Actor-Critic With Synthesis Loss for Solving Approximation Biases.

Approximation biases of value functions are considered a key problem in reinforcement learning (RL). In particular, existing RL algorithms are hindered by overestimation and underestimation biases, i.e., value mismatching between RL's actual returns and action-value approximations limits the performance of RL algorithms. In this article, we first develop a new synthesis loss function for RL's action-value estimation integrating a regularization term and a modified "clipped double Q -learning" structure for solving overestimation and underestimation biases. To minimize the differences between action-value estimations and actual returns in RL, we develop a new discrepancy function to determine the type and magnitude of approximation biases. Then, two coefficients embedded in the synthesis loss are automatically tuned by minimizing the discrepancy function during training to minimize approximation biases. We further design a new actor-critic (AC) algorithm, named AC with synthesis loss (ACSL), by integrating the synthesis loss function and an error-controlled mechanism. Experimental results on continuous control tasks illustrate that the proposed ACSL algorithm outperforms other cutting-edge RL methods in many tasks and that the proposed synthesis loss function is easily implemented into other algorithms and significantly reduces approximation biases while improving performance. The proposed method can successfully handle many complex continuous control tasks and can greatly outperform other state-of-the-art algorithms on most tasks.

A compound enzyme as an additive to a continuous anaerobic dynamic membrane bioreactor for enhanced lignocellulose removal from codigestion: Performance, membrane characteristics and microorganisms.

To explore the enzyme-enhanced strategy of a continuous anaerobic dynamic membrane reactor (AnDMBR), the anaerobic codigestion system of food waste and corn straw was first operated stably, and then the best combination of compound enzymes (laccase, endo-ß-1,4-glucanase, xylanase) was determined via a series of batch trials. The results showed that the methane yield (186.8 ± 19.9 mL/g VS) with enzyme addition was 12.2 % higher than that without enzyme addition. Furthermore, the removal rates of cellulose, hemicellulose and lignin increased by 31 %, 36 % and 78 %, respectively. In addition, dynamic membranes can form faster and more stably with enzyme addition. The addition of enzymes changed the structure of microbial communities while maintaining sufficient hydrolysis bacteria (Bacteroidetes), promoting the proliferation of Proteobacteria as a dominant strain and bringing stronger acetylation ability. In summary, the compound enzyme strengthening strategy successfully improved the methane production, dynamic membrane effect, and degradation rate of lignocellulose in AnDMBR.

Self-Organizing Type-2 Fuzzy Double Loop Recurrent Neural Network for Uncertain Nonlinear System Control.

Nonlinear systems, such as robotic systems, play an increasingly important role in our modern daily life and have become more dominant in many industries; however, robotic control still faces various challenges due to diverse and unstructured work environments. This article proposes a double-loop recurrent neural network (DLRNN) with the support of a Type-2 fuzzy system and a self-organizing mechanism for improved performance in nonlinear dynamic robot control. The proposed network has a double-loop recurrent structure, which enables better dynamic mapping. In addition, the network combines a Type-2 fuzzy system with a double-loop recurrent structure to improve the ability to deal with uncertain environments. To achieve an efficient system response, a self-organizing mechanism is proposed to adaptively adjust the number of layers in a DLRNN. This work integrates the proposed network into a conventional sliding mode control (SMC) system to theoretically and empirically prove its stability. The proposed system is applied to a three-joint robot manipulator, leading to a comparative study that considers several existing control approaches. The experimental results confirm the superiority of the proposed system and its effectiveness and robustness in response to various external system disturbances.

Study of the relationship between pressure and sensitivity of energetic materials based on first-principles calculation.

CONTEXT: In order to study the relationship between the sensitivity and pressure of energetic materials, six kinds of energetic materials were selected as the research object. The crystal structure, electronic, and phonon properties under hydrostatic pressure of 0 ~ 45 GPa were calculated by first principles. The calculation results show that the lattice parameters and band gap values of these six energetic materials decrease with the increase of pressure. The peak of the density of states decreases and moves to the low energy direction, and the electrons become more active. Meanwhile, the effect of pressure on the sensitivity of the energetic materials is analyzed based on the multi-phonon up-pumping theory. The number of doorway modes and integral of projected phonon density of states under high pressure is calculated. The results show that both of them increase with the increase of pressure. And the smaller the value of the band gap, the larger the number of doorway modes and integral of projected phonon density of states, and the more sensitive the energetic material is. METHODS: All calculations are performed using the Materials Studio software based on density functional theory. The Perdew-Burke-Ernzerhof (PBE) functional of the generalized gradient approximation (GGA) is used to calculate the exchange correlation function, and the Grimme dispersion correction method is used to deal with the weak intermolecular interaction. The structure of the compound was optimized by BFGS algorithm. The linear response is used to calculate the phonon properties of energetic materials. The plane wave cutoff energy was set to 830 eV. The K-point grids of TATB, FOX-7, TNX, RDX, TNT, and HMX were chosen as 2 × 2 × 2, 2 × 2 × 1, 2 × 1 × 1, 1 × 1 × 1, 1 × 2 × 1, and 2 × 1 × 2.

Synthesis of pyrazino[1,2-b]indazoles via cascade cyclization of indazole aldehydes with propargylic amines.

An efficient intermolecular annulation of indazole aldehydes with propargylic amines has been developed for the synthesis of pyrazinoindazoles under catalyst- and additive-free conditions. This straightforward methodology was found to feature a wide substrate scope, high atom economy and environmental advantages. The bioactivity results of these new pyrazino[1,2-b]indazoles showed that some of them exhibited significant antifungal activity.

Association between alcohol consumption and sleep traits: observational and mendelian randomization studies in the UK biobank.

Previous studies have shown that excessive alcohol consumption is associated with poor sleep. However, the health risks of light-to-moderate alcohol consumption in relation to sleep traits (e.g., insomnia, snoring, sleep duration and chronotype) remain undefined, and their causality is still unclear in the general population. To identify the association between alcohol consumption and multiple sleep traits using an observational and Mendelian randomization (MR) design. Observational analyses and one-sample MR (linear and nonlinear) were performed using clinical and individual-level genetic data from the UK Biobank (UKB). Two-sample MR was assessed using summary data from genome-wide association studies from the UKB and other external consortia. Phenotype analyses were externally validated using data from the National Health and Nutrition Examination Survey (2017-2018). Data analysis was conducted from January 2022 to October 2022. The association between alcohol consumption and six self-reported sleep traits (short sleep duration, long sleep duration, chronotype, snoring, waking up in the morning, and insomnia) were analysed. This study included 383,357 UKB participants (mean [SD] age, 57.0 [8.0] years; 46% male) who consumed a mean (SD) of 9.0 (10.0) standard drinks (one standard drink equivalent to 14 g of alcohol) per week. In the observational analyses, alcohol consumption was significantly associated with all sleep traits. Light-moderate-heavy alcohol consumption was linearly linked to snoring and the evening chronotype but nonlinearly associated with insomnia, sleep duration, and napping. In linear MR analyses, a 1-SD (14 g) increase in genetically predicted alcohol consumption was associated with a 1.14-fold (95% CI, 1.07-1.22) higher risk of snoring (P < 0.001), a 1.28-fold (95% CI, 1.20-1.37) higher risk of evening chronotype (P < 0.001) and a 1.24-fold (95% CI, 1.13-1.36) higher risk of difficulty waking up in the morning (P < 0.001). Nonlinear MR analyses did not reveal significant results after Bonferroni adjustment. The results of the two-sample MR analyses were consistent with those of the one-sample MR analyses, but with a slightly attenuated overall estimate. Our findings suggest that even low levels of alcohol consumption may affect sleep health, particularly by increasing the risk of snoring and evening chronotypes. The negative effects of alcohol consumption on sleep should be made clear to the public in order to promote public health.

A highly sensitive and selective fluorescent probe for rapid detection and intracellular imaging of Pd(II).

A novel near-infrared fluorescent probe (SWJT-13) for detecting Pd2+ ions was designed and synthesized using 3-bromopropargyne group as a recognition site. SWJT-13 can detect Pd2+ ions specifically, which can be quickly recognized by naked eye under natural light. SWJT-13 has a large Stokes shift (155 nm) with LOD of 10.5 nM. The mechanism was verified by 1H NMR, MS, and Gaussian calculations. In addition, the detection of Pd2+ ions by the probe was studied in HeLa cells.

Danggui-Shaoyao-San Promotes Amyloid-ß Clearance through Regulating Microglia Polarization via Trem2 in BV2 Cells.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder currently without satisfactory therapeutic treatments. Triggering receptors expressed on a myeloid cells-2 (Trem2) gene mutation has been reported as a powerful AD risk factor that induces Trem2 gene deletion aggravated microglia disfunction and Amyloid-ß (Aß) aggregation in the brain. The traditional Chinese medicine (TCM) formula Danggui-Shaoyao-San (DSS) has shown therapeutic effect on alleviating the symptoms of AD. However, the neuroprotective effect and underlying mechanism of DSS against AD is still far from fully understood. METHODS: Double-label immunofluorescence and Western blotting were employed to evaluate the different polarization states of mouse BV2 microglial (BV2) cells after lipopolysaccharide (LPS) or interleukin (IL)-4 treatment. Trem2 over-expression lentiviral vector and Trem2 siRNA were used respectively to evaluate the effect of Trem2 on microglia polarization via detecting the proteins expression of iNOS and arginase1 (Arg1) by Western blotting while the Aß-scavenging capacity of BV2 cells was assessed by flow cytometry. Cell counting kit-8 (CCK8) assay was performed to assess the effect of DSS on the viability of BV2 cells. Flow cytometry was used to investigate the effect of DSS on the Aß-scavenging capacity of BV2 cells treated with corresponding concentration of DSS-containing serum. Protein of Trem2 and the gene expression of the M1 or M2 phenotype in BV2 cells treated with DSS after Trem2 over-expression or silence were detected by Western blot and RT-qPCR, respectively. RESULTS: In vitro experiments. DSS exhibited anti-inflammatory and neuroprotective functions. It was found that Trem2 had an effect on inducing a shift of M1 microglia towards the M2 phenotype and enhanced the Aß-scavenging capacity of BV2 cells, further that DSS administration relieved inflammation by engulfing Aß through the activities of Trem2. Importantly, DSS treatment effectively increased the Aß-scavenging capacity of BV2 cells through accelerating the shift of M1 microglia towards an M2 phenotype via increasing Trem2 expression. CONCLUSIONS: Results demonstrated that DSS promoted the clearance of Aß through the regulation of microglia polarization via increased expression of Trem2 in BV2 cells.

Emerging effects of non-coding RNA in vascular endothelial cells during strokes.

Vascular and neurological damage are the typical outcomes of ischemic strokes. Vascular endothelial cells (VECs), a substantial component of the blood-brain barrier (BBB), are necessary for normal cerebrovascular physiology. During an ischemic stroke (IS), changes in the brain endothelium can lead to a BBB rupture, inflammation, and vasogenic brain edema, and VECs are essential for neurotrophic effects and angiogenesis. Non-coding RNAs (nc-RNAs) are endogenous molecules, and brain ischemia quickly changes the expression patterns of several non-coding RNA types, such as microRNA (miRNA/miR), long non-coding RNA (lncRNA), and circular RNA (circRNA). Furthermore, vascular endothelium-associated nc-RNAs are important mediators in the maintenance of healthy cerebrovascular function. In order to better understand how VECs are regulated epigenetically during an IS, in this review, we attempted to assemble the molecular functions of nc-RNAs that are linked with VECs during an IS.

Long-term in-situ starvation and reactivation of co-digestion with food waste and corn straw in a continuous AnDMBR: Performance, sludge characteristics, and microorganism community.

To explore the effects of in-situ starvation and reactivation in a continuous anaerobic dynamic membrane reactor (AnDMBR), the anaerobic co-digestion system of food waste and corn straw was firstly start-up and stability operated, and then stopped feeding substrate approximately 70 days. After long-term in-situ starvation, the continuous AnDMBR was reactivated using the same operation conditions and organic loading rate as the continuous AnDMBR used before in-situ starvation. Results shown that the anaerobic co-digestion of corn straw and food waste in the continuous AnDMBR can resume stable operation within 5 days, and the corresponding methane production of 1.38 ± 0.26 L/L/d was completely returned to the methane production before in-situ starvation (1.32 ± 0.10 L/L/d). Through analysis of the specific methanogenic activity and key enzyme activity of the digestate sludge, only the acetic acid degradation activity of methanogenic archaea can be partially recovered, however, the activities of lignocellulose enzyme (lignin peroxidase, laccase, and endoglucanase), hydrolase (α-glucosidase) and acidogenic enzyme (acetate kinas, butyrate kinase, and CoA-transferase) can be fully recovered. Analysis of microorganism community structure using metagenomic sequencing technology showed that starvation decreased the abundance of hydrolytic bacteria (Bacteroidetes and Firmicutes) and increased the abundance of small molecule-utilizing bacteria (Proteobacteria and Chloroflexi) due to lack of substrate during the long-term in-situ starvation stage. Furthermore, the microbial community structure and key functional microorganism still maintained and similar with that of starvation final stage even after long-term continuous reactivation. The reactor performance and sludge enzymes activity in the continuous AnDMBR co-digestion of food waste and corn straw can be well reactivated after long-term in-situ starvation, even though the microbial community structure can not be recovered to the initiating stage.

[Appropriate Use and Abuse of Sedative-Hypnotic Drugs].

The incidence of insomnia has been increasing in recent years. In addition, due to the impact of the COVID-19 pandemic, more and more people are experiencing a variety of insomniac problems, including having difficulty in sleep initation, waking up too early, and short sleep duration. Chronic insomnia may seriously affect patients' life and work, increase their risks of developing physical and mental illnesses, and cause crushing social and economic burdens. Sedative-hypnotics, including benzodiazepine agonists, melatonin receptor agonists, orexin receptor antagonists, and antidepressants with hypnotic effects, are widely used to treat most patients suffering from insomnia. However, there is the phenomenon of the non-medical use and abuse of sedative-hypnotic drugs, especially benzodiazepine receptor agonists. The abuse of sedative-hypnotic drugs may lead to mental and physical dependence, cognitive impairment, depression and anxiety, as well as an increased risks of falls and death. Therefore, drug regulatory authorities in China and other countries have issued relevant policies to reinforce regulation. Herein, we reviewed the prevalent use and safety of sedative-hypnotic drugs and proposed suggestions concerning their appropriate use. Both the efficacy and safety of sedative-hypnotic drugs should be carefully considered so that patients suffering from insomnia receive thorough and prompt treatment and the problem of potential abuse of sedative-hypnotic drugs is assessed in an objective and scientific manner. We also hope to provide references for the standardized clinical use of insomnia drugs.

Modified Bamboo Charcoal as a Bifunctional Material for Methylene Blue Removal.

Biomass-derived raw bamboo charcoal (BC), NaOH-impregnated bamboo charcoal (BC-I), and magnetic bamboo charcoal (BC-IM) were fabricated and used as bio-adsorbents and Fenton-like catalysts for methylene blue removal. Compared to the raw biochar, a simple NaOH impregnation process significantly optimized the crystal structure, pore size distribution, and surface functional groups and increase the specific surface area from 1.4 to 63.0 m2/g. Further magnetization of the BC-I sample not only enhanced the surface area to 84.7 m2/g, but also improved the recycling convenience due to the superparamagnetism. The maximum adsorption capacity of BC, BC-I, and BC-IM for methylene blue at 328 K was 135.13, 220.26 and 497.51 mg/g, respectively. The pseudo-first-order rate constants k at 308 K for BC, BC-I, and BC-IM catalytic degradation in the presence of H2O2 were 0.198, 0.351, and 1.542 h-1, respectively. A synergistic mechanism between adsorption and radical processes was proposed.

A Near-Infrared Fluorescent Probe for Recognition of Hypochlorite Anions Based on Dicyanoisophorone Skeleton.

A novel near-infrared (NIR) fluorescent probe (SWJT-9) was designed and synthesized for the detection of hypochlorite anion (ClO-) using a diaminomaleonitrile group as the recognition site. SWJT-9 had large Stokes shift (237 nm) and showed an excellent NIR fluorescence response to ClO- with the color change under the visible light. It showed a low detection limit (24.7 nM), high selectivity, and rapid detection (within 2 min) for ClO-. The new detection mechanism of SWJT-9 on ClO- was confirmed by 1H NMR, MS spectrum, and the density functional theory (DFT) calculations. In addition, the probe was successfully used to detect ClO- in HeLa cells.

Efficacy and tolerability of pharmacological treatments for insomnia in adults: A systematic review and network meta-analysis.

Insomnia is one of the most common and burdensome disorders in adults. We compared and ranked insomnia medication on the basis of their efficacy and tolerability. We performed a systematic review and network meta-analysis of placebo-controlled or head-to-head randomized controlled trials for primary insomnia in adults comparing 20 drugs. We searched eight databases and seven trial registers from inception to March 1st, 2022. Primary outcomes included sleep latency (SL), awake time after sleep onset (WASO) and discontinuation for adverse events (AED), and secondary outcomes included total sleep time (TST), sleep efficiency (SE), sleep quality (SQ) and adverse events (ADE). Pooled standardized mean differences or odds ratios with 95% credible intervals were estimated using pairwise and network meta-analysis with random-effects. Differences among trial findings were explored in subgroup and sensitivity analyses. Confidence in evidence was assessed using GRADE. The PROSPERO registered number is CRD42020182144. We identified 22,538 records and included 69 studies (17,319 patients). Orexin receptor antagonists (ORAs) are more efficacious than benzodiazepine-like drugs (Z-drugs) and placebo for WASO and SE, and better than melatonin receptor agonists (MRAs) for SL, WASO and SE. ORAs ranked the best in SL (SUCRA value: 0.84), WASO (0.93), TST (0.86) and SE (0.96). Lemborexant and daridorexant (two ORAs) showed greater efficacy than placebo for SL, WASO, and TST, with good tolerability. Z-drugs were more efficacious than placebo for SL, WASO, TST and SE, but with higher risk to safety. Zaleplon and eszopiclone had better efficacy than placebo for TST and SQ respectively. MRAs may also be efficacious for sleep-onset insomnia with good safety. However, the long-term adverse effects of all medications are unclear. Insomnia medications differ in their efficacy and tolerability. ORAs have superior efficacy and tolerability. These findings should aid clinicians in matching risk/benefits of drugs available in their countries to insomnia symptoms.

Efficacy and safety of epidural clonidine by continuous infusion or patient-controlled analgesia in labor: A meta-analysis of randomized controlled trials.

BACKGROUND: Epidural clonidine improves analgesia but may induce adverse effects in labor. OBJECTIVE: To evaluate the efficacy and safety of epidural clonidine as local anesthetics (LA) adjuvant by continuous infusion or patient-controlled epidural analgesia (PCEA) in labor. SEARCH STRATEGY: PubMed, Embase, Web of Science, and CENTRAL were searched from inception to May 10, 2022 without language restriction; references of the retrieved studies were hand searched. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing epidural LA with and without clonidine using continuous infusion or PCEA in labor were included. DATA COLLECTION AND ANALYSIS: A random effects model was used to pool the data on analgesia and adverse effects. MAIN RESULTS: Eight RCTs were included. Clonidine did not reduce the incidence of parturients requiring additional epidural boluses but reduced LA consumption and pain scores without increasing adverse effects, except for a higher incidence of instrumental delivery when clonidine was combined with LA and opioid (risk ratio 2.38, 95% confidence interval 1.26-4.50). Clonidine offered similar analgesia to opioids but had reduced opioid-related adverse effects. Trial sequential analysis showed that the evidence was insufficient. CONCLUSIONS: Epidural clonidine by continuous infusion or PCEA does not increase significant adverse effects and offers similar analgesia to opioids in labor. PROSPERO registration no. CRD42022306565.

Linking Nonalcoholic Fatty Liver Disease and Brain Disease: Focusing on Bile Acid Signaling.

A metabolic illness known as non-alcoholic fatty liver disease (NAFLD), affects more than one-quarter of the world's population. Bile acids (BAs), as detergents involved in lipid digestion, show an abnormal metabolism in patients with NAFLD. However, BAs can affect other organs as well, such as the brain, where it has a neuroprotective effect. According to a series of studies, brain disorders may be extrahepatic manifestations of NAFLD, such as depression, changes to the cerebrovascular system, and worsening cognitive ability. Consequently, we propose that NAFLD affects the development of brain disease, through the bile acid signaling pathway. Through direct or indirect channels, BAs can send messages to the brain. Some BAs may operate directly on the central Farnesoid X receptor (FXR) and the G protein bile acid-activated receptor 1 (GPBAR1) by overcoming the blood-brain barrier (BBB). Furthermore, glucagon-like peptide-1 (GLP-1) and the fibroblast growth factor (FGF) 19 are released from the intestine FXR and GPBAR1 receptors, upon activation, both of which send signals to the brain. Inflammatory, systemic metabolic disorders in the liver and brain are regulated by the bile acid-activated receptors FXR and GPBAR1, which are potential therapeutic targets. From a bile acid viewpoint, we examine the bile acid signaling changes in NAFLD and brain disease. We also recommend the development of dual GPBAR1/FXR ligands to reduce side effects and manage NAFLD and brain disease efficiently.

Kai-Xin-San Protects Depression Mice Against CORT-Induced Neuronal Injury by Inhibiting Microglia Activation and Oxidative Stress.

Objective: Traditional Chinese medicine formula Kai-Xin-San (KXS) is used to treat psychiatric disorders, especially in anxiety and depression. However, the precise molecular mechanism of action remains unclear. In this study, we investigated the antidepressant effect of KXS on inhibiting inflammation and oxidative stress in corticosterone (CORT)-induced depression. Methods: The therapeutic efficacy of KXS was evaluated in a mouse model of depression induced by CORT. Behavioral tests were conducted to evaluate the effectiveness of KXS in treating depressive-like behavior. Nissl staining and ß-galactosidase staining were used to assess the effects of KXS on neuronal injury in depressed mice. To screen key potential therapeutic targets of KXS, transcriptome sequences and data analysis were performed. Then, Iba1 immunofluorescence staining and their relative inflammatory factors mRNA expression were conducted to assess the effect of KXS in inhibiting microglial inflammation activation response. Concurrently, the measurement of 4-Hydroxynonenal (4-HNE) immunohistochemistry staining, malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) were performed to evaluate the effect of KXS on anti-oxidative stress of depression in vivo. Besides, nitric oxide (NO), relative inflammatory factors mRNA expression, JC-1 staining, and ROS were used to evaluate the effect of KXS by lipopolysaccharide (LPS)/interferon-gamma (IFNγ)-induced BV2 cells. Results: KXS significantly relieved the depressive-like symptoms induced by CORT, as well as ameliorating the neuronal damage, which decreased microglia inflammatory activation response of IL-1ß, IL-6, and tumor necrosis factor α (TNFα) in vivo or in vitro too. Transcriptome Sequencing and Data Analysis showed that KXS mainly by regulating immune system and transduction pathways decreased CORT-induced depression in mice. And showed that there were 19 Principal components and 10 genes in the main regulatory position with the strongest correlation in depression mice. Meanwhile, KXS effectively decreased senescence, the expression of 4-HNE, MDA content, and the production of ROS, while increasing the SOD activity in CORT-induced mice. Besides, KXS significantly reversed the mitochondrial membrane potential loss and excessive ROS production in LPS/IFNγ-induced BV2 cells. Conclusion: Our research suggested that KXS might protect depressed mice against CORT-induced neuronal injury by inhibiting microglia activation and oxidative stress.

Comparative study of the effect of loading increments on the mesophilic codigestion of waste activated sludge and food waste: Reactor performance, stability analysis, and microbial community.

The performance and stability of mesophilic codigestion of waste activated sludge (WAS) and food waste (FW) were compared in two parallel, continuously stirred tank reactors using high- and low-magnitude loading increments for the loading regimes. The results indicated that a high methane (CH4) production of 6.98 L L-1·d-1 was realized without volatile fatty acid accumulation via low-magnitude loading increments at a high loading of 26.5 g-COD·L-1·d-1, and this system was more stable and achieved a higher efficiency than the codigestion system that used high-magnitude loading increments at similar loading and operating conditions. Furthermore, higher CH4 yields of 258-334 mL-CH4·g-COD-1, TCOD removal efficiencies of 64-79%, conversion ratios of 62-88%, and methanogenic activities of 0.37-0.40 g-CH4-COD·g-VS-1·d-1 were consistently maintained via the low-magnitude loading increments during the high-rate period. High abundances of the phyla Firmicutes (63.3%) and genus Methanosarcina (94.5%) contributed to the high rates and stable operating conditions of the mesophilic system for WAS and FW codigestion using low-magnitude loading increments.