Gut microbiota-derived short chain fatty acids act as mediators of the gut-brain axis targeting age-related neurodegenerative disorders: a narrative review.

Neurodegenerative diseases associated with aging are often accompanied by cognitive decline and gut microbiota disorder. But the impact of gut microbiota on these cognitive disturbances remains incompletely understood. Short chain fatty acids (SCFAs) are major metabolites produced by gut microbiota during the digestion of dietary fiber, serving as an energy source for gut epithelial cells and/or circulating to other organs, such as the liver and brain, through the bloodstream. SCFAs have been shown to cross the blood-brain barrier and played crucial roles in brain metabolism, with potential implications in mediating Alzheimer's disease (AD) and Parkinson's disease (PD). However, the underlying mechanisms that SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, the dietary sources which determine these SCFAs production was not thoroughly evaluated yet. This comprehensive review explores the production of SCFAs by gut microbiota, their transportation through the gut-brain axis, and the potential mechanisms by which they influence age-related neurodegenerative disorders. Also, the review discusses the importance of dietary fiber sources and the challenges associated with harnessing dietary-derived SCFAs as promoters of neurological health in elderly individuals. Overall, this study suggests that gut microbiota-derived SCFAs and/or dietary fibers hold promise as potential targets and strategies for addressing age-related neurodegenerative disorders.

The relationship between screen time and attention deficit/hyperactivity disorder in Chinese preschool children under the multichild policy: a cross-sectional survey.

BACKGROUND: Long screen time has become a public health problem that cannot be ignored. The association between screen time and attention-deficit/hyperactivity disorder (ADHD) in preschool children has received widespread attention. METHODS: A questionnaire was used to survey 2452 people. ADHD symptoms were assessed by the Conners Child Behavior Scale. Considering that the ADHD symptoms of boys and girls might be different, we stratified the data by gender. Logistic regression model was used for regression analysis. To exclude the influence of multichild family and obesity level, we also conducted a sensitivity analysis. P values were two-tailed with a significance level at 0.05. RESULTS: The results showed that the association between screen time and ADHD symptoms in preschool children was significant (OR = 1.826, 95%CI: 1.032, 3.232). After grouping the genders, the correlation was not significant. There was an association between screen time and ADHD symptoms in children from families with multiple children. However, after excluding overweight and obese children from the overall population, the association between screen time and ADHD symptoms did not have statistical significance. CONCLUSIONS: The issue of screen time for preschoolers needs to be taken seriously. Although the results indicate a significant correlation between screen time and ADHD symptoms, clearer evidence is needed to provide recommendations to policy makers.

Brassinosteroids Regulate the Water Deficit and Latex Yield of Rubber Trees.

Brassinolide (BR) is an important plant hormone that regulates the growth and development of plants and the formation of yield. The yield and quality of latex from Hevea brasiliensis are regulated by phytohormones. The understanding of gene network regulation mechanism of latex formation in rubber trees is still very limited. In this research, the rubber tree variety CATAS73397 was selected to analyze the relationship between BR, water deficit resistance, and latex yield. The results showed that BR improves the vitality of rubber trees under water deficit by increasing the rate of photosynthesis, reducing the seepage of osmotic regulatory substances, increasing the synthesis of energy substances, and improving the antioxidant system. Furthermore, BR increased the yield and quality of latex by reducing the plugging index and elevating the lutoid bursting index without decreasing mercaptan, sucrose, and inorganic phosphorus. This was confirmed by an increased expression of genes related to latex flow. RNA-seq analysis further indicated that DEG encoded proteins were enriched in the MAPK signaling pathway, plant hormone signal transduction and sucrose metabolism. Phytohormone content displayed significant differences, in that trans-Zeatin, ethylene, salicylic acid, kinetin, and cytokinin were induced by BR, whereas auxin, abscisic acid, and gibberellin were not. In summary, the current research lays a foundation for comprehending the molecular mechanism of latex formation in rubber trees and explores the potential candidate genes involved in natural rubber biosynthesis to provide useful information for further research in relevant areas.

Separate neural subsystems support goal-directed speech listening.

How do humans excel at tracking the narrative of a particular speaker with a distracting noisy background? This feat places great demands on the collaboration between speech processing and goal-related regulatory functions. Here, we propose that separate subsystems with different cross-task dynamic activity properties and distinct functional purposes support goal-directed speech listening. We adopted a naturalistic dichotic speech listening paradigm in which listeners were instructed to attend to only one narrative from two competing inputs. Using functional magnetic resonance imaging with inter- and intra-subject correlation techniques, we discovered a dissociation in response consistency in temporal, parietal and frontal brain areas as the task demand varied. Specifically, some areas in the bilateral temporal cortex (SomMotB_Aud and TempPar) and lateral prefrontal cortex (DefaultB_PFCl and ContA_PFCl) always showed consistent activation across subjects and across scan runs, regardless of the task demand. In contrast, some areas in the parietal cortex (DefaultA_pCunPCC and ContC_pCun) responded reliably only when the task goal remained the same. These results suggested two dissociated functional neural networks that were independently validated by performing a data-driven clustering analysis of voxelwise functional connectivity patterns. A subsequent meta-analysis revealed distinct functional profiles for these two brain correlation maps. The different-task correlation map was strongly associated with language-related processes (e.g., listening, speech and sentences), whereas the same-task versus different-task correlation map was linked to self-referencing functions (e.g., default mode, theory of mind and autobiographical topics). Altogether, the three-pronged findings revealed two anatomically and functionally dissociated subsystems supporting goal-directed speech listening.

Association between maternal vitamin D status with pregnancy outcomes and offspring growth in a population of Wuxi, China.

BACKGROUND AND OBJECTIVES: The role of maternal vitamin D in infantile growth remains unclear. METHODS AND STUDY DESIGN: Serum 25-hydroxyvitamin D [25(OH)D] concentrations were examined for pregnancies who visited the Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University from January 2016 to December 2017. Anthropometric measurements of corresponding offspring were performed from birth to 2 to 3 years old. Infantile body mass index (BMI) was transformed into age-, sex- and height- normalized z scores, and Latent Class Growth Mixture (LCGM) model was used to identify trajectories of BMI-Z. RESULTS: Among the 329 included pregnancy women, 109 (33.13 %), 190 (57.75%) and 30 (9.12%) were defined as vitamin D deficiency [25(OH)D <30 nmol/L], insufficiency [30 nmol/L≤25(OH)D<50 nmol/L] and sufficiency [25(OH)D ≥50 nmol/L], respectively. When compared with vitamin D sufficiency, maternal vitamin D deficiency was not associated with preterm birth [odds ratio (OR)=2.69, 95% confidence interval (95% CI)=0.57-12.80], small for gestation age (OR=0.99, 95% CI=0.29-3.46), and low birth weight (OR=1.69, 95% CI=0.34-8.51). Similarly, no significant relationships were found between maternal vitamin D concentrations and anthropometric indices (such as weight, length, BMI) during 0 to 3 years old. Furthermore, LCGM model identified two patterns of offspring growth: stable moderate BMI-Z and early transient BMI-Z groups. Maternal vitamin D levels were higher in the former group than the latter (p=0.037); however, maternal vitamin D status appeared to be unrelated with offspring BMI-Z trajectories in multivariable logistic regression models. CONCLUSIONS: Maternal vitamin D deficiency may not be related to adverse pregnancy outcomes as well as offspring growth.

[Analysis of FGD1 gene variant in a child with Aarskog-Scott syndrome].

OBJECTIVE: To detect pathogenic variant of the FGD1 gene in a boy with Aarskog-Scott syndrome. METHODS: Genetic variant was detected by high-throughput sequencing. Suspected variant was verified by Sanger sequencing. The nature and impact of the candidate variant were predicted by bioinformatic analysis. RESULTS: The child was found to harbor a novel c.1906C>T hemizygous variant of the FGD1 gene, which has led to conversion of Arginine to Tryptophane at codon 636(p.Arg636Trp). The same variant was found in his mother but not father. Based on the American College of Medical Genetics and Genomics guidelines, the c.1906C>T variant of FGD1 gene was predicted to be likely pathogenic(PM1+PM2+PM5+PP2+PP3+PP4). CONCLUSION: The novel c.1906C>T variant of the FGD1 gene may underlay the Aarskog-Scott syndrome in this child. Above finding has enabled diagnosis for the boy.

Forensic Identification of Diving Deaths. / 潜水死亡的法医学鉴定.

Investigation of the cause of death during diving is one of the contents of forensic pathology. In this article, relevant foreign literature is reviewed to summarize the techniques and methods used in the identification of diving deaths, such as accident reconstruction, diving monitoring data, postmortem CT examination and gas analysis (location and quantity) in the body of the corpse, in order to provide a reference for forensic identification of such cases.

Fabrication of (4, 10) and (4, 12)-Connected Multifunctional Zirconium Metal-Organic Frameworks for the Targeted Adsorption of a Guest Molecule.

Following the principle of a topology guide, a zirconium MOF (PCN-207) based on the H4TPTA ligand (tetramethyl(4,4',4″,4‴-(pyrazine-2,3,5,6-tetrayl))tetrabenzoic acid) with C2 symmetry and an 8-connected Zr6(µ3-OH)8(OH)8]8+ cluster with D4h symmetry has been synthesized. PCN-206 can also be obtained by modulating the benzoic acid usage to change the flexibility of the H4TPTA ligand. The unique positions of 8-connected Zr6 clusters in the flu and scu networks and the flexibility of the tetratopic primary linker enable the precise insertion of fumarate (FA), 1,4-benzenedicarboxylic acid (H2BDC), and even 2,6-naphthalenedicarboxylic acid (H2NDC) in a one-pot reaction. Auxiliary linkers are used to generate new MOF structures or topologies or to split the pore spaces, which may significantly change the porosity and chemical and physical properties of scaffold MOFs. The results provide a successful strategy for the rational design of multicomponent Zr-MOFs. Because of differences in composition and configuration between structures, PCN-207 shows the highest separation capability of light hydrocarbons; moreover, PCN-206 exhibits the highest adsorption capacity of 2,4-D and DCF among MOFs at present.

Amphipathic Pentiptycene-Based Water-Resistant Cu-MOF for Efficient Oil/Water Separation.

Creating novel and practical materials to separate oil/water mixtures with high efficacy is in urgent demand. Herein, we demonstrate an amphipathic pentiptycene-based copper metal-organic framework (Cu-MOF; UPC-29) to satisfy this purpose. UPC-29 exhibits a efficient separation performance for mixtures of naphtha/water, gasoline/water, and diesel/water. Furthermore, materials under loose-packed and tight-pressed forms exhibit opposite hydrophilic-hydrophobic phenomena. This unique feature of UPC-29 provides a new avenue for the application of MOF materials.

Molecular Pivot-Hinge Installation to Evolve Topology in Rare-Earth Metal-Organic Frameworks.

Linker desymmetrization has been witnessed as a powerful design strategy for the discovery of highly connected metal-organic frameworks (MOFs) with unprecedented topologies. Herein, we introduce molecular pivot-hinge installation as a linker desymmetrization strategy to evolve the topology of highly connected rare-earth (RE) MOFs, where a pivot group is placed in the center of a linker similar to a hinge. By tuning the composition of pivot groups and steric hindrances of the substituents on various linker rotamers, MOFs with various topologies can be obtained. The combination of L-SO2 with C2v symmetry and 12-connected RE9 clusters leads to the formation of a fascinating (4,12)-c dfs new topology. Interestingly, when replacing L-SO2 with a tetrahedra linker L-O, the stacking behaviors of RE-organic layers switch from an eclipsed mode to a staggered stacking mode, leading to the discovery of an intriguing hjz topology. Additionally, the combination of the RE cluster and a linker [(L-(CH3 )6 )] with more bulky groups gives rise to a flu topology with a new 8-c inorganic cluster. The diversity of these RE-MOFs was further enhanced through post-synthetic installation of linkers with various functional groups. Functionalization of each linker with acidic and basic units in the mesoporous RE-based PCN-905-SO2 allows for efficient cascade catalytic transformation within the functionalized channels.

Regulatory T cells as a new therapeutic target for atherosclerosis.

Atherosclerosis is an autoimmune disease caused by self- and non-self-antigens contributing to excessive activation of T and B cell immune responses. These responses further aggravate vascular infiammation and promote progression of atherosclerosis and vulnerability to plaques via releasing pro-infiammatory cytokines. Regulatory T cells (Tregs) as the major immunoregulatory cells, in particular, induce and maintain immune homeostasis and tolerance by suppressing the immune responses of various cells such as T and B cells, natural killer (NK) cells, monocytes, and dendritic cells (DCs), as well as by secreting inhibitory cytokines interleukin (IL)-10, IL-35 and transcription growth factor ß (TGF-ß) in both physiological and pathological states. Numerous evidence demonstrates that reduced numbers and dysfunction of Treg may be involveved in atherosclerosis pathogenesis. Increasing or restoring the numbers and improving the immunosuppressive capacity of Tregs may serve as a fundamental immunotherapy to treat atherosclerotic cardiovascular diseases. In this article, we briefiy present current knowledge of Treg subsets, summarize the relationship between Tregs and atherosclerosis development, and discuss the possibilities of regulating Tregs for prevention of atherosclerosis pathogenesis and enhancement of plaque stability. Although the exact molecular mechanisms of Treg-mediated protection against atherosclerosis remain to be elucidated, the strategies for targeting the regulation of Tregs may provide specific and significant approaches for the prevention and treatment of atherosclerotic cardiovascular diseases.

Pore-Environment Engineering with Multiple Metal Sites in Rare-Earth Porphyrinic Metal-Organic Frameworks.

Multi-component metal-organic frameworks (MOFs) with precisely controlled pore environments are highly desired owing to their potential applications in gas adsorption, separation, cooperative catalysis, and biomimetics. A series of multi-component MOFs, namely PCN-900(RE), were constructed from a combination of tetratopic porphyrinic linkers, linear linkers, and rare-earth hexanuclear clusters (RE6 ) under the guidance of thermodynamics. These MOFs exhibit high surface areas (up to 2523 cm2 g-1 ) and unlimited tunability by modification of metal nodes and/or linker components. Post-synthetic exchange of linear linkers and metalation of two organic linkers were realized, allowing the incorporation of a wide range of functional moieties. Two different metal sites were sequentially placed on the linear linker and the tetratopic porphyrinic linker, respectively, giving rise to an ideal platform for heterogeneous catalysis.

[Association between overweight/obesity in parents and autism spectrum disorders in offspring].

OBJECTIVE: To study the association between overweight/obesity in parents before maternal pregnancy and the development of autism spectrum disorders (ASD) in offspring. METHODS: A total of 36 children who were diagnosed with ASD (ASD group) and 72 normal children matched for sex and age (control group) were enrolled. A questionnaire survey was performed to collect the general information, including body height and body weight of parents before maternal pregnancy and maternal weight gain during pregnancy. Univariate and multivariate logistic regression analyses were used to investigate the association between overweight/obesity in parents before maternal pregnancy and ASD in offspring. RESULTS: The ASD group had a significantly higher detection rate of overweight/obesity in the father than the control group (56% vs 32%; P=0.018) before maternal pregnancy. The univariate and multivariate logistic regression analyses showed that overweight/obesity of the father before maternal pregnancy was a risk factor for ASD in offspring (OR=2.66 and 2.58 respectively; P<0.05). CONCLUSIONS: Overweight/obesity of the father before maternal pregnancy is an independent risk factor for ASD in offspring, and therefore, it is important for the father to control his body mass index within the normal range before maternal pregnancy.

The impact of long-term school-based physical activity interventions on body mass index of primary school children - a meta-analysis of randomized controlled trials.

BACKGROUND: Physical activity (PA) intervention is a commonly recommended strategy to combat childhood obesity. However, its effectiveness has long been controversial. This paper aims to examine the effectiveness of long-term (≥12 months) school-based PA interventions on body mass index (BMI) in primary school children, who are gaining BMI. METHODS: Original papers were retrieved from PubMed, Google Scholar, the Cochrane Library and Web of Science, published between 1990 and 2015. The inclusion criteria were those research studies that were: randomized controlled trials (RCTs), conducted in primary school settings, had valid data on BMI at baseline and at the final follow up (or on BMI changes), and involved PA intervention that lasted for at least 12 months. RESULTS: Out of 11,158 potentially eligible articles, 18 papers were included in the analysis, involving 22,381 primary school children with intervention durations ranging from 12 to 72 months. Compared to the control groups, the BMI increment was 2.23 kg/m(2) less in the intervention groups (p < 0.05). The heterogeneity was high across the studies (99.8 %), but declined after sub-group analyses. The intervention type, intervention duration, and weekly PA intervention time were among the factors leading to the heterogeneity. CONCLUSION: Long-term school-based interventions containing PA as a core component appear to be effective in achieving healthier BMI. However, the results should be interpreted with caution due to the high heterogeneity among the studies. More high quality school-based RCTs among diverse populations are needed to improve the homogeneity and to yield a more robust conclusion.

Screening of Diatom Strains and Characterization of Cyclotella cryptica as A Potential Fucoxanthin Producer.

Fucoxanthin has been receiving ever-increasing interest due to its broad health beneficial effects. Currently, seaweeds are the predominant source of natural fucoxanthin. However, the disappointingly low fucoxanthin content has impeded their use, driving the exploration of alternative fucoxanthin producers. In the present study, thirteen diatom strains were evaluated with respect to growth and fucoxanthin production potential. Cyclotella cryptica (CCMP 333), which grew well for fucoxanthin production under both photoautotrophic and heterotrophic growth conditions, was selected for further investigation. The supply of nitrate and light individually or in combination were all found to promote growth and fucoxanthin accumulation. When transferring heterotrophic cultures to light, fucoxanthin responded differentially to light intensities and was impaired by higher light intensity with a concomitant increase in diadinoxanthin and diatoxanthin, indicative of the modulation of Diadinoxanthin Cycle to cope with the light stress. Taken together, we, for the first time, performed the screening of diatom strains for fucoxanthin production potential and investigated in detail the effect of nutritional and environmental factors on C. cryptica growth and fucoxanthin accumulation. These results provide valuable implications into future engineering of C. cryptica culture parameters for improved fucoxanthin production and C. cryptica may emerge as a promising microalgal source of fucoxanthin.

The encoding of category-specific versus nonspecific information in human inferior temporal cortex.

Several brain areas in the inferior temporal (IT) cortex, such as the fusiform face area (FFA) and parahippocampal place area (PPA), are hypothesized to be selectively responsive to a particular category of visual objects. However, how category-specific and nonspecific information may be encoded at this level of visual processing is still unclear. Using fMRI, we compared averaged BOLD activity as well as multi-voxel activation patterns in the FFA and PPA corresponding to high-contrast and low-contrast face and house images. The averaged BOLD activity in the FFA and PPA was modulated by the image contrast regardless of the stimulus category. Interestingly, unlike the univariate averaged BOLD activity, multi-voxel activation patterns in the FFA and PPA were barely affected by variations in stimulus contrast. In both the FFA and PPA, decoding the categorical information about whether participants saw faces or houses was independent of stimulus contrast. Moreover, the multivariate pattern analysis (MVPA) results were highly stable when either the voxels that were more sensitive to stimulus contrast or the voxels that were less sensitive were used. Taken together, these findings demonstrate that both category-specific (face versus house) information and nonspecific (image contrast) information are available to be decoded orthogonally in the same brain areas (FFA and PPA), suggesting that complementary neural mechanisms for processing visual features and categorical information may occur in the same brain areas but respectively be revealed by averaged activity and multi-voxel activation patterns. Whereas stimulus strength, such as contrast, modulates overall activity amplitudes in these brain areas, activity patterns across populations of neurons appear to underlie the representation of object category.

Dynamic introduction of cell adhesive factor via reversible multicovalent phenylboronic acid/cis-diol polymeric complexes.

In this work, dynamic introduction of bioactive RGD peptide on a matrix was successfully demonstrated via reversible multicovalent interactions within PBA/cis-diol polymeric complexes. These reversible, stable multiple interaction sites, in addition to a long accessible polymeric linker, enabled "reversible" control of cell adhesion by specific biomolecular exchange (e.g., glucose or fructose). This biomolecule-triggered, noninvasive strategy shows great promise for use in real-time biological research and mimics natural biomolecular feedback systems, thus having potential application in medical diagnoses and regenerative medicine.

Oncogenic induction of cellular high CpG methylation by Epstein-Barr virus in malignant epithelial cells.

Epstein-Barr virus (EBV) is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancer (GC) worldwide. Increasing evidence shows that acquired genetic and epigenetic alterations lead to the initiation and progression of NPC and GC. However, even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC (EBVaGC), suggesting a predominant role of epigenetic abnormities, especially promoter CpG methylation, in the pathogenesis of NPC and EBVaGC. High frequencies of promoter methylation of tumor suppressor genes (TSGs) have been frequently reported in NPC and EBVaGC, with several EBV-induced methylated TSGs identified. Further characterization of the epigenomes (genome-wide CpG methylation profile--methylome) of NPC and EBVaGC shows that these EBV-associated tumors display a unique high CpG methylation epigenotype with more extensive gene methylation accumulation, indicating that EBV acts as a direct epigenetic driver for these cancers. Mechanistically, oncogenic modulation of cellular CpG methylation machinery, such as DNA methyltransferases (DNMTs), by EBV-encoded viral proteins accounts for the EBV-induced high CpG methylation epigenotype in NPC and EBVaGC. Thus, uncovering the EBV-associated unique epigenotype of NPC and EBVaGC would provide new insight into the molecular pathogenesis of these unique EBV-associated tumors and further help to develop pharmacologic strategies targeting cellular methylation machinery in these malignancies.

Comprehensive analysis of distribution characteristics and horizontal gene transfer elements of blaNDM-1-carrying bacteria.

The worldwide dissemination of New Delhi metallo-ß-lactamase-1 (NDM-1), which mediates resistance to almost all clinical ß-lactam antibiotics, is a major public health problem. The global distribution, species, sources, and potential transfer risk of blaNDM-1-carrying bacteria are unclear. Results of a comprehensive analysis of literature in 2010-2022 showed that a total of 6002 blaNDM-1 carrying bacteria were widely distributed around 62 countries with a high trend in the coastal areas. Opportunistic pathogens or pathogens like Klebsiella sp., Escherichia sp., Acinetobacter sp. and Pseudomonas sp. were the four main species indicating the potential microbial risk. Source analysis showed that 86.45 % of target bacteria were isolated from the source of hospital (e.g., Hospital patients and wastewater) and little from surface water (5.07 %) and farms (3.98 %). A plasmid-encoded blaNDM-1Acinetobacter sp. with the resistance mechanisms of antibiotic efflux pump, antibiotic target change and antibiotic degradation was isolated from the wastewater of a typical tertiary hospital. Insertion sequences (IS3 and IS30) located in the adjacent 5 kbp of blaNDM-1-bleMBL gene cluster indicating the transposon-mediated horizontal gene transfer risk. These results showed that the worldwide spread of blaNDM-1-carrying bacteria and its potential horizontal gene transfer risk deserve good control.

Fucoxanthin restructures the gut microbiota and metabolic functions of non-obese individuals in an in vitro fermentation model.

Fucoxanthin, a carotenoid exclusively derived from algae, exerts its bioactivities with the modulation of the gut microbiota in mice. However, mechanisms through which fucoxanthin regulates the gut microbiota and its derived metabolites/metabolism in humans remain unclear. In this study, we investigated the effects of fucoxanthin on the gut microbiota and metabolism of non-obese individuals using an in vitro simulated digestion-fermentation cascade model. The results showed that about half of the fucoxanthin was not absorbed in the intestine, thus reaching the colon. The gut microbiota from fecal samples underwent significant changes after 48 or 72 hours in vitro fermentation. Specifically, fucoxanthin significantly enhanced the relative abundance of Bacteroidota and Parabacteroides, leading to improved functions of the gut microbiota in its development, glycan biosynthesis and metabolism as well as in improving the digestive system, endocrine system and immune system. The recovery of fucoxanthin during fermentation showed a decreasing trend with the slight bio-conversion of fucoxanthinol. Notably, fucoxanthin supplementation significantly altered metabolites, especially bile acids and indoles in the simulated human gut ecosystem. Correlation analysis indicated the involvement of the gut microbiota in the manipulation of these metabolites by fucoxanthin. Moreover, all these altered metabolites revealed the improvement in the capacity of fucoxanthin in manipulating gut metabolism, especially lipid metabolism. Overall, fucoxanthin determinedly reshaped the gut microbiota and metabolism, implying its potential health benefits in non-obese individuals.