The hippocampus as a structural and functional network epicentre for distant cortical thinning in neurocognitive aging.

Alterations in grey matter (GM) and white matter (WM) are associated with memory impairment across the neurocognitive aging spectrum and theorised to spread throughout brain networks. Functional and structural connectivity (FC,SC) may explain widespread atrophy. We tested the effect of SC and FC to the hippocampus on cortical thickness (CT) of connected areas. In 419 (223 F) participants (agemean=73 ±â€¯8) from the Alzheimer's Disease Neuroimaging Initiative, cortical regions associated with memory (Rey Auditory Verbal Learning Test) were identified using Lasso regression. Two structural equation models (SEM), for SC and resting-state FC, were fitted including CT areas, and SC and FC to the left and right hippocampus (LHIP,RHIP). LHIP (ß=-0.150,p=<.001) and RHIP (ß=-0.139,p=<.001) SC predicted left temporopolar/rhinal CT; RHIP SC predicted right temporopolar/rhinal CT (ß=-0.191,p=<.001). LHIP SC predicted right fusiform/parahippocampal (ß=-0.104,p=.011) and intraparietal sulcus/superior parietal CT (ß=0.101,p=.028). Increased RHIP FC predicted higher left inferior parietal CT (ß=0.132,p=.042) while increased LHIP FC predicted lower right fusiform/parahippocampal CT (ß=-0.97; p=.023). The hippocampi may be epicentres for cortical thinning through disrupted connectivity.

Reversal of the concreteness effect can be detected in the natural speech of older adults with amnestic, but not non-amnestic, mild cognitive impairment.

INTRODUCTION: Patients with Alzheimer's disease present with difficulty in lexical retrieval and reversal of the concreteness effect in nouns. Little is known about the phenomena before the onset of symptoms. We anticipate early linguistic signs in the speech of people who suffer from amnestic mild cognitive impairment (MCI). Here, we report the results of a corpus-linguistic approach to the early detection of cognitive impairment. METHODS: One hundred forty-eight English-speaking Singaporeans provided natural speech data, on topics of their choice; 74 were diagnosed with single-domain MCI (38 amnestic, 36 non-amnestic), 74 cognitively healthy. The recordings yield 267,310 words, which are tagged for parts of speech. We calculate the per-minute word counts and concreteness scores of all tagged words, nouns, and verbs in the dataset. RESULTS: Compared to controls, subjects with amnestic MCI produce fewer but more abstract nouns. Verbs are not affected. DISCUSSION: Slower retrieval of nouns and the reversal of the concreteness effect in nouns are manifested in natural speech and can be detected early through corpus-based analysis. Highlights: Reversal of the concreteness effect is manifested in patients with Alzheimer's disease (AD) and semantic dementia.The paper reports a corpus-based analysis of natural speech by people with amnestic and non-amnestic mild cognitive impairment (MCI) and cognitively healthy controls.People with amnestic MCI produce fewer and more abstract nouns than people with non-amnestic MCI and healthy controls. Verbs appear to be unaffected.The imageability problem can be detected in natural everyday speech by people with amnestic MCI, which carries a higher risk of conversion to AD.

Annotation of 2,507 Saccharomyces cerevisiae genomes.

Saccharomyces cerevisiae (baker's yeast, budding yeast) is one of the most important model organisms for biological research and is a crucial microorganism in industry. Currently, a huge number of Saccharomyces cerevisiae genome sequences are available at the public domain. However, these genomes are distributed at different websites and a large number of them are released without annotation information. To provide one complete annotated genome data resource, we collected 2,507 Saccharomyces cerevisiae genome assemblies and re-annotated 2,506 assemblies using a custom annotation pipeline, producing a total of 15,407,164 protein-coding gene models. With a custom pipeline, all these gene sequences were clustered into families. A total of 1,506 single-copy genes were selected as marker genes, which were then used to evaluate the genome completeness and base qualities of all assemblies. Pangenomic analyses were performed based on a selected subset of 847 medium-high-quality genomes. Statistical comparisons revealed a number of gene families showing copy number variations among different organism sources. To the authors' knowledge, this study represents the largest genome annotation project of S. cerevisiae so far, providing rich genomic resources for the future studies of the model organism S. cerevisiae and its relatives.IMPORTANCESaccharomyces cerevisiae (baker's yeast, budding yeast) is one of the most important model organisms for biological research and is a crucial microorganism in industry. Though a huge number of Saccharomyces cerevisiae genome sequences are available at the public domain, these genomes are distributed at different websites and most are released without annotation, hindering the efficient reuse of these genome resources. Here, we collected 2,507 genomes for Saccharomyces cerevisiae, performed genome annotation, and evaluated the genome qualities. All the obtained data have been deposited at public repositories and are freely accessible to the community. This study represents the largest genome annotation project of S. cerevisiae so far, providing one complete annotated genome data set for S. cerevisiae, an important workhorse for fundamental biology, biotechnology, and industry.

Virtual screening and biological evaluation of natural products as urate transporter 1 (URAT1) inhibitors.

Hyperuricemia is mainly caused by insufficient renal urate excretion. Urate transporter 1 (URAT1), an organic anion transporter, is the main protein responsible for urate reabsorption. In this study, we utilized artificial intelligence-based AlphaFold2 program to construct URAT1 structural model. After molecular docking and conformational evaluation, four e-pharmacophoric models were constructed based on the complex structures of probenecid-URAT1, benzbromarone-URAT1, lesinurad-URAT1, and verinurad-URAT1. Combining pharmacophore modeling, molecular docking, MM/GBSA calculation and ADME prediction, 25 flavonoids were selected from the natural products database containing 10,968 molecules. Then, a model of HEK-293T cells overexpressing URAT1 was constructed, and the inhibitory activity to URAT1 of 25 flavonoids was evaluated by measuring their effect on cellular uptake of 6-carboxyfluorescein (6-CFL). Fisetin, baicalein, and acacetin showed the best activity with IC50 values of 12.77, 26.71, and 57.30 µM, respectively. Finally, the structure-activity relationship of these three flavonoids was analyzed by molecular docking and molecular dynamics simulations. The results showed that the carbonyl group on C-4 and hydroxyl group on C-7, C-4', and C-5' in flavonoids were conducive for URAT1 inhibitory effects. This study facilitates the application of flavonoids in the development of URAT1 inhibitors.Communicated by Ramaswamy H. Sarma.

Enhancing malting performance of harder barley varieties through ultrasound treatment.

Harder kernels of barley are regarded as one of the factors that restrict water and enzyme movement within the endosperm during malting. A comprehensive study of two domestic varieties was performed for evaluating malting quality. Both ß-glucan and total protein content of the Chinese domestic barley (Ganpi-6 and Kenpi-14) were significantly higher than Copeland. Grain hardness of the Chinese domestic barley was higher and water uptake ratio was lower compared with the Copeland. During germination, the expression levels of NCED1, NCED2 (major key regulatory enzymes for abscisic acid biosynthesis genes) were higher, whereas gibberelic acid (GA) synthesis genes (GA20ox1, GA2ox3, GA3ox2) were lower in the Ganpi-6, Kenpi-14 compared with Copeland. These two domestic barley varieties also showed significantly lower limit dextrinase and ß-glucanase activity compared with Copeland. Ultrasound treatment improved the malting quality of Ganpi-6 by enhancing water uptake and GA synthesis gene expression increased. Therefore, these findings provided insights into the future direction on the utilization of ultrasonication for the applications towards the improvement of the harder barley variety.

Intrinsic Self-Trapped Excitons in Graphitic Carbon Nitride.

Graphitic carbon nitrides (g-C3N4) as low-cost, chemically stable, and ecofriendly layered semiconductors have attracted rapidly growing interest in optoelectronics and photocatalysis. However, the nature of photoexcited carriers in g-C3N4 is still controversial, and an independent charge-carrier picture based on the band theory is commonly adopted. Here, by performing transient spectroscopy studies, we show characteristics of self-trapped excitons (STEs) in g-C3N4 nanosheets including broad trapped exciton-induced absorption, picosecond exciton trapping without saturation at high photoexcitation density, and transient STE-induced stimulated emissions. These features, together with the ultrafast exciton trapping polarization memory, strongly suggest that STEs intrinsically define the nature of the photoexcited states in g-C3N4. These observations provide new insights into the fundamental photophysics of carbon nitrides, which may enlighten novel designs to boost energy conversion efficiency.

Virtual screening of natural products targeting ubiquitin-specific protease 7.

Ubiquitin-specific protease 7 (USP7) is a promising prognostic and druggable target for cancer therapy. Inhibition of USP7 can activate the MDM2-P53 signaling pathway, thereby promoting cancer cell apoptosis. This study based on watvina molecular docking of virtual screening method and biological evaluation found the new USP7 inhibitors targeting catalytic active site. Three hits were screened from 3760 natural products and validated as USP7 inhibitors by enzymatic and kinetic assays. The IC50 values of scutellarein (Scu), semethylzeylastera (DML) and salvianolic acid C (SAC) were 3.017, 6.865 and 8.495 µM, respectively. Further, we reported that the hits could downregulate MDM2 and activate p53 signal pathway in HCT116 cells. Molecular dynamics simulation was used to investigate the binding mechanism of USP7 to Scu, the compound with the best performance, which formed stable contact with Val296, Gln297, Phe409, Tyr465 and Tyr514. These interactions are essential for maintaining the biological activity of Scu. Three natural products are suitable as lead compounds for the development of novel USP7 inhibitors, especially anti-colon cancer drugs.Communicated by Ramaswamy H. Sarma.

Technology and physical activity for preventing cognitive and physical decline in older adults: Protocol of a pilot RCT.

BACKGROUND: Cognitive frailty, defined as having both physical frailty and cognitive impairment that does not satisfy the criteria for Major Neurocognitive Disorder, represents an elevated risk for morbidity. Hence, it is crucial to mitigate such risks. Physical activity interventions have been found effective in protecting against physical frailty and cognitive deterioration. This pilot RCT examines if smartwatches and mobile phone applications can help to increase physical activity, thereby improving physical and cognitive outcomes. METHODS: Older individuals (n = 60) aged 60 to 85 years old will have their physical activity tracked using a smartwatch. The subjects will be randomized into two arms: one group will receive daily notification prompts if they did not reach the recommended levels of PA; the control group will not receive prompts. Outcome variables of physical activity level, neurocognitive scores, and physical frailty scores will be measured at baseline, T1 (3 months), and T2 (6 months). Sleep quality, levels of motivation, anxiety, and depression will be controlled for in our analyses. We hypothesize that the intervention group will have higher levels of physical activity resulting in improved cognitive and physical outcomes at follow-up. This study was approved by the National University of Singapore's Institutional Review Board on 17 August 2020 (NUS-IRB Ref. No.: H-20-038). DISCUSSION: Wearable sensors technology could prove useful by facilitating self-management in physical activity interventions. The findings of this study can justify the use of technology in physical activity as a preventive measure against cognitive frailty in older adults. This intervention also complements the rapidly rising use of technology, such as smartphones and wearable health devices, in our lives today. REGISTRATION DETAILS: This study has been retrospectively registered on clinicaltrials.gov on 5th January 2021 (NCT Identifier: NCT04692974), after the first participant was recruited.

LFC study: Protocol for a longitudinal follow-up cohort study on ageing and mental health in community-dwelling older adults in Singapore.

The rapid pace of population ageing worldwide has prompted the need to better understand the ageing process. The current study, titled the Longitudinal Follow-up of the CHI (LFC) study, was a 3-year follow-up study of an earlier study titled the Community Health and Intergenerational (CHI) study. The LFC study looked to examine longitudinal changes in their cognitive functioning and psychosocial outcomes across the 3-year period. Additionally, the current study built upon the earlier CHI study by collecting neuroimaging data and exploring the long-term effects of non-pharmacological interventions, which were not examined in the prior study. A total of 653 community-dwelling participants from the baseline CHI study cohort were invited to take part in the LFC study, where they underwent a battery of neuropsychological assessments, psychosocial questionnaires, a Magnetic Resonance Imaging scan and a voice recording segment. The current study would holistically track longitudinal changes in cognitive functioning and psychosocial outcomes in the ageing population in Singapore. Unique associations between linguistics and neuroimaging data alongside cognitive and psychosocial outcomes would be explored. This study also serves to guide the development of new interventions for older adults and assist in improving the well-being of the local and global ageing population.

Cognitive and physical age gaps in relation to mild cognitive impairment and behavioral phenotypes.

We can study how fast our biological aging clocks tick by calculating the difference (i.e., age gaps) between machine learning estimations of biological age and chronological age. While this approach has been increasingly used to study various aspects of aging, few had applied this approach to study cognitive and physical age gaps; not much is known about the behavioral and neurocognitive factors associated with these age gaps. In the present study, we examined these age gaps in relation to behavioral phenotypes and mild cognitive impairment (MCI) among community-dwelling older adults. Participants (N = 822, Agemean = 67.6) were partitioned into equally-sized training and testing samples. Cognitive and physical age-prediction models were fitted using nine cognitive and eight physical fitness test scores, respectively, within the training samples, and subsequently used to estimate cognitive and physical age gaps for each subject in the testing sample. These age gaps were then compared among those with and without MCI and correlated with 17 behavioral phenotypes in the domains of lifestyle, well-being, and attitudes. Across 5000 random train-test split iterations, we showed that older cognitive age gaps were significantly associated with MCI (versus cognitively normal) and worse outcomes across several well-being and attitude-related measures. Both age gaps were also significantly correlated with each other. These results suggest accelerated cognitive and physical aging were linked to worse well-being and more negative attitudes about the self and others and reinforce the link between cognitive and physical aging. Importantly, we have also validated the use of cognitive age gaps in the diagnosis of MCI.

Left superior parietal lobe mediates the link between spontaneous mind-wandering tendency and task-switching performance.

While increasing studies have documented the link between mind wandering and task switching, less is known about which brain regions mediate this relationship. Using the MPI-Leipzig Mind-Brain-Body dataset (N = 173), we investigated the association between trait-level tendencies of mind wandering, task-switching performance, structural connectivity, and resting-state functional connectivity. At the behavioral level, we found that higher spontaneous mind-wandering trait scores were associated with shorter reaction times on both repeat and switch trials. The whole brain cortical thickness analysis revealed a strong mediating role of the left superior parietal lobe, which is part of the dorsal attention network, in the link between spontaneous mind-wandering tendency and task-switching performance. The resting-state functional connectivity analysis further demonstrated that this association was partly mediated by the negative dorsal attention network-default mode network functional connectivity. No significant mediating effects were found for deliberate mind-wandering tendency. Overall, the findings highlight the pivotal role of the left superior parietal lobe in activating new mental set during mind-wandering and task-switching processes, providing another evidence in favor of a role for switching in mind wandering.

Age-related decrease in inter-subject similarity of cortical morphology and task and resting-state functional connectivity.

"All old people are the same" is an unfortunate characterization of the perceived homogeneity in the older age group. This study attempts to debunk this myth in the context of the structural and functional brain. Within older relative to younger age groups, individuals are hypothesized to be more dissimilar to their similar-aged peers-thus demonstrating an age-related divergence. This study analyzed functional connectivity (FC) during multiple fMRI paradigms (2 rest + 5 tasks) and cortical thickness (CT) data from two lifespan datasets (Ntotal = 1161). On average, between-subject FC/CT correlations became weaker in the older age groups. Further analyses ruled out the possibility that more rapid age-related changes in older brains have increased the dissimilarity in these older age groups. Brain-wide analyses revealed significant effects of age-related divergence across most of the brain. Finally, CT similarity between a dyad significantly predicted their FC similarity across multiple fMRI task paradigms-demonstrating a close relationship between brain structure and function even at the between-dyad level. Contrary to the myth that "all old people are the same," these findings suggest young people are more similar to each other. This study presents major implications in the study of neural fingerprinting and brain-behavior associations.

Effective Degradation of Brewer Spent Grains by a Novel Thermostable GH10 Xylanase.

Brewer spent grains (BSGs) are one of the most abundant by-products in brewing industry. Due to microbiological instability and high perishability, the efficient degradation of BSGs is of environmental and economic importance. Streptomyces sp. F-3 could grow in the medium with BSGs as the only carbon and nitrogen source. Proteome mass spectrometry revealed that a GH10 xylanase SsXyn10A could be secreted in large quantities. SsXyn10A showed optimum activity at pH 7.0 and 60 °C. SsXyn10A exhibited excellent thermostability which retained approximately 100% and 58% after incubation for 5 h at 50 and 60 °C. SsXyn10A displayed high activity to beechwood xylan (BX) and wheat arabinoxylan (WAX). SsXyn10A is active against xylotetracose (X4), xylopentose (X5), and xylohexose (X6) to produce main products xylobiose (X2) and xylotriose (X3). Ssxyn10A showed synergistic effects with commercial cellulase on BSGs hydrolyzing into soluble sugar. In addition, the steam explosion pretreatment of BSGs as the substrate produced twice as much reducing sugar as the degradation of the original substrate. This study will contribute to efficient utilization of BSGs and provide a thermostable GH10 xylanase which has potential application in biomass hydrolysis.

Discovery of Bacteroides uniformis F18-22 as a Safe and Novel Probiotic Bacterium for the Treatment of Ulcerative Colitis from the Healthy Human Colon.

Previous studies have demonstrated that the intestinal abundance of Bacteroides uniformis is significantly higher in healthy controls than that in patients with ulcerative colitis (UC). However, what effect B. uniformis has on the development of UC has not been characterized. Here, we show for the first time that B. uniformis F18-22, an alginate-fermenting bacterium isolated from the healthy human colon, protects against dextran-sulfate-sodium (DSS)-induced UC in mice. Specifically, oral intake of B. uniformis F18-22 alleviated colon contraction, improved intestinal bleeding and attenuated mucosal damage in diseased mice. Additionally, B. uniformis F18-22 improved gut dysbiosis in UC mice by increasing the abundance of anti-inflammatory acetate-producing bacterium Eubacterium siraeum and decreasing the amount of pro-inflammatory pathogenetic bacteria Escherichia-Shigella spp. Moreover, B. uniformis F18-22 was well-tolerated in mice and showed no oral toxicity after repeated daily administration for 28 consecutive days. Taken together, our study illustrates that B. uniformis F18-22 is a safe and novel probiotic bacterium for the treatment of UC from the healthy human colon.

Mindfulness-based randomized controlled trials led to brain structural changes: an anatomical likelihood meta-analysis.

Mindfulness has become increasingly popular and the practice presents in many different forms. Research has been growing extensively with benefits shown across various outcomes. However, there is a lack of consensus over the efficacy of randomized controlled mindfulness interventions, both traditional and mind-body formats. This study aimed to investigate the structural brain changes in mindfulness-based interventions through a meta-analysis. Scopus, PubMed, Web of Science, and PsycINFO were searched up to April 2023. 11 studies (n = 581) assessing whole-brain voxel-based grey matter or cortical thickness changes after a mindfulness RCT were included. Anatomical likelihood estimation was used to carry out voxel-based meta-analysis with leave-one-out sensitivity analysis and behavioural analysis as follow-ups. One significant cluster (p < 0.001, Z = 4.76, cluster size = 632 mm3) emerged in the right insula and precentral gyrus region (MNI = 48, 10, 4) for structural volume increases in intervention group compared to controls. Behavioural analysis revealed that the cluster was associated with mental processes of attention and somesthesis (pain). Mindfulness interventions have the ability to affect neural plasticity in areas associated with better pain modulation and increased sustained attention. This further cements the long-term benefits and neuropsychological basis of mindfulness-based interventions.

Synthesis of fused 3-trifluoromethyl-1,2,4-triazoles via base-promoted [3 + 2] cycloaddition of nitrile imines and 1H-benzo[d]imidazole-2-thiols.

Here we report a strategy for the facile assembly of fused 3-trifluoromethyl-1,2,4-triazoles, which are difficult to synthesize using traditional strategies, in 50-96% yields through a triethylamine-promoted intermolecular [3 + 2] cycloaddition pathway. This protocol features high efficiency, good functional group tolerance, mild conditions, and easy operation. Furthermore, a gram-scale reaction and product derivatizations were carried out smoothly to illustrate the practicability of this method.

Recent advances in the efficient degradation of lignocellulosic metabolic networks by lytic polysaccharide monooxygenase.

Along with long-term evolution, the plant cell wall generates lignocellulose and other anti-degradation barriers to confront hydrolysis by fungi. Lytic polysaccharide monooxygenase (LPMO) is a newly defined oxidase in lignocellulosic degradation systems that significantly fuels hydrolysis. LPMO accepts electrons from wide sources, such as cellobiose dehydrogenase (CDH), glucose-methanol-choline (GMC) oxidoreductases, and small phenols. In addition, the extracellular cometabolic network formed by cosubstrates improves the degradation efficiency, forming a stable and efficient lignocellulose degradation system. In recent years, using structural proteomics to explore the internal structure and the complex redox system of LPMOs has become a research hotspot. In this review, the diversity of LPMOs, catalytic domains, carbohydrate binding modules, direct electron transfer with CDH, cosubstrates, and degradation networks of LPMOs are explored, which can provide a systematic reference for the application of lignocellulosic degradation systems in industrial approaches.

Psychosocial profiles within community-dwelling older adults with Mild Cognitive Impairment: A prevalence and latent profile analysis study.

OBJECTIVES: Mild Cognitive Impairment (MCI) is an at-risk stage for dementia and accurate prevalence studies are lacking in Singapore. From the literature, it is evident that psychosocial factors increase the risk of conversion to dementia. In this study, we sought to establish the prevalence of MCI in Singapore and study the associated psychosocial factors using latent profile analysis. METHOD: 902 community-dwelling older adults, aged between 60 and 99 years old (Mage = 70.48 years), were recruited as part of the Community Health and Intergenerational Study (CHI). They completed neurocognitive assessments and questionnaires on depression and anxiety symptoms, quality of life, social support, satisfaction with life, and social connectivity. Petersen's criteria was used to diagnose MCI. Within the MCI sample, 166 subjects' psychosocial scores were entered into a latent profile analysis to identify profiles of psychosocial functioning. RESULTS: The prevalence of MCI in our sample was 21.5%. They had significantly lower years of education and perceived social support and higher depressive symptoms than the normal ageing group. Three distinct profiles emerged within the MCI group corresponding to a positive (45.2%), neutral (38.5%), and negative (16.3%) pattern of psychosocial scores. These profiles did not differ significantly in terms of demographic or cognitive variables. DISCUSSION: The three psychosocial profiles might reflect the differing implications of MCI on a person's well-being and the negative psychosocial profile might likely be most at risk of conversion to dementia. Future longitudinal studies are required to confirm these implications.

Observation of Phonon Cascades in Cu-Doped Colloidal Quantum Wells.

Electronic doping has endowed colloidal quantum wells (CQWs) with unique optical and electronic properties, holding great potential for future optoelectronic device concepts. Unfortunately, how photogenerated hot carriers interact with phonons in these doped CQWs still remains an open question. Here, through investigating the emission properties, we have observed an efficient phonon cascade process (i.e., up to 27 longitudinal optical phonon replicas are revealed in the broad Cu emission band at room temperature) and identified a giant Huang-Rhys factor (S ≈ 12.4, more than 1 order of magnitude larger than reported values of other inorganic semiconductor nanomaterials) in Cu-doped CQWs. We argue that such an ultrastrong electron-phonon coupling in Cu-doped CQWs is due to the dopant-induced lattice distortion and the dopant-enhanced density of states. These findings break the widely accepted consensus that electron-phonon coupling is typically weak in quantum-confined systems, which are crucial for optoelectronic applications of doped electronic nanomaterials.

Ultrafast modulation of a high harmonic generation in a bulk ZnO single crystal.

Optical modulation of high harmonic generation (HHG) is of fundamental interest in science and technology, which can facilitate understanding of HHG generation mechanisms and expand the potential optoelectronic applications. However, the current established works have neither shown the advanced modulation performance nor provided a deep understanding of modulation mechanisms. In this work, taking wurtzite zinc oxide (ZnO) single crystal as a prototype, we have demonstrated an all-optical intensity modulation of high-order HHG with a response time of less than 0.2 ps and a depth of more than 95%, based on the pump-probe configuration with two different pumping wavelengths. Besides the achieved excellent modulation performance, we have also revealed that the modulation dynamics in ZnO single crystal highly depend on the excitation conditions. Specifically, the modulation dynamics with the near-bandgap or above-bandgap excitation are attributed to the non-equilibrium interband carrier relaxations, while for mid-gap excitation, the modulation dynamics are dominated by the nonlinear frequency mixing process. This work may enhance the current understanding of the HHG modulation mechanism and enlighten novel device designs.