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Aims: The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ‐associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear. Methods: Mouse pups were injected with N‐methyl‐D‐aspartate receptor antagonist (MK‐801) or vehicle twice daily on postnatal days (PND) 7–11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity. Results: We found that the hippocampal theta oscillations were enhanced in MK‐801‐treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK‐801 treatment. Conclusions: These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ. [ABSTRACT FROM AUTHOR]

Selective acetylene hydrogenation is a strongly exothermic process, easy to cause coking and metal agglomeration, and thus leads to deactivation. In this work, Pd/TiO2 with different oxygen vacancies (Vo) were synthesized by controlling reduction temperature in 300–700°C, in which Pd/TiO2‐HT300 (HT is reduction temperature) possessed the highest Vo content. It was found highly dispersed Pd nanoparticles adjacent to more Vo exhibited enhanced catalytic behavior (near 100% conversion at 55°C with 80% selectivity and turnover frequency of 0.12 s−1) due to hydrogen spillover generation and electron donation originating from Vo sites, confirmed by in situ x‐ray photoelectron spectroscopy, in situ Raman, and H2‐temperature programmed desorption. More importantly, the increasing Vo sites trap the released heat and devote to a decrease of heat accumulation over a single active Pd site, and consequently inhibit Pd agglomeration and polymerization, affirmed by high‐resolution transmission electron microscopy, CO chemisorption, and thermogravimetric analysis. [ABSTRACT FROM AUTHOR]

Functional reprogramming of tumor‐associated macrophages (TAMs) is crucial to their potent tumor‐supportive capacity. However, the molecular mechanism behind the reprogramming process remains poorly understood. Here, we identify engulfment and cell motility protein 1 (ELMO1) as a crucial player for TAM reprogramming in colorectal cancer (CRC). The expression of ELMO1 in stromal but not epithelial tumor cells was positively associated with advanced clinical stage and poor disease‐free survival in CRC. An increase in ELMO1 expression was specifically found in TAMs, but not in other multiple nonmalignant stromal cells. Gain‐ and loss‐of‐function assays indicated ELMO1 reprogrammed macrophages to a TAM‐like phenotype through Rac1 activation. In turn, ELMO1‐reprogrammed macrophages were shown to not only facilitate the malignant behaviors of CRC cells but exhibited potent phagocytosis of tumor cells. Taken together, our work underscores the importance of ELMO1 in determining functional reprogramming of TAMs and could provide new insights on potential therapeutic strategies against CRC. [ABSTRACT FROM AUTHOR]

Anisakidae nematode larvae is one of the most common parasites in wild anadromous Coilia nasus. This study aims to explore the mechanism of the C. nasus immune response to the parasitism of Anisakid nematode larvae. Results found that Anisakid nematode larvae parasitism caused liver injury as evidenced by histomorphology results as well as high levels of aminotransferase and aspertate aminotransferase. Furthermore, Anisakid nematode larvae parasitism induced an immune response in the host, which was characterized by the elevated populations of macrophages and neutrophils in the liver and head‐kidney in the Anisakidae‐infected group compared to the noninfected group. The expression of immunoglobulin IgM and IgD in the liver and head‐kidney was also increased in the Anisakidae‐infected group. The Anisakidae‐infected group showed higher activity of antioxidant enzymes catalase and superoxide dismutase, which indicates severe oxidative stress, and increased production of pro‐inflammatory cytokines, TNF‐α, IL‐6 as well as MCP‐1 in the liver compared with the noninfected group. As a result of inflammation, livers of hosts in the Anisakidae‐infected group showed fibrosis, and elevated expression of associated proteins including α‐smooth muscle actin, fibronectin, collagen type I and type III compared with the noninfected group. We demonstrated that Anisakid nematode larvae parasitism results in injury and fibrosis in the liver, and triggers immune cell infiltration and inflammation in the liver and head‐kidney of C. nasus. Altogether, the results provide a foundation for building an interaction between parasite and host, and will contribute to C. nasus population and fishery resource protection. [ABSTRACT FROM AUTHOR]

The effect of Cu on the microstructure and corrosion behavior in 360°C lithiated water was investigated on Zr–xCu alloys (x = 0.05, 0.2, and 1.0, wt%), with remelted pure Zr as reference material. The results revealed that the tetragonal Zr2Cu phase was induced by Cu addition higher than 0.2 wt% and its size and number density were increased with the increase of Cu content. The weight gain and oxide thickness were decreased by Cu addition, but when the Cu content increased to 1.0 wt%, they were both significantly increased and even larger than that of remelted Zr. It was supposed that structural defects, such as pores and microcracks, in the oxide film may result in such degradation in the corrosion property of Zr–1.0Cu alloy. [ABSTRACT FROM AUTHOR]

It is of paramount importance to explore novel 2D materials with unique structural and physical properties that are promising for application in a specific field. Herein, eleven monolayers with novel square lattice are studied, including S‐SeN2, S‐TeN2, S‐SP2, S‐SeP2, S‐TeP2, S‐SAs2, S‐SeAs2, S‐TeAs2, S‐SSb2, S‐SeSb2, and S‐TeSb2, via first‐principles calculations. Through stability screening, only the S‐SeN2 monolayer, where each Se atom is tetracoordinated with four N atoms, and each N atom bridges two atoms, thus forming a tri‐sublayer structure with square lattice, is verified as a stable 2D crystal because it has high cohesive energy, all positive modes in the phonon spectrum, and structural integrity through the molecular dynamics simulation up to 500 K. It is an indirect‐bandgap semiconductor with high hole mobility, and the direct‐bandgap feature can be easily obtained under external uniaxial compressions or biaxial tensions, which can be applied in electronics, photoelectronics, etc. [ABSTRACT FROM AUTHOR]

Summary: The LRK10‐like receptor kinases (LRK10L‐RLKs) are ubiquitously present in higher plants, but knowledge of their expression and function is still limited. Here, we report expression and functional analysis of TtdLRK10L‐1, a typical LRK10L‐RLK in durum wheat (Triticum turgidum L. ssp. durum). The introns of TtdLRK10L‐1 contained multiple kinds of predicted cis‐elements. To investigate the potential effect of these cis‐elements on TtdLRK10L‐1 expression and function, two types of transgenic wheat lines were prepared, which expressed a GFP‐tagged TtdLRK10L‐1 protein (TtdLRK10L‐1:GFP) from the cDNA or genomic DNA (gDNA) sequence of TtdLRK10L‐1 under the native promoter. TtdLRK10L‐1:GFP expression was up‐regulated by the powdery mildew pathogen Blumeria graminis f. sp. tritici (Bgt) in both types of transgenic plants, with the scale of the elevation being much stronger in the gDNA lines. Both types of transgenic plants exhibited enhanced resistance to Bgt infection relative to wild type control. Notably, the Bgt defence activated in the gDNA lines was significantly stronger than that in the cDNA lines. Further analysis revealed that a putative MYB transcription factor binding site (MYB‐BS, CAGTTA) located in TtdLRK10L‐1 intron I was critical for the efficient expression and function of TtdLRK10L‐1 in Bgt defence. This MYB‐BS could also increase the activity of a superpromoter widely used in ectopic gene expression studies in plants. Together, our results deepen the understanding of the expression and functional characteristics of LRK10L‐RLKs. TtdLRK10L‐1 is likely useful for further dissecting the molecular processes underlying wheat defence against Bgt and for developing Bgt resistant wheat crops. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusions Auxiliary diagnosis of different types of cystic lung diseases (CLDs) is important in the clinic and is instrumental in facilitating early and specific treatments. Current clinical methods heavily depend on accumulated experience, restricting their applicability in regions with less developed medical resources. Thus, how to realize the computer‐aided diagnosis of CLDs is of great clinical value.This work proposed a deep learning‐based method for automatically segmenting the lung parenchyma in computed tomography (CT) slice images and accurately diagnosing the CLDs using CT scans.A two‐stage deep learning method was proposed for the automatic classification of normal cases and five different CLDs using CT scans. Lung parenchyma segmentation is the foundation of CT image analysis and auxiliary diagnosis. To meet the requirements of different sizes of the lung parenchyma, an adaptive region‐growing and improved U‐Net model was employed for mask acquisition and automatic segmentation. The former was achieved by a self‐designed adaptive seed point selection method based on similarity measurement, and the latter introduced multiscale input and multichannel output into the original U‐Net model and effectively achieved the lightweight design by adjusting the structure and parameters. After that, the middle 30 consecutive CT slice images of each sample were segmented to obtain lung parenchyma, which was employed for training and testing the proposed multichannel parallel input recursive MLP‐Mixer network (MPIRMNet) model, achieving the computer‐aided diagnosis of CLDs.A total of 4718 and 16 290 CT slice images collected from 543 patients were employed to validate the proposed segmentation and classification methods, respectively. Experimental results showed that the improved U‐Net model can accurately segment the lung parenchyma in CT slice images, with the Dice, precision, volumetric overlap error, and relative volume difference of 0.96 ± 0.01, 0.93 ± 0.04, 0.05 ± 0.02, and 0.05 ± 0.03, respectively. Meanwhile, the proposed MPIRMNet model achieved appreciable classification effect for normal cases and different CLDs, with the accuracy, sensitivity, specificity, and F1 score of 0.8823 ± 0.0324, 0.8897 ± 0.0325, 0.9746 ± 0.0078, and 0.8831 ± 0.0334, respectively. Compared with classical machine learning and convolutional neural networks‐based methods for this task, the proposed classification method had a preferable performance, with a significant improvement of accuracy of 10.74%.The work introduced a two‐stage deep learning method, which can achieve the segmentation of lung parenchyma and the classification of CLDs. Compared to previous diagnostic tasks targeting single CLD, this work can achieve various CLDs’ diagnosis in the early stage, thereby achieving targeted treatment and increasing the potential and value of clinical applications. [ABSTRACT FROM AUTHOR]

Currently, the clinical treatment of bone cancer pain (BCP) is mainly related to its pathogenesis. The aim of the present study was to elucidate the potential role of N6‐methyladenosine (m6A) in BCP in the spinal cord dorsal root ganglia (DRG) of BCP rats and its specific regulatory mechanism in N‐methyl‐d‐aspartate receptor subunit 2B (NR2B). A rat model of BCP was constructed by tibial injection of Walker256 cells, and ALKBH5 and NR2B expression in the spinal cord DRG was detected. ALKBH5 was silenced or overexpressed in PC12 cells to verify the regulatory effect of ALKBH5 on NR2B. The specific mechanism underlying the interaction between ALKBH5 and NR2B was investigated using methylated RNA immunoprecipitation and dual‐luciferase reporter gene assays. The results showed increased expression of m6A, decreased expression of ALKBH5, and increased expression of NR2B in the DRG of the BCP rat model. Overexpression of ALKBH5 inhibited NR2B expression, whereas interference with ALKBH5 caused an increase in NR2B expression. In NR2B, interference with ALKBH5 caused an increase in m6A modification, which caused an increase in NR2B. Taken together, ALKBH5 affected the expression of NR2B by influencing the stability of the m6A modification site of central NR2B, revealing that ALKBH5 is a therapeutic target for BCP. [ABSTRACT FROM AUTHOR]

Plant height (PH) plays a very important role for plant breeding and also serves as a model trait to dynamic development study. The dynamic quantitative trait locus (QTL) analysis for PH of Agropyron Gaertn. was carried out in a cross‐pollination (CP) hybrid population of A. Gaertn. based on the phenotypic data of PH at different developmental stages in four year‐sites and the constructed single‐nucleotide polymorphism (SNP) genetic map. The results showed that 69 QTL and nine major QTL were detected by unconditional QTL mapping. A total of 107 QTL and 13 major QTL were found using conditional QTL mapping. Forty‐seven QTL were detected by two methods. Two unconditional QTL, Qph2‐5 and Qph3‐4, were expressed as major and stable QTL for PH. Four major stable conditional QTL for PH, cQph4‐1, cQph4‐8, cQph6‐2 and cQph6‐7, were detected. Two conditional PH QTL, cQph3‐5 and cQPh3‐7, were identified in four environments over multiple stages. The gene/QTL controlling PH was expressed in a certain spatiotemporal manner. These results could also provide a reference for genetic and breeding research of related plant. [ABSTRACT FROM AUTHOR]

Constructing 2D gold nanorods monolayer films with precise particle assembly is of great importance to fundamental and real applications. However, it is usually difficult to achieve macroscopic size, freestanding feature, high density of particle packing, and precisely controllable particle orientation in monolayer films. In this work, a macroscopic, uniform, freestanding orientational monolayer film is facilely and controllably prepared through precise assembly of asymmetrically modified gold nanorods at water–oil interface. The assembling morphologies can be controlled through regulating the interaction between gold nanorods by varying the amounts and sites of modified molecules. The intriguing tunable assemblies exhibit not only adjustable absorption spectrum in a wide range attributed to different particle coupling, but also optimized photothermal conversion capability under low energy density (0.08 W cm‐2). Together with a commercial thermochromic dye, the patterned assemblies show excellent photothermal anti‐counterfeiting performance by reproducing accurate full images in 20 s that are invisible after laser off in 10 min. The excellent laser writing performance is also demonstrated by writing any information on thermochromic dye‐coated assemblies. With the advantages of being macroscopic, equipment‐free, transferable, scalable and with high photothermal conversion capability, the orientational monolayer films pave the way for on‐demand design of sensing and device applications. [ABSTRACT FROM AUTHOR]

In this study, we investigated the activity levels of two major digestive enzymes (pepsin and lipase) in the commercially important Japanese grenadier anchovy Coilia nasus during its upstream migration to analyse the digestive physiological responses to starvation and to analyse the influence of the water temperature on enzyme activity. Water temperature had a significant effect on pepsin activity, while long‐term starvation resulted in a significant decrease in pepsin activity. As starvation continued, however, a slight increase in pepsin activity between the Wuhu (440 river km) and Anqing (620 river km) regions may indicate that C. nasus had refeeding behaviour due to its large expenditure of energy reserves. In contrast, lipase activity was not significantly affected by the water temperature but the effect of fasting increased as much as 13% of lipase activity from the Chongming region (20 river km) to Anqing region, suggesting that the stored lipids of grenadier anchovy were mobilised to meet energy requirements of upstream migration activity and gonad development. Lipid mobilisation activated lipoprotein lipase (LPL; proteins with lipase activity) to hydrolyse triacylglycerides (TAG), which is the first step of lipid assimilation and obtained energy from fatty acids under fasting conditions. Therefore, the increased lipase activity is attributed mainly to the lipase that is involved in endogenous lipid hydrolysis. Grenadier anchovy appears to adapt to long‐term starvation during migration and the increased lipase activity may indicate a crucial effect on lipid metabolism. This study demonstrated that distinct alterations occur in pepsin and lipase activities during the spawning migration of grenadier anchovy due to exogenous nutrition and endogenous metabolism. Furthermore, it provides a basis for further research on the digestive physiology and energy metabolism in this species. [ABSTRACT FROM AUTHOR]

Abstract: 1q21 gain is a common cytogenetic abnormality featuring high‐risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF‐1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF‐1β protein level. Hypoxia induced HIF‐1β expression via a NF‐κB‐dependent process. Notably, HIF‐1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia‐mediated drug resistance. Together, these findings suggest that ARNT/HIF‐1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain‐ or microenvironment‐mediated and acquired drug resistance in MM. [ABSTRACT FROM AUTHOR]

ABSTRACT A synthesized rosin-based polymeric monomer, N-dehydroabietic acrylamide (DHA-AM), was introduced into an acrylated epoxidized soybean oil (AESO)/DHA-AM system to afford a thermosetting resin through thermocuring. Different molar ratios of the thermosetting AESO/DHA-AM samples were obtained through curing in the presence of an initiator, and the curing processes of the AESO/DHA-AM systems were evaluated by differential scanning calorimetry. The structures and performances of the resulting thermosets were characterized by Fourier transform infrared spectroscopy, dynamic mechanical analysis, elemental analysis, thermogravimetric analysis, and contact angle (θ) analysis. The analyses showed that with increasing content of DHA-AM introduced into the copolymer, the storage modulus, glass-transition temperature, thermal stability, and θ values of the cured samples all increased. Moreover, the copolymers changed from hydrophilic materials to hydrophobic materials. The results also demonstrate that the rosin acid derivatives showed comparable properties to those of reported petroleum-based rigid compounds for the preparation of soybean-oil-based thermosets. The presence of DHA-AM moieties in the composite structures could expand the use of AESO into the development of heat-resistant and hydrophobic materials. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 44545. [ABSTRACT FROM AUTHOR]

ABSTRACT Paraquat is a nitrogen herbicide imposing severe organ toxicity in human leading to acute lung injury and heart failure. The present study was designed to examine the impact of ablation of the innate proinflammatory mediator toll-like receptor 4 (TLR4) in paraquat-induced cardiac contractile dysfunction and the underlying mechanisms involved with a focus on endoplasmic reticulum (ER) stress and apoptosis. Adult male wild-type (WT) and TLR4 knockout (TLR4−/−) mice were challenged with paraquat (45 mg/kg, i.p.) for 48 h prior to the assessment of myocardial and cardiomyocyte sarcomere function, ER stress, apoptosis and inflammation. Acute paraquat challenge exerted myocardial functional and geometric alterations including enlarged left ventricular end systolic diameter (LVESD), reduced fractional shortening, decreased sarcomere shortening, maximal velocities of sarcomere shortening and relengthening associated with unchanged LV posterior wall thickness, septal thickness, LV end diastolic diameter (LVEDD), heart rate, sarcomere length, time-to-peak shortening and time-to-90% relengthening. Although TLR4 ablation did not affect mechanical properties in the heart, it significantly attenuated or ablated paraquat-induced cardiac contractile anomalies. Moreover, paraquat imposed overt ER stress, apoptosis and inflammation as evidenced by upregulation of Bip, CHOP, Caspase-3, −9, Bax, Bad, and IL-1β, phosphorylation of PERK, eIF2α and IΚB, as well as activation of the stress molecules ERK and p38, with unchanged Caspase-8, Bcl2, TNF-α, p53, HMGB1, MyD88 and phosphorylation of Akt, GSK3β and JNK, the effects of which were attenuated or negated by TLR4 knockout. Taken together, our results suggested that TLR4 ablation alleviated paraquat-induced myocardial contractile dysfunction possibly through attenuation of ER stress, apoptosis and inflammation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 656-668, 2017. [ABSTRACT FROM AUTHOR]

Iodo-1,2,3-triazoles are of considerable interest for chemical and biomedical applications. However, current synthetic methods for preparing iodo-1,2,3-triazoles cannot easily be applied to the direct modification of bioactive molecules in water. Through the combination of water-compatible oxidative iodination and the copper-catalyzed alkyne-azide cycloaddition reaction, a novel copper-catalyzed aqueous multicomponent synthetic method for the preparation of 5-iodo-1,2,3-triazoles has been developed. The method is highly effective and selective for substrates including biologically relevant compounds with nucleoside, sugar, and amino acid moieties. Based on this aqueous tandem reaction, a direct single-step multicomponent dual modification of peptide is developed from readily available starting materials. Furthermore, the method could also be applied to concise and fast multicomponent radioactive 125I labeling from an aqueous solution of commercially available sodium 125iodide as a starting material. [ABSTRACT FROM AUTHOR]

A novel amphipathic trimethylolpropane-dehydroabietic acid ester was successfully prepared with acyl chloride method. Various analytical techniques such as liquid chromatography-mass spectrometry, Fourier transform infrared spectrometry, proton and carbon nuclear magnetic resonance spectroscopy were employed to evaluate the chemical structure of the ester. The surface properties of the ester were investigated by surface tension and resonance light-scattering techniques. The surfactant molecules are adsorbed at the water-air interface in different adsorption states, i.e., state 1 and 2. The dynamic adsorption behavior was studied by combining experimental results and a reorientation model. The molar fraction of solvent decreased, while the molar fraction of surfactant molecules increased with increasing ester concentration at the surface layer. The adsorption value of state 1 presented a unimodal shape and the adsorption value of state 2 presented an s-shape with the increase in surface pressure. The free energy of adsorption is −36.06 kJ mol, more negative than the free energy of micellization (−29.69 kJ mol), it is actually easier for surfactant molecules to adsorb on the air-water interface. [ABSTRACT FROM AUTHOR]

With the rapid development of industrialization and urbanization, water pollution and water shortage are increasingly serious problems. Detecting potential contaminants and further extracting purified water from polluted water is considered to be an effective way for sewage management and recycling. Herein, an all‐in‐one solar‐driven evaporator is developed by alternatively depositing carbon nanotube (CNT) films and gold nanoparticle films on flexible cotton fabric surfaces for both solar‐driven pollution detection and water collection. Based on the facile and robust interfacial self‐assembly strategy, a large‐area CNT film at the air/water interface and closely packed Au nanoparticle (AuNP) film assembled at the liquid/liquid interface are readily achieved, which can be further alternatively transferred onto the cotton fabric surface for solar‐to‐thermal conversion applications. Owing to the favorable flexibility and foldability of the cotton fabric, the CNT film–modified cotton enables the configurable transition from a 2D flat structure to adjusted 3D wave‐like structures for enhanced solar steam generation. Furthermore, when the AuNP film is further deposited onto the surface of the CNT film for polluted water evaporation, the resultant CNT‐loaded Au hybrid can realize effective pollutant detection through surface‐enhanced Raman scattering (SERS) signals. [ABSTRACT FROM AUTHOR]

Review: 122 refs. [ABSTRACT FROM AUTHOR]

LINS1 is the human homolog of the Drosophila segment polarity gene that encodes an essential regulator of the wingless/Wnt signaling. By 2011, only seven pedigrees (16 patients) with eight causative variants in LINS1 gene have been reported. These cases mainly presented with infancy-/child-onset neurodevelopmental disorders, facial dysmorphia, and other clinical features, and a wide spectrum of clinically distinct phenotypes were also manifested. In our study, two brothers in a family were admitted and diagnosed with child-onset movement disorders, slight intellectual disability, psychological symptoms, eye problems, urinary and bowel dysfunction, mitral value prolapse, and Q-T prolongation. By exome sequencing, we identified a nonsense homozygous pathogenic variant (LINS1: c.274C > T (p.Q92X)), which had been reported in a case diagnosed with intellectual disability and psychiatric disorders (such as schizophrenia and anxiety). Compared with this case, the clinical features of our cases were distinct. In particular, our cases displayed unusual features of heart and blood system. Furthermore, the genotype-phenotype relationship analysis suggested that distinct phenotypes presented in cases carrying variants in different domains of the LINS1 gene. In conclusions, our findings suggest the high clinical variations in the LINS1 variants-related disorders. Moreover, the Q92X might be a recurrent variant in Hans of Southern China., (© 2024 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)