion channel-related disorders.

Capacity analysis over fractional order Rayleigh fading channel under additive white generalized Gaussian noise

AbstractThis study presents an innovative fractional order Rayleigh fading model that can be used for channel capacity estimation in the presence of additive white generalized Gaussian noise. The proposed model assumes that the real and imaginary parts of channel gains are generalized Gaussian random variables, which makes it possible to consider the traditional Rayleigh fading model as a special case of fractional order Rayleigh fading. Compared to the Rayleigh model, the fractional order Rayleigh fading model offers a more precise representation of new real‐world communication, such as integrating terrestrial and underwater networks in sixth‐generation communications channels. The probability density function of the channel gain with additive white generalized Gaussian noise is analyzed here. Furthermore, the ergodic and outage capacities of the channel are determined, taking into account the assumption that the channel state information is only available at the receiver. The ergodic capacity is calculated using Meijer's G‐functions, resulting in a closed‐form expression. Numerical simulations demonstrate the superiority of the fractional order Rayleigh fading model over the Rayleigh channel. Moreover, the impact of ergodic and outage capacities under diverse channel characteristics is assessed.

Integrated optimization of logistics routing problem considering chance preference

PurposeThis study aims to examine the impact of the decision makers’ risk preference on logistics routing problem, contributing to logistics behavior analysis and route integration optimization under uncertain environment. Due to the unexpected events and complex environment in modern logistics operations, the logistics process is full of uncertainty. Based on the chance function of satisfying the transportation time and cost requirements, this paper focuses on the fourth party logistics routing integrated optimization problem considering the chance preference of decision makers from the perspective of satisfaction.Design/methodology/approachThis study used the quantitative method to investigate the relationship between route decision making and human behavior. The cumulative prospect theory is used to describe the loss, gain and utility function based on confidence levels. A mathematical model and an improved ant colony algorithm are employed to solve the problems. Numerical examples show the effectiveness of the proposed model and algorithm.FindingsThe study’s findings reveal that the dual-population improvement strategy enhances the algorithm’s global search capability and the improved algorithm can solve the risk model quickly, verifying the effectiveness of the improvement method. Moreover, the decision-maker is more sensitive to losses, and the utility obtained when considering decision-makers' risk attitudes is greater than that obtained when the decision-maker exhibits risk neutrality.Practical implicationsIn an uncertain environment, the logistics decision maker’s risk preference directly affects decision making. Different parameter combinations in the proposed model could be set for decision-makers with different risk attitudes to fit their needs more accurately. This could help managers design effective transportation plans and improve service levels. In addition, the improved algorithm can solve the proposed problem quickly, stably and effectively, so as to help the decision maker to make the logistics path decision quickly according to the required confidence level.Originality/valueConsidering the uncertainty in logistics and the risk behavior of decision makers, this paper studies integrated routing problem from the perspective of opportunity preference. Based on the chance function of satisfying the transportation time and cost requirements, a fourth party logistics routing integrated optimization problem model considering the chance preference of decision makers is established. According to the characteristics of the problem, an improved dual-population ant colony algorithm is designed to solve the proposed model. Numerical examples show the effectiveness the proposed methods.

Long-term follow-up of Bonebridge BCI 601 implantation for microtia patients with aural atresia: acoustic and subjective benefits.

This study evaluated the long-term acoustic and subjective outcomes of Bonebridge bone conduction implant (BCI) 601 implantation in Taiwanese microtia patients with aural atresia (AA). A total of 41 microtia patients (26 with bilateral AA and 15 with unilateral AA) who received Bonebridge BCI 601 implantation between December 2014 and March 2021 at Chang Gung Memorial Hospital, Linkou, Taiwan, were included in this retrospective study. Acoustic outcomes, including the functional hearing gain (FHG), speech reception threshold (SRT), and word recognition score (WRS), were assessed. Subjective outcomes were assessed using the Chinese versions of four questionnaires: the Abbreviated Profile of Hearing Aid Benefit (APHAB); the Speech, Spatial and Qualities of Hearing Scale; the International Outcome Inventory for Hearing Aids; and the Satisfaction with Amplification in Daily Living. The mean follow-up duration was 6.3 years (range, 2.8-9.1). The mean unaided air conduction pure tone average (PTA4) was 65.3 ± 8.8 decibels (dB) hearing level (HL) and the mean aided sound field PTA4 was 31.1 ± 9.1 dB HL, resulting in a FHG of 34.2 ± 11.7 dB HL (p < 0.05). After Bonebridge implantation, the mean SRT in quiet, SRT in noise, WRS in quiet, and WRS in noise improved from 58.3 ± 7.4 dB HL to 29.4 ± 7.0 dB HL, from -1.4 ± 7.3 dB signal-to-noise ratio (SNR) to -9.6 ± 5.4 dB SNR, from 46.4 ± 26.9% to 93.8 ± 3.1%, and from 46.7 ± 21.8% to 72.7 ± 19.3%, respectively (p < 0.05). Additionally, the bilateral AA group exhibited greater SRT and WRS improvements compared to the unilateral AA group (p < 0.05). All mean subscale scores in the four questionnaires showed improvement after Bonebridge implantation, except for the mean aversiveness to sounds subscale score in the APHAB questionnaire. Bonebridge BCI 601 implantation provided long-term acoustic and subjective benefits to microtia patients with AA, particularly those with bilateral AA.

Mutagenesis Sensitivity Mapping of Human Enhancers In Vivo.

Distant-acting enhancers are central to human development. However, our limited understanding of their functional sequence features prevents the interpretation of enhancer mutations in disease. Here, we determined the functional sensitivity to mutagenesis of human developmental enhancers in vivo. Focusing on seven enhancers active in the developing brain, heart, limb and face, we created over 1700 transgenic mice for over 260 mutagenized enhancer alleles. Systematic mutation of 12-basepair blocks collectively altered each sequence feature in each enhancer at least once. We show that 69% of all blocks are required for normal in vivo activity, with mutations more commonly resulting in loss (60%) than in gain (9%) of function. Using predictive modeling, we annotated critical nucleotides at base-pair resolution. The vast majority of motifs predicted by these machine learning models (88%) coincided with changes to in vivo function, and the models showed considerable sensitivity, identifying 59% of all functional blocks. Taken together, our results reveal that human enhancers contain a high density of sequence features required for their normal in vivo function and provide a rich resource for further exploration of human enhancer logic.

Rosetta stone for the population dynamics of spiking neuron networks.

Populations of spiking neuron models have densities of their microscopic variables (e.g., single-cell membrane potentials) whose evolution fully capture the collective dynamics of biological networks, even outside equilibrium. Despite its general applicability, the Fokker-Planck equationgoverning such evolution is mainly studied within the borders of the linear response theory, although alternative spectral expansion approaches offer some advantages in the study of the out-of-equilibrium dynamics. This is mainly due to the difficulty in computing the state-dependent coefficients of the expanded system of differential equations. Here, we address this issue by deriving analytic expressions for such coefficients by pairing perturbative solutions of the Fokker-Planck approach with their counterparts from the spectral expansion. A tight relationship emerges between several of these coefficients and the Laplace transform of the interspike interval density (i.e., the distribution of first-passage times). "Coefficients" like the current-to-rate gain function, the eigenvalues of the Fokker-Planck operator and its eigenfunctions at the boundaries are derived without resorting to integral expressions. For the leaky integrate-and-fire neurons, the coupling terms between stationary and nonstationary modes are also worked out paving the way to accurately characterize the critical points and the relaxation timescales in networks of interacting populations.

Increased Susceptibility of WHIM Mice to Papillomavirus-induced Disease is Dependent upon Immune Cell Dysfunction.

Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome is a rare primary immunodeficiency disease in humans caused by a gain of function in CXCR4, mostly due to inherited heterozygous mutations in CXCR4. One major clinical symptom of WHIM patients is their high susceptibility to human papillomavirus (HPV) induced disease, such as warts. Persistent high risk HPV infections cause 5% of all human cancers, including cervical, anogenital, head and neck and some skin cancers. WHIM mice bearing the same mutation identified in WHIM patients were created to study the underlying causes for the symptoms manifest in patients suffering from the WHIM syndrome. Using murine papillomavirus (MmuPV1) as an infection model in mice for HPV-induced disease, we demonstrate that WHIM mice are more susceptible to MmuPV1-induced warts (papillomas) compared to wild type mice. Namely, the incidence of papillomas is higher in WHIM mice compared to wild type mice when mice are exposed to low doses of MmuPV1. MmuPV1 infection facilitated both myeloid and lymphoid cell mobilization in the blood of wild type mice but not in WHIM mice. Higher incidence and larger size of papillomas in WHIM mice correlated with lower abundance of infiltrating T cells within the papillomas. Finally, we demonstrate that transplantation of bone marrow from wild type mice into WHIM mice normalized the incidence and size of papillomas, consistent with the WHIM mutation in hematopoietic cells contributing to higher susceptibility of WHIM mice to MmuPV1-induced disease. Our results provide evidence that MmuPV1 infection in WHIM mice is a powerful preclinical infectious model to investigate treatment options for alleviating papillomavirus infections in WHIM syndrome.

Assessment of the reliability, responsiveness, and meaningfulness of the scale for the assessment and rating of ataxia (SARA) for lysosomal storage disorders.

To evaluate the reliability, responsiveness, and validity of theScale for the Assessment and Rating of Ataxia (SARA) in patients with lysosomal storage disorders (LSDs) who present with neurological symptoms, and quantify the threshold for a clinically meaningful change. We analyzed data from three clinical trial cohorts (IB1001-201, IB1001-202, and IB1001-301) of patients with Niemann-Pick disease type C (NPC) and GM2 Gangliosidoses (Tay-Sachs and Sandhoff disease) comprising 122 patients and 703 visits. Reproducibility was described as re-test reliability between repeat baseline visits or baseline and post-treatment washout visits. Responsiveness was determined in relation to the Investigator's, Caregiver's, and Patient's Clinical Global Impression of Improvement (CGI-I). The CGI-I data was also used to quantify a threshold for a clinically meaningful improvement on the SARA scale. Using a qualitative methods approach, patient/caregiver interviews from the IB1001-301 trial were further used to assess a threshold of meaningful change as well as the breadth of neurological signs and symptoms captured and evaluated by the SARA scale. The Inter-Class Correlation (ICC) was 0.95 or greater for all three trials, indicating a high internal consistency/reliability. The mean change in SARA between repeat baseline and post-treatment washout visit assessments in all trials was -0.05, SD 1.98, i.e., minimal, indicating no significant differences, learning effects or other systematic biases. For the CGI-I responses and change in SARA scores, Area Under the Curve (AUC) values were 0.82, 0.71, and 0.77 for the Investigator's, Caregiver's, and Patient's CGI-I respectively, indicating strong agreement. Further qualitative analyses of the patient/caregiver interviews demonstrated a 1-point or greater change on SARA to be a clinically meaningful improvement which is directly relevant to the patient's everyday functioning and quality of life. Changes captured by the SARA were also paralleled by improvement in a broad range of neurological signs and symptoms and beyond cerebellar ataxia. Qualitative and quantitative data demonstrate the reliability and responsiveness of the SARA score as a valid measure of neurological signs and symptoms in LSDs with CNS involvement, such as NPC and GM2 Gangliosidoses. A 1-point change represents a clinically meaningful transition reflecting the gain or loss of complex function.

Neural Operator Approximations for Boundary Stabilization of Cascaded Parabolic PDEs

ABSTRACTThis article proposes a novel method to accelerate the boundary feedback control design of cascaded parabolic difference equations (PDEs) through DeepONet. The backstepping method has been widely used in boundary control problems of PDE systems, but solving the backstepping kernel function can be time‐consuming. To address this, a neural operator (NO) learning scheme is leveraged for accelerating the control design of cascaded parabolic PDEs. DeepONet, a class of deep neural networks designed for approximating nonlinear operators, has shown potential for approximating PDE backstepping designs in recent studies. Specifically, we focus on approximating gain kernel PDEs for two cascaded parabolic PDEs. We utilize neural operators to map only two kernel functions, while the other two are computed using the analytical solution, thus simplifying the training process. We establish the continuity and boundedness of the kernels, and demonstrate the existence of arbitrarily close DeepONet approximations to the kernel PDEs. Furthermore, we demonstrate that the DeepONet approximation gain kernels ensure stability when replacing the exact backstepping gain kernels. Notably, DeepONet operator exhibits computation speeds two orders of magnitude faster than PDE solvers for such gain functions, and their theoretically proven stabilizing capability is validated through simulations.

Simultaneous credible bands for transfer function estimates

This paper deals with simultaneous credible bands (SCBs) for transfer function estimates based on Gaussian posteriors of the impulse response vector derived from identification of high-order FIR models, where SCBs quantify estimation errors of functions over their entire domain. Though conservative, SCBs for step responses and gain/phase functions are obtained by maximizing and minimizing them over the uncertainty sets specified by critical values of χ2 statistics associated with the Gaussian posterior. This procedure also applies to deriving (exact) pointwise credible bands (PCBs) using relevant critical values. In numerical studies, we compute the failure rates that SCBs fail to include the true step response or gain function over their respective domains; thereby an empirical method for computing less conservative SCBs is developed.

Zhimu-Huangbai herb-pair ameliorates hepatic steatosis in mice by regulating IRE1α/XBP1s pathway to inhibit SREBP-1c

BackgroundCurrently, there is a lack of validated pharmacological interventions for non-alcoholic fatty liver disease (NAFLD), which is characterized by the accumulation of hepatic triglyceride. Zhimu-Huangbai (ZH) herb-pair is a traditional Chinese medicine that regulates glucose and lipid metabolism disorders. However, the precise mechanisms underlying the preventive effects of hepatic triglyceride induced by high-fat diet (HFD) remain elusive. PurposeThe study aimed to examine the impact of ZH herb-pair on NAFLD in mice and explore the underlying mechanisms, particularly its effects on endoplasmic reticulum (ER) stress and lipid metabolism. MethodsNAFLD was induced in mice using HFD, and the treated mice were orally administered ZH, metformin (Glucophage) or lovastatin. The lipid metabolism factors, ER stress markers, and the unfolded protein response (UPR) branch factors were measured using immunohistochemistry, western blotting or qRT-PCR. Co-Immunoprecipitation (CoIP) was performed to reveal the connection between SCAP and SREBP-1c. Tunicamycin (TM) and plasmid delivery were used to induce acute ER stress or crease XBP1 gain function models. The main compounds in ZH binding to IRE1α protein were studied by molecular docking and cellular thermal shift assay (CETSA). ResultsTreatment with ZH significantly ameliorated hepatic steatosis and reduced lipid synthesis process mainly inhibiting the expression of mature active form of SREBP-1c through relieving ER stress. The expression of IRE1α and XBP1s was inhibited after treatment with ZH. In addition, ZH improved the fatty liver phenotype caused by XBP1 overexpression via decreasing srebp1c transcription. In vitro experimental results suggested that the main compounds in ZH decreased cellular TG contents. Mechanistically, ZH targeted IRE1α and inhibited XBP1s mRNA expression to relieve ER stress and inhibit SREBP-1c production. ConclusionsZH herb-pair can protect against NAFLD by reducing the expression of SREBP-1c, in part, via regulating IRE1α/XBP1s pathway.