Comparative efficacy of seven nonpharmacological interventions on global cognition in older adults with and without mild cognitive impairment: a network meta-analysis of randomized controlled trials.

To maintain current cognitive function and access greater cognitive reserves, nonpharmacological interventions may be a viable alternative for older adults with or without cognitive impairment. This study aimed to compare different nonpharmacological interventions for enhancing global cognition, including mind-body exercise, physical exercise, non-invasive brain stimulation, cognitive training intervention (CTI), acutherapy (ACU), meditation, and music therapy, by applying a network meta-analysis (NMA). Sixty-one randomized controlled trials evaluating the efficacy of interventions on global cognition in older adults with or without mild cognitive decline were selected. An NMA was conducted to compare the efficacy of different nonpharmacological interventions. The NMA revealed that mind-body exercise (standardized mean difference, 1.384; 95% confidence interval, 0.777-1.992); ACU (1.283; 0.478-2.088); meditation (0.910; 0.097-1.724); non-invasive brain stimulation (1.242; 0.254-2.230); CTI (1.269; 0.736-1.802); and physical exercise (0.977; 0.212-1.742), showed positive effects compared to passive controls. There were no significant differences between the efficacies of other interventions. Nonpharmacological interventions may potentially enhance and maintain global cognition through various pathways, such as memorizing movements and enhancing brain plasticity by reducing stress in the older adult population. Additional studies are needed to clarify the impact of other variables, including intervention methods or psychological variables.

High-κ Dielectric (HfO2)/2D Semiconductor (HfSe2) Gate Stack for Low-Power Steep-Switching Computing Devices.

Herein, a high-quality gate stack (native HfO2 formed on 2D HfSe2) fabricated via plasma oxidation is reported, realizing an atomically sharp interface with a suppressed interface trap density (Dit ≈ 5 × 1010 cm-2 eV-1). The chemically converted HfO2 exhibits dielectric constant, κ ≈ 23, resulting in low gate leakage current (≈10-3 A cm-2) at equivalent oxide thickness ≈0.5 nm. Density functional calculations indicate that the atomistic mechanism for achieving a high-quality interface is the possibility of O atoms replacing the Se atoms of the interfacial HfSe2 layer without a substitution energy barrier, allowing layer-by-layer oxidation to proceed. The field-effect-transistor-fabricated HfO2/HfSe2 gate stack demonstrates an almost ideal subthreshold slope (SS) of ≈61 mV dec-1 (over four orders of IDS) at room temperature (300 K), along with a high Ion/Ioff ratio of ≈108 and a small hysteresis of ≈10 mV. Furthermore, by utilizing a device architecture with separately controlled HfO2/HfSe2 gate stack and channel structures, an impact ionization field-effect transistor is fabricated that exhibits n-type steep-switching characteristics with a SS value of 3.43 mV dec-1 at room temperature, overcoming the Boltzmann limit. These results provide a significant step toward the realization of post-Si semiconducting devices for future energy-efficient data-centric computing electronics.

The Effects of ICT-Based Interventions on Physical Mobility of Older Adults: A Systematic Literature Review and Meta-Analysis.

Systematic literature review and meta-analysis were conducted to integrate and analyze intervention studies dealing with the effects of information and communications technology- (ICT-) based interventions on the physical mobility of older adults in the community. The PubMed/MEDLINE, Embase, CINAHL, and Cochrane CENTRAL databases were searched for studies published from January 2000 to December 2022. We used the Risk of Bias 2 (RoB 2) tool to evaluate the quality of the randomized controlled studies in the systematic review. The meta-analysis was performed using a random-effects model. The model was used to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) for both effect measures. I2 tests were used to measure the presence of heterogeneity. Thirty-seven randomized controlled trials were included (2,419 intervention participants), of which 23 were included in the meta-analysis. ICT interventions significantly improved Timed Up and Go (TUG) as a marker of physical mobility variable in older adults (SMD = -0.33, 95% CI: -0.57 to -0.10, p=0.005, I2 = 74.7%). A sensitivity analysis was performed on subgroups, and interventions were found to be effective in improving TUG in the exergame group (SMD = -0.40, 95% CI: -0.72 to -0.08, p < 0.001, I2 = 75.0%) and in the exergame with virtual reality (VR) group (SMD = -0.33, 95% CI: -1.01 to 0.35, p < 0.001, I2 = 91.0%) but both groups showed high heterogeneity. A meta-analysis was also performed on Short Physical Performance Battery (SPPB) but statistically significant results were not found (SMD = -0.19, 95% CI: -0.61 to 0.23, p=0.375, I2 = 87.7%). For the Berg Balance Scale (BBS), the post-intervention scores were significantly better than baseline (SMD = 1.52, 95% CI: 0.48 to 2.57, p=0.004, I2 = 93.5%). However, the number of studies included in the meta-analysis was small and heterogeneity was high, so follow-up studies are needed. This study confirmed that exergames, telecommunication, e-health, information applications, and robots were used as effective ICT-based interventions for improving the physical mobility of older adults. It is necessary to develop and apply more diverse ICT-based interventions that will prevent impairments of mobility and encourage older adults to live more independently, with a higher quality of life, based on extensive research on ICT-based interventions.

Generation of reproductive transgenic pigs of a CRISPR-Cas9-based oncogene-inducible system by somatic cell nuclear transfer.

Alternative cancer models that are close to humans are required to create more valuable preclinical results during oncology studies. Here, a new onco-pig model via developing a CRISPR-Cas9-based Conditional Polycistronic gene expression Cassette (CRI-CPC) system to control the tumor inducing simian virus 40 large T antigen (SV40LT) and oncogenic HRASG12V . After conducting somatic cell nuclear transfer (SCNT), transgenic embryos were transplanted into surrogate mothers and five male piglets were born. Umbilical cord analysis confirmed that all piglets were transgenic. Two of them survived and they expressed a detectable green fluorescence. The test was made whether CRI-CPC models were naturally fertile and whether the CRI-CPC system was stably transferred to the offspring. By mating with a normal female pig, four offspring piglets were successfully produced. Among them, only three male piglets were transgenic. Finally, their applicability was tested as cancer models after transduction of Cas9 into fibroblasts from each CRI-CPC pig in vitro, resulting in cell acquisition of cancerous characteristics via the induction of oncogene expression. These results showed that our new CRISPR-Cas9-based onco-pig model was successfully developed.

Multifocal Organoid Capturing of Colon Cancer Reveals Pervasive Intratumoral Heterogenous Drug Responses.

Intratumor heterogeneity (ITH) stands as one of the main difficulties in the treatment of colorectal cancer (CRC) as it causes the development of resistant clones and leads to heterogeneous drug responses. Here, 12 sets of patient-derived organoids (PDOs) and cell lines (PDCs) isolated from multiple regions of single tumors from 12 patients, capturing ITH by multiregion sampling of individual tumors, are presented. Whole-exome sequencing and RNA sequencing of the 12 sets are performed. The PDOs and PDCs of the 12 sets are also analyzed with a clinically relevant 24-compound library to assess their drug responses. The results reveal unexpectedly widespread subregional heterogeneity among PDOs and PDCs isolated from a single tumor, which is manifested by genetic and transcriptional heterogeneity and strong variance in drug responses, while each PDO still recapitulates the major histologic, genomic, and transcriptomic characteristics of the primary tumor. The data suggest an imminent drawback of single biopsy-originated PDO-based clinical diagnosis in evaluating CRC patient responses. Instead, the results indicate the importance of targeting common somatic driver mutations positioned in the trunk of all tumor subregional clones in parallel with a comprehensive understanding of the molecular ITH of each tumor.

Beneficial Effects of Neurotrophin-4 Supplementation During in vitro Maturation of Porcine Cumulus-Oocyte Complexes and Subsequent Embryonic Development After Parthenogenetic Activation.

Neurotrophin-4 (NT-4) is a neurotrophic factor that plays an important role in follicular development and oocyte maturation. However, it is not yet known whether NT-4 is related to oocyte maturation and follicular development in pigs. This study aims to investigate the effects of NT-4 supplementation during in vitro maturation (IVM) of porcine oocytes and subsequent embryonic development after parthenogenetic activation (PA). First, NT-4 and its receptors (TrkB and p75NTR) were identified through fluorescent immunohistochemistry in porcine ovaries. NT-4 was mainly expressed in theca and granulosa cells; phospho-TrkB and total TrkB were expressed in theca cells, granulosa cells, and oocytes; p75NTR was expressed in all follicular cells. During IVM, the defined maturation medium was supplemented with various concentrations of NT-4 (0, 1, 10, and 100 ng/mL). After IVM, the nuclear maturation rate was significantly higher in the 10 and 100 ng/mL NT-4 treated groups than in the control. There was no significant difference in the intracellular reactive oxygen species levels in any group after IVM, but the 1 and 10 ng/mL NT-4 treatment groups showed a significant increase in the intracellular glutathione levels compared to the control. In matured cumulus cells, the 10 ng/mL NT-4 treatment group showed significantly increased cumulus expansion-related genes and epidermal growth factor (EGF) signaling pathway-related genes. In matured oocytes, the 10 ng/mL treatment group showed significantly increased expression of cell proliferation-related genes, antioxidant-related genes, and EGF signaling pathway-related genes. We also investigated the subsequent embryonic developmental competence of PA embryos. After PA, the cleavage rates significantly increased in the 10 and 100 ng/mL NT-4 treatment groups. Although there was no significant difference in the total cell number of blastocysts, only the 10 ng/mL NT-4 treatment group showed a higher blastocyst formation rate than the control group. Our findings suggest that supplementation with the 10 ng/mL NT-4 can enhance porcine oocyte maturation by interacting with the EGF receptor signaling pathway. In addition, we demonstrated for the first time that NT-4 is not only required for porcine follicular development, but also has beneficial effects on oocyte maturation and developmental competence of PA embryos.

Effect of Interleukin-7 on In Vitro Maturation of Porcine Cumulus-Oocyte Complexes and Subsequent Developmental Potential after Parthenogenetic Activation.

Interleukin-7 (IL-7) is a cytokine essential for cell development, proliferation and survival. However, its role in oocyte maturation is largely unknown. To investigate the effects of IL-7 on the in vitro maturation (IVM) of porcine oocytes, we analyzed nuclear maturation, intracellular glutathione (GSH) and reactive oxygen species (ROS) levels, and subsequent embryonic developmental competence after parthenogenetic activation (PA) under several concentrations of IL-7. After IVM, IL-7 treated groups showed significantly higher nuclear maturation and significantly decreased intracellular ROS levels compared with the control group. All IL-7 treatment groups exhibited significantly increased intracellular GSH levels compared with the control group. All oocytes matured with IL-7 treatment during IVM exhibited significantly higher cleavage and blastocyst formation rates after PA than the non-treatment group. Furthermore, significantly higher mRNA expression levels of developmental-related genes (PCNA, Filia, and NPM2) and antioxidant-related genes (GSR and PRDX1) were observed in the IL-7-supplemented oocytes than in the control group. IL-7-supplemented cumulus cells showed significantly higher mRNA expression of the anti-apoptotic gene BCL2L1 and mitochondria-related genes (TFAM and NOX4), and lower transcript levels of the apoptosis related-gene, Caspase3, than the control group. Collectively, the present study suggests that IL-7 supplementation during porcine IVM improves oocyte maturation and the developmental potential of porcine embryos after PA.

The effect of copper supplementation on in vitro maturation of porcine cumulus-oocyte complexes and subsequent developmental competence after parthenogenetic activation.

Copper (Cu) ions have redox activity and act as cofactors of enzymes related to respiration, radical detoxification, and iron metabolism. In this study, we aimed to examine the effects of copper (II) chloride dihydrate (CuCl2·2H2O) on porcine oocytes during in vitro maturation (IVM) and subsequent embryonic development following parthenogenetic activation (PA). Nuclear maturation, intracellular glutathione (GSH) and reactive oxygen species (ROS) levels, cumulus expansion, the mRNA expression levels of various genes, and developmental competence were analyzed. During IVM, the maturation medium was supplemented with various concentrations of Cu (0, 0.7, 1.4, and 2.8 µg/mL). After 42 h of IVM, Cu supplementation significantly increased the number of oocytes in the metaphase II stage. Further, the 1.4 µg/mL Cu group showed significantly higher intracellular GSH levels than the control group. However, Cu supplementation increased intracellular ROS levels regardless of their concentration. Additionally, the mRNA levels of Has-2, the cumulus cell expansion-related gene, were higher in all the Cu-treated groups than in the control group. The cumulus cell expansion index was higher in the 0.7 and 1.4 µg/mL Cu groups than in the other groups. In the 0.7 µg/mL Cu group, the mRNA expression levels of PCNA, Zar1, and NPM2, which are related to developmental competence, were significantly higher than those in the control group. Moreover, increased levels of Sod1 transcript, correlated with the antioxidative response, were observed in the 0.7 and 1.4 µg/mL Cu groups. The apoptosis rate in Cu-treated cumulus cells and oocytes was decreased compared to that in the corresponding control groups. Upon evaluation of subsequent embryonic development after PA, the 0.7 µg/mL Cu group showed significantly improved cleavage and blastocyst formation rate compared to the control group. In conclusion, our results suggest that Cu supplementation at appropriate concentrations in IVM medium improves porcine oocyte maturation and the subsequent embryonic potential of PA embryos by reducing oxidative stress and apoptosis.

Resting-state prefrontal EEG biomarkers in correlation with MMSE scores in elderly individuals.

We investigated whether cognitive decline could be explained by resting-state electroencephalography (EEG) biomarkers measured in prefrontal regions that reflect the slowing of intrinsic EEG oscillations. In an aged population dwelling in a rural community (total = 496, males = 165, females = 331), we estimated the global cognitive decline using the Mini-Mental State Examination (MMSE) and measured resting-state EEG parameters at the prefrontal regions of Fp1 and Fp2 in an eyes-closed state. Using a tertile split method, the subjects were classified as T3 (MMSE 28-30, N = 162), T2 (MMSE 25-27, N = 179), or T1 (MMSE ≤ 24, N = 155). The EEG slowing biomarkers of the median frequency, peak frequency and alpha-to-theta ratio decreased as the MMSE scores decreased from T2 to T1 for both sexes (-5.19 ≤ t-value ≤ -3.41 for males and -7.24 ≤ t-value ≤ -4.43 for females) after adjusting for age and education level. Using a double cross-validation procedure, we developed a prediction model for the MMSE scores using the EEG slowing biomarkers and demographic covariates of sex, age and education level. The maximum intraclass correlation coefficient between the MMSE scores and model-predicted values was 0.757 with RMSE = 2.685. The resting-state EEG biomarkers showed significant changes in people with early cognitive decline and correlated well with the MMSE scores. Resting-state EEG slowing measured in the prefrontal regions may be useful for the screening and follow-up of global cognitive decline in elderly individuals.

Variability of electrochemical skin conductance for screening diabetes mellitus.

Electrochemical skin conductance (ESC) has been suggested as a noninvasive diabetic screening tool. We examined the relevance of ESC method for screening type 2 diabetes. A meal tolerance test (MTT) was conducted for 40 diabetic and 42 control subjects stratified by age, sex and body mass index (BMI). The glucose levels and ESC were measured before the MTT and every 30 min after meal intake up to 120 min. There was no correlation between the blood glucose level and ESC (r = 0.249) or ESC variability (ESCV) (r = - 0.173). ESC (ESCV) was higher (lower) in diabetic patients than in normal control (p = 0.02 for ESC and p = 0.06 for ESCV). Receiver operating characteristic analysis showed that the area under the curve (AUC) values of the ESC and ESCV were 0.654 and 0.691, respectively. The novel variable, ESCV, showed 5.7% higher AUC than ESC. Contrary to some previous reports, ESC values in diabetic patients was higher than in age, sex and BMI matched control group. In our study, ESC or ESCV showed a marginal accuracy to be used as a screening tool for diabetes mellitus.

A histidine substitution confers metal binding affinity to a Schistosoma japonicum Glutathione S-transferase.

Glutathione S-transferases (GSTs) are multifunctional enzymes that are used as fusion tags on recombinant proteins in mammalian and Escherichia coli expression systems. We recently found that the Schistosoma japonicum GST (SjGST) displays weak Ni(2+) ion binding affinity. Glu26 and His79 were assumed to be its Ni(2+) binding sites based on the structure of the 26-kDa Clonorchis sinensis GST. To enhance SjGST Ni(2+) binding affinity, Glu26 was mutated to His. SjGST-E26H was expressed and purified at a high concentration of imidazole to a higher purity than wild type SjGST. In addition, human biotin protein ligase fused to SjGST-E26H was purified with a immobilized Ni affinity column.