Concurrent Encoding of Sequence Predictability and Event-Evoked Prediction Error in Unfolding Auditory Patterns.

Human listeners possess an innate capacity to discern patterns within rapidly unfolding sensory input. Core questions, guiding ongoing research, focus on the mechanisms through which these representations are acquired and whether the brain prioritizes or suppresses predictable sensory signals. Previous work, using fast auditory sequences (tone-pips presented at a rate of 20 Hz), revealed sustained response effects that appear to track the dynamic predictability of the sequence. Here, we extend the investigation to slower sequences (4 Hz), permitting the isolation of responses to individual tones. Stimuli were 50 ms tone-pips, ordered into random (RND) and regular (REG; a repeating pattern of 10 frequencies) sequences; Two timing profiles were created: in "fast" sequences, tone-pips were presented in direct succession (20 Hz); in "slow" sequences, tone-pips were separated by a 200 ms silent gap (4 Hz). Naive participants (N = 22; both sexes) passively listened to these sequences, while brain responses were recorded using magnetoencephalography (MEG). Results unveiled a heightened magnitude of sustained brain responses in REG when compared to RND patterns. This manifested from three tones after the onset of the pattern repetition, even in the context of slower sequences characterized by extended pattern durations (2,500 ms). This observation underscores the remarkable implicit sensitivity of the auditory brain to acoustic regularities. Importantly, brain responses evoked by single tones exhibited the opposite pattern-stronger responses to tones in RND than REG sequences. The demonstration of simultaneous but opposing sustained and evoked response effects reveals concurrent processes that shape the representation of unfolding auditory patterns.

Development and validation of prediction model for older adults with cognitive frailty.

OBJECTIVE: This study sought to develop and validate a 6-year risk prediction model in older adults with cognitive frailty (CF). METHODS: In the secondary analysis of Chinese Longitudinal Healthy Longevity Survey (CLHLS), participants from the 2011-2018 cohort were included to develop the prediction model. The CF was assessed by the Chinese version of Mini-Mental State Exam (CMMSE) and the modified Fried criteria. The stepwise regression was used to select predictors, and the logistic regression analysis was conducted to construct the model. The model was externally validated using the temporal validation method via the 2005-2011 cohort. The discrimination was measured by the area under the curve (AUC), and the calibration was measured by the calibration plot. A nomogram was conducted to vividly present the prediction model. RESULTS: The development dataset included 2420 participants aged 60 years or above, and 243 participants suffered from CF during a median follow-up period of 6.91 years (interquartile range 5.47-7.10 years). Six predictors, namely, age, sex, residence, body mass index (BMI), exercise, and physical disability, were finally used to develop the model. The model performed well with the AUC of 0.830 and 0.840 in the development and external validation datasets, respectively. CONCLUSION: The study could provide a practical tool to identify older adults with a high risk of CF early. Furthermore, targeting modifiable factors could prevent about half of the new-onset CF during a 6-year follow-up.

Detection of genomic variations and selection signatures in Wagyu using whole-genome sequencing data.

Wagyu is recognized for producing marbled beef with high nutritional value and flavor. Reportedly, Wagyu has been widely used to improve the meat quality of local breeds around the world. However, studies on the genetic mechanism of meat quality in Wagyu at the whole-genome level are rarely reported. Here, whole-genome sequencing data of 11 Wagyu and 115 other individuals were used to explore the genomic variations and genes under selection pressure in Wagyu. A total of 31 349 non-synonymous variants and 53 102 synonymous variants were identified in Wagyu. The population structure analysis showed that Wagyu had the closest genetic relationship with Mishima-Ushi cattle and was apparently separated from other cattle breeds. Then, composite likelihood ratio (CLR), integrated haplotype score, fixation index and cross-population composite likelihood ratio (XP-CLR) tests were performed to identify the candidate genes under positive selection in Wagyu. In total, 770 regions containing 312 genes were identified by at least three methods. Among them, 97 regions containing 27 genes were detected by all four methods. We specifically illustrate a list of interesting genes, including LRP2BP, GAA, CACNG6, CXADR, GPCPD1, KLF2, KLF13, SOX5, MYBPC1, SLC25A10, ATP8A1 and MYH15, which are associated with lipid metabolism, fat deposition, muscle development, bone development, feed intake and growth traits in Wagyu. This is the first study to explore the genomic variations and selection signatures of Wagyu at the whole-genome level. These results will provide significant help to beef cattle improvement and breeding.

Effects of choline deficiency and supplementation on lipid droplet accumulation in bovine primary liver cells in vitro.

Rumen-protected choline (RPC) supplementation in the periparturient period has in some instances prevented and alleviated fatty liver disease in dairy cows. Mechanistically, however, it is unclear how choline prevents the accumulation of lipid droplets (LD) in liver cells. In this study, primary liver cells isolated from liver tissue obtained via puncture biopsy from 3 nonpregnant mid-lactation multiparous Holstein cows (∼160 d postpartum) were used. Analyses of LD via oil red O staining, protein abundance via Western blotting, and phospholipid content and composition measured by thin-layer chromatography and HPLC/mass spectrometry were performed in liver cells cultured in choline-deficient medium containing 150 µmol/L linoleic acid for 24 h. In a subsequent experiment, lipophagy was assessed in liver cells cultured with 30, 60, or 90 µmol/L choline-chloride. All data were analyzed statistically using SPSS 20.0 via t-tests or one-way ANOVA. Compared with liver cells cultured in Dulbecco's Modified Eagle Medium alone, choline deficiency increased the average diameter of LD (1.59 vs. 2.10 µm), decreased the proportion of small LD (<2 µm) from 75.3% to 56.6%, and increased the proportion of large LD (>4 µm) from 5.6% to 15.0%. In addition, the speed of LD fusion was enhanced by the absence of choline. Among phospholipid species, the phosphatidylcholine (PC) content of liver cells decreased by 34.5%. Seventeen species of PC (PC [18:2_22:6], PC [15:0_16:1], PC [14:0_20:4], and so on) and 6 species of lysophosphatidylcholine (LPC; LPC [15:0/0:0]), PC (22:2/0:0), LPC (20:2/0:0), and so on] were decreased, while PC (14:1_16:1) and LPC (0:0/20:1) were increased. Choline deficiency increased the triglyceride (TAG) content (0.57 vs. 0.39 µmol/mg) in liver cells and increased the protein abundance of sterol regulatory element binding protein 1, sterol regulatory element binding protein cleavage activation protein, and fatty acid synthase by 23.5%, 17%, and 36.1%, respectively. Upon re-supplementation with choline, the phenotype of LD (TAG content, size, proportion, and phospholipid profile) was reversed, and the ratio of autophagy marker LC3II/LC3I protein was significantly upregulated in a dose-dependent manner. Overall, at least in vitro in mid-lactation cows, these data demonstrated that PC synthesis is necessary for normal LD formation, and both rely on choline availability. According to the limitation of the source of liver cells used, further work should be conducted to ascertain that these effects are applicable to liver cells from postpartum cows, the physiological stage where the use of RPC has been implemented for the prevention and treatment of fatty liver.

Correlates of stigma for poststroke patients: A meta-analysis.

AIMS: A meta-analysis was carried out to review and identify correlates of stigma in poststroke patients. BACKGROUND: Patients suffer from impaired physical functions and sequelae of stroke. Stroke-related stigma hinders the recovery process and produces poorer clinical outcomes of stroke, leading to compromised quality of life. DESIGN: A systematic review and meta-analysis was reported by following PRISMA 2020 guidelines. REVIEW METHODS: Nine databases were searched from their inception to May 2021 to identify studies focused on the relationships among demographics, disease-related factors, psychosocial factors and poststroke stigma. Included studies were assessed by using the Agency for Healthcare Research and Quality (AHRQ) scale. The statistical software R studios were used to perform statistical analysis. RESULTS: Nineteen studies were included in the meta-analysis. Four demographic factors (age, caregiver, residence, monthly income), seven stroke-related characteristics (type of stroke, mRS, ADLs, stroke duration, recurrence, sequelae, chronic disease comorbidity) and three psychosocial factors (depression, social support, quality of life) showed significant associations with stroke-related stigma. CONCLUSIONS: The results of our study can serve as a foundation for designing interventions to reduce stigma and improve the overall quality of life of poststroke patients and may produce positive clinical outcomes. Healthcare professionals should be aware of stroke patients who are characterised by correlates of stigma. Relevance to clinical practice Poststroke patients showed a moderate-to-high level of stigma, and this issue warrants more attention. This review provides a preliminary foundation for healthcare professionals to develop interventions to address stroke-related stigma by focusing on demographic, disease-related and psychosocial factors. Additionally, stigma identification should be a part of clinical nursing evaluation. The involvement of clinical and community nursing is very important to screen stroke-related stigma and pay attention to this population.

Size, number and phospholipid composition of milk fat globules are affected by dietary conjugated linoleic acid.

Milk fat globules (MFGs) surround the triacylglycerol core that composes milk fat. The aim of this study is to induce milk fat depression via dietary conjugated linoleic acid (CLA) supplementation to study MFG size parameters, number and glycerophospholipid composition. Eighteen Holstein dairy cows (136 ± 28 days in milk, 571 ± 37.9 kg body weight, 27.6 ± 2.1 kg milk/day) were selected and randomly assigned to a control or CLA group for a 14-day period. Cows were fed a basal diet (control, n = 8) or the control plus 400 g/day CLA (C18:2 cis-9, trans-11 38.1% and C18:2 trans-10, cis-12 36.8%) (n = 10) for 7 days after which the CLA group was switched to the basal diet for another 7 days along with the control group. Cow performance, milk composition, MFG size and numbers were measured daily. On the seventh day after the start of the experiment, milk samples were identified and the quantification of glycerophospholipid compounds, and RNA were isolated from milk fat samples for a real-time polymerase chain reaction. Compared with control, at Day 7 from the start of feeding, supplemental CLA did not affect milk production (28.09 vs. 28.50 kg/day), dry matter intake (14.9 vs. 15.4 kg/day), or milk protein (3.55/100 vs. 3.70 g/100 ml) and lactose contents (5.11/100 vs. 5.17 g/100 ml). However, although the specific surface area of MFG (2138 vs. 1815 m²/kg) was greater, CLA reduced milk fat content (1.95/100 vs 3.64 g/100 ml on Day 7) and particle size parameters of MFG. The number of MFG gradually decreased until Day 7 of feeding, and then increased by Day 14 (2.96 × 109 on Day 1, 1.63 × 109 on Day 7 and 2.28 × 109 on Day 14) in the CLA group. Compared with control, glycerophospholipid analysis revealed that concentrations of phosphatidylcholine (PC) (e.g., PC [16:0/18:1] 20322 vs. 29793 nmol/L), lysophosphatidylethanolamine (LPE) (e.g., LPE [18:1] 956 vs. 4610 nmol/L) and phosphatidylethanolamine (PE) (e.g., PE [16:0/18:1] 7000 vs. 9769 nmol/L) in milk lipids decreased during CLA feeding. In contrast, concentrations of phosphatidylinositol (PI) (e.g., PI [18:0/18:1] 4052 vs. 1799 nmol/L) and phosphatidylserine (PS) (e.g., PS [18:1/18:2] 9500 vs. 6843 nmol/L) increased. The messenger RNA abundance of fatty acid synthase, diacylglycerol O-acyltransferase 1, glycerol-3-phosphate acyltransferase 4 and phosphate cytidylyltransferase 1, choline, alpha (PCYT1A) were downregulated in the CLA group, confirming published data demonstrating a negative effect of CLA on lipogenesis in the mammary gland. Overall, these results provided evidence for the important role of lipogenic gene expression in the regulation of MFG size, number and glycerophospholipid composition.

Bone marrow mesenchymal stem cells combined with estrogen synergistically promote endometrial regeneration and reverse EMT via Wnt/ß-catenin signaling pathway.

BACKGROUND: Intrauterine adhesion (IUA) is a clinical disease characterized by the uterine cavity occlusion caused by the damage of the endometrial basal layer. Bone marrow mesenchymal stem cells (BMSCs) transplantation have the potential to promote endometrial regeneration mainly through paracrine ability. Estrogen is an indispensable and important factor in the repair of endometrial damage, which has been reported as a promising and adjunctive therapeutic application for stem cell transplantation therapy. This study aims to investigate the synergistic effect of BMSCs and estrogen on improving the endometrial regeneration and restoring the endometrium morphology in a dual damage model of IUA in rabbits and the underlying molecular mechanisms. METHODS: BMSCs were isolated and identified by adipogenic and osteogenic differentiation and flow cytometry assays. The rabbit IUA animal model was established by a dual damage method of mechanical curettage and lipopolysaccharide infection. Additionally, we investigated the therapeutic impact of both BMSCs and estrogen either separately or in combination in a rabbit model. The retention of PKH26-labeled BMSCs was observed by vivo fluorescence imaging.The number of endometrial glands and the degree of fibrosis were observed by H&E and Masson staining respectively. Western blotting, Immunohistochemistry and immunofluorescence staining were performed to detect biomarkers related to endometrial epithelium, endometrial fibrosis and EMT. Finally, the protein expression of core molecules of Wnt/ß-catenin pathway was detected by Western blotting. RESULTS: PKH26-labeled fluorescence results revealed that BMSCs appeared and located in the endometrial glands and extracellular matrix area when orthotopic transplanted into the uterine cavity. Histological assays showed that remarkably increasing the number of endometrial glands and decreasing the area of endometrial fibrosis in the BMSCs combined with estrogen treatment group. Moreover, downregulated expression of fibrosis markers (fibronectin, CollagenI, a-SMA) and interstitial markers (ZEB1, Vimentin, N-cadherin), as well as upregulated E-cadherin expression were found in the combined group. Further study of in vivo staining revealed that fluorescence intensity of CK7 was stronger in the combined group than that of direct BMSCs intrauterine transplantation, while vimentin showed the opposite results. Moreover, the protein levels of ß-catenin, Axin2, C-myc, CycinE of Wnt/ß-catenin signaling pathway increased in the BMSCs combined with estrogen group than in the other treatment groups. CONCLUSION: BMSCs combined with estrogen can promote the differentiation of stem cells into endometrial epithelial cells to facilitate the regeneration of damaged endometrium. The potential mechanism of the synergistic effect may inhibit the occurrence of EMT by activating the Wnt/ß-catenin signaling pathway.

Detection of selection signatures in South African Mutton Merino sheep using whole-genome sequencing data.

The South African Mutton Merino (SAMM), a dual-purpose (meat and wool) sheep breed, is characterized by its excellent performance on growth, carcass traits and meat quality compared to other fine-wool Merino breeds. Nowadays, the SAMM breed has been widely used to cross with commercial and indigenous fine-wool or coarse-wool breeds to improve the growth and meat performance in many countries. To date, however, little is known about the genetic basis for its prominent characteristics. In this study, whole-genome sequences of 10 SAMM were sequenced and the selection signatures were analyzed together with those of 39 Australian Merino and Chinese Merino (wool-type Merino) by FST , iHS, and XP-EHH methods. In total, 313 genes in 277 regions were identified by at least 2 methods with the signal of selection and 21 of them were identified by all three methods. We highlighted a list of interesting genes, including GHR, LCORL, SMO, NCAPG, DCC, IBSP, PPARGC1A, PACRGL, PRDM5, XYLB, AHCYL2, TEFM, AFG1L, and FAM184B, which have been shown to be involved in growth, carcass traits, and meat quality by previous studies. Herein, GHR, encoding a transmembrane receptor for growth hormone, is the most notable one. We report the first study on selection signatures analysis of SAMM at whole-genome sequence level. These results provide new insights into the genetic mechanisms underlying the growth and carcass traits in SAMM.

Milk fat globule membrane proteins are involved in controlling the size of milk fat globules during conjugated linoleic acid-induced milk fat depression.

Milk fat globule membrane (MFGM) proteins surround the triacylglycerol core comprising milk fat globules (MFG). We previously detected a decrease in the size of fat globules during conjugated linoleic acid (CLA)-induced milk fat depression (MFD), and other studies have reported that some MFGM proteins play a central role in regulating mammary cellular lipid droplet size. However, little is known about the relationship between MFD, MFG size, and MFGM proteins in bovine milk. The aim of this study was to investigate the profile of MFGM proteins during MFD induced by CLA. Sixteen mid-lactating Holstein cows (145 ± 24 d in milk) with similar body condition and parity were divided into control and CLA groups over a 10-d period. Cows were fed a basal diet (control, n = 8) or control plus 15 g/kg of dry matter (DM) CLA (n = 8) to induce MFD. Cow performance, milk composition, and MFG size were measured daily. On d 10, MFGM proteins were extracted and identified by quantitative proteomic analysis, and western blotting was used to verify a subset of the identified MFGM proteins. Compared with controls, supplemental CLA did not affect milk production, DM intake, or milk protein and lactose contents. However, CLA reduced milk fat content (3.73 g/100 mL vs. 2.47 g/100 mL) and the size parameters volume-related diameter D[4,3] (3.72 µm vs. 3.35 µm) and surface area-related diameter D[3,2] (3.13 µm vs. 2.80 µm), but increased specific surface area of MFG (1,905 m2/kg vs. 2,188 m2/kg). In total, 177 differentially expressed proteins were detected in milk from cows with CLA-induced MFD, 60 of which were upregulated and 117 downregulated. Correlation analysis showed that MFG size was negatively correlated with various proteins, including XDH and FABP3, and positively correlated with MFG-E8, RAB19, and APOA1. The results provide evidence for an important role of MFGM proteins in regulating MFG diameter, and they facilitate a mechanistic understanding of diet-induced MFD.

Dose-response relationship in non-pharmacological interventions for individuals with mild cognitive impairment: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Non-pharmacological interventions (NPIs) are important in cognitive decline prevention in individuals with mild cognitive impairment (MCI). However, the dose-response relationship remains unclear. DESIGN: Systematic review and meta-analysis of randomised controlled trials. METHODS: Seven databases were searched until April 2020. RCTs of NPIs in individuals with MCI were eligible for inclusion. Hedge's g was used to calculate the effect size. A random-effect meta-analysis was used to explore the impact of NPIs on cognition. Subgroup analysis was used to investigate the moderates. The dose was measured by prescription (frequency, intensity, type, time and volume) and intervention characteristics (period, energy expenditure, delivery mode and setting) in NPIs. RESULTS: Forty-two studies with 4401 participants were included. In the NPIs, cognitive intervention (g = 0.167), physical exercise (g = 0.536) and multicomponent intervention (g = 0.386) had significant effect on cognition in individuals with MCI. Dose-response results showed cognition could be significantly improved in 1-2 times/week (p < .05), 60-120 min/session (p < .05), ≥12 weeks (p < .05), supervised (p < .05), clinical setting (p < .05) in cognitive intervention. In physical exercise, cognition could be improved in ≥3 times/week (p < .05), vigorous-intensity (p < .05), muscle-strengthening activity (p < .05), 30-60 min/session (p < .05), 6-12 weeks (p < .05), unsupervised (p < .05), community setting (p < .05). In the multicomponent intervention, cognition could be improved in 1-2 times/week (p < .05), 30-60 min/session (p < .05), 8-16 weeks (p < .05), clinical (p < .05). In nutrition intervention, cognition could be better improved DHA (p < .05), >1000 mg/day (p < .05). CONCLUSIONS: The effectiveness of cognitive intervention is significantly influenced by frequency, time, period, delivery mode and setting. The effectiveness of physical exercise is significantly influenced by frequency, intensity, type, time, period, delivery mode and setting. The effectiveness of multicomponent intervention is significantly influenced by frequency, time, period and setting. The effectiveness of nutrition intervention is significantly influenced by dose and type. RELEVANCE TO CLINICAL PRACTICE: The research summarised the evidence to guide the best prescription of NPIs and helped clinicians design more effective interventions in individuals with MCI.

Loss of Heterozygosity for KrasG12D Promotes Malignant Phenotype of Pancreatic Ductal Adenocarcinoma by Activating HIF-2α-c-Myc-Regulated Glutamine Metabolism.

Loss of heterozygosity (LOH) for KRAS, in which a wild-type KRAS allele is progressively lost, promotes invasive and migratory abilities of pancreatic ductal adenocarcinoma (PDAC) cells and tissues. Moreover, the occurrence of KrasG12D-LOH activates nonclassical glutamine metabolism, which is related to the malignant behavior of PDAC cells. Herein, we aim to demonstrate the regulatory link between hypoxia-inducible factor-2α (HIF-2α) and glutamine metabolism that mediates malignant phenotypes in KrasG12D-LOH PDAC cells. HIF-2α-shRNA knockdown lentivirus transfection and metabolite analysis were performed in KrasG12D-LOH and KrasG12D cell lines, respectively. Cell proliferation, migration, and invasion were examined using Cell Counting Kit-8, colony formation, and Transwell assays. Cell cycle phase and apoptosis were determined using flow cytometry. Western blotting and real-time quantitative PCR were also performed. Additionally, a subcutaneous xenograft mouse model was established. LOH stimulated HIF-2α activity and transactivated c-Myc, which has a central regulatory effect on glutamine metabolism independent of hypoxia. Meanwhile, HIF-2α silencing repressed KrasG12D-LOH PDAC cell proliferation, invasion, and migration. HIF-2α knockdown inhibited glutamine uptake and GOT1 expression via a c-Myc-dependent pathway. Collectively, KrasG12D-LOH can activate HIF-2α to regulate c-Myc-mediated glutamine metabolism and promote malignant phenotypes. Moreover, targeting HIF-2α-c-Myc regulated nonclassical glutamine metabolism, providing a new therapeutic perspective for KrasG12D-LOH PDAC.

A Risk Prediction Model Based on Machine Learning for Cognitive Impairment Among Chinese Community-Dwelling Elderly People With Normal Cognition: Development and Validation Study.

BACKGROUND: Identifying cognitive impairment early enough could support timely intervention that may hinder or delay the trajectory of cognitive impairment, thus increasing the chances for successful cognitive aging. OBJECTIVE: We aimed to build a prediction model based on machine learning for cognitive impairment among Chinese community-dwelling elderly people with normal cognition. METHODS: A prospective cohort of 6718 older people from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) register, followed between 2008 and 2011, was used to develop and validate the prediction model. Participants were included if they were aged 60 years or above, were community-dwelling elderly people, and had a cognitive Mini-Mental State Examination (MMSE) score ≥18. They were excluded if they were diagnosed with a severe disease (eg, cancer and dementia) or were living in institutions. Cognitive impairment was identified using the Chinese version of the MMSE. Several machine learning algorithms (random forest, XGBoost, naïve Bayes, and logistic regression) were used to assess the 3-year risk of developing cognitive impairment. Optimal cutoffs and adjusted parameters were explored in validation data, and the model was further evaluated in test data. A nomogram was established to vividly present the prediction model. RESULTS: The mean age of the participants was 80.4 years (SD 10.3 years), and 50.85% (3416/6718) were female. During a 3-year follow-up, 991 (14.8%) participants were identified with cognitive impairment. Among 45 features, the following four features were finally selected to develop the model: age, instrumental activities of daily living, marital status, and baseline cognitive function. The concordance index of the model constructed by logistic regression was 0.814 (95% CI 0.781-0.846). Older people with normal cognitive functioning having a nomogram score of less than 170 were considered to have a low 3-year risk of cognitive impairment, and those with a score of 170 or greater were considered to have a high 3-year risk of cognitive impairment. CONCLUSIONS: This simple and feasible cognitive impairment prediction model could identify community-dwelling elderly people at the greatest 3-year risk for cognitive impairment, which could help community nurses in the early identification of dementia.

CircRHOT1 mediated cell proliferation, apoptosis and invasion of pancreatic cancer cells by sponging miR-125a-3p.

Pancreatic cancer patients are asymptomatic at early stages and leading to late diagnoses. Additionally, pancreatic cancer easily metastasizes and is resistant to radiotherapy and chemotherapy. Therefore, it is critical to understand the underlying molecular mechanisms involved in pancreatic cancer to develop more efficient diagnostic and treatment strategies. In this study, we demonstrated that circRHOT1 was overexpressed in pancreatic cancer tissues and cell lines, and it was found to directly bind to miR-125a-3p, acting as an endogenous sponge to inhibit its activity. Knockdown of circRHOT1 expression significantly inhibited proliferation as well as invasion, and it promoted apoptosis of pancreatic cancer cells via the regulation of E2F3 through the targeting of miR-125a-3p. Taken together, our results showed that circRHOT1 plays critical roles in regulating the biological functions of pancreatic cancer cells, suggesting that circRHOT1 may serve as a potential diagnostic marker and therapeutic target for patients with pancreatic cancer.

Loss of heterozygosity for KrasG12D promotes REDD1-dependent, non-canonical glutamine metabolism in pancreatic ductal adenocarcinoma.

Pancreatic cancer is associated with high mortality, and pancreatic ductal adenocarcinoma (PDAC) is its most common subtype. The rapid growth of PDAC is dependent on the non-canonical pathway of glutamine (Gln) utilization, and loss of heterozygosity for KrasG12D (KrasG12D-LOH) frequently observed in PDAC is associated with an aggressive and invasive phenotype. However, it remains unclear whether KrasG12D-LOH contributes to non-canonical Gln metabolism in PDAC. Here, we showed that KrasG12D-LOH leads to a substantial increase in non-canonical Gln metabolism in PDAC cells. Importantly, we observed elevated expression of regulated in DNA damage and development 1 (REDD1), which is activated in response to hypoxia and nutrient deprivation, in KrasG12D-LOH PDAC, and that REDD1 knockdown efficiently repressed KrasG12D-LOH-regulated Gln metabolism and suppressed proliferation, migration, and invasion of KrasG12D-LOH PDAC cells. These data provide evidence that REDD1 is a downstream target of KrasG12D-LOH and is involved in promoting non-canonical Gln metabolism in PDAC.

Sleep Quality and Health-Related Quality of Life in Older People With Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer Disease.

We aimed to investigate sleep quality and health-related quality of life (HRQOL) in older adults with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer disease (AD). A total of 221 participants were divided into the following five groups: normal controls (NCs), SCD without memory concerns (SCD-0), SCD with memory concerns (SCD-1), MCI, and AD according to their cognitive status. Compared with NC, individuals with SCD-0, SCD-1, MCI, and AD had more sleep problems and reduced HRQOL. Participants with poor sleep quality had an increased risk of cognitive impairment compared with participants with good sleep quality. Within all five subgroups, individuals with poor sleep quality reported more difficulties in HRQOL than individuals with good sleep quality. Future studies employing a longitudinal design, larger samples, and objective evaluation tools are needed.

Evaluation of quality improvement intervention with nurse training in nursing homes: A systematic review.

INTRODUCTION: Quality improvement may be a promising approach to improve the quality of care in nursing homes, and nurse training is a key step in a successful quality improvement practice. The implementation of training measures may be related to the quality of quality improvement practice. Little is known about the quality of quality improvement practice or effective nurse training measures that affect the quality of quality improvement interventions in nursing homes. AIMS: The aim of this review was to assess the quality of available quality improvement intervention designs and present effective nurse training measures that contribute to a high-quality quality improvement intervention. METHODS: We searched the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medline, Embase and the Cochrane Library for articles published before March 2019. quality improvement intervention quality was evaluated using a standardised assessment tool. Descriptive synthesis was used for the analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Checklist was used for transparency. RESULTS: We included 12 articles, 1 was rated as perfect quality and 7 good quality. Out of these 8 studies, 3 features primarily reflected differences in quality: compliance, sustainability and replication ability of the interventions. They were affected by measures included provision of advanced training, available training resources, feedback process, building quality improvement teams, setting up mentors and nursing leadership training. Other recommended measures included external cooperation and leadership empowerment. CONCLUSION: A high-quality quality improvement intervention should consider how to improve compliance, sustainability and replication ability. Adapting measures that are compatible with nurse training may ensure a successful implementation of quality improvement programmes that are conducive to the effective improvement of service quality. RELEVANCE TO CLINICAL PRACTICE: Quality improvement programmes should take into account measures that are compatible with nursing staff training. These measures should help improve the quality of interventions and promote care service of nursing homes.

Nursing home staff experiences of implementing mentorship programmes: A systematic review and qualitative meta-synthesis.

AIM: To determine nursing home staff experiences in mentorship programmes, and staff perceptions of the enablers and barriers to implement mentorship programmes. BACKGROUND: Mentorship programmes are perceived as playing an important role in improving the quality of care in nursing homes. However, little is known about research evidence across the global about staff's experiences in the programmes. METHODS: A search for studies published from the earliest available date to April 2019 was undertaken. Two reviewers performed data extraction and an appraisal of eight studies using tools from the Joanna Briggs Institute. A pragmatic meta-aggregative approach was applied to synthesise the findings. The qualitative research that was included was analysed to identify 63 findings that were organised into 12 categories and combined into three syntheses. RESULTS: The implementation of effective mentorship programmes is influenced by three factors: mentor capability, opportunity in the mentorship programmes, and motivation in the mentorship programmes. CONCLUSIONS: There are a number of studies of nursing home staff experiences of mentorship programmes. However, systematic reviews that synthesise findings in this field are lacking. It is crucial to tailor the programme design to suit each unique nursing home care setting. We identified barriers and enablers, and learned that no barriers are insurmountable. IMPLICATIONS FOR NURSING MANAGEMENT: Findings will inform nurse managers of an ideal environment for the implementation of a successful mentorship programme. Nursing homes need to establish and sustain mentorship programmes to help improve workforce capacity in delivering high-quality care for residents.

Multi-angles of smoking and mild cognitive impairment: is the association mediated by sleep duration?

Although the association between cigarette smoking and risk of mild cognitive impairment (MCI) is controversial, most recent studies have shown that this influence is negative. However, it is unknown how multiple factors of smoking affect MCI, and the mechanisms of different smoking factors are not yet clarified. This study will examine the impact of various angles of smoking on MCI and the potential mediating effects of sleep duration on smoking MCI association in the elderly. In the case group, 109 elderly people who met the inclusion criteria were selected, and 123 were selected in the control group. Participant characteristics include sleep duration and a detailed lifetime history of smoking. After adjusting the relevant covariates, higher odds of MCI occurrence were found in ex-smokers/current smokers; moderate/heavy smokers; smokers for 30-44, 45-59 and more than 60 years; smokers with cumulative smoking duration of 30-44 or more than 60 years and smokers with cumulative dose smoking intensity of 200-399 or 400-599 cigarettes monthly. Elderly subjects who had quit smoking for 21 years or longer were found to have lower odds of MCI occurrence. The indirect effects of smoking on MCI via sleep duration were statistically significant, as the ratio of indirect effect to total effect ranged from 0.14 to 0.29. Smoking affects cognitive function through multi-angles of smoking and influences the cognitive function partly via the duration of sleep.

Web-Based Interventions to Improve Mental Health in Home Caregivers of People With Dementia: Meta-Analysis.

BACKGROUND: Dementia is a major cause of disability and dependency in older adults worldwide. It is often accompanied by general psychological distress, such as depression and anxiety symptoms, among caregivers of people with dementia (PwD). The physical and mental health of the caregiver is a prerequisite and a promise to help PwD continue to live as long and as well as possible. Web-based interventions can provide convenient and efficient support and an education tool to potentially reduce the negative outcomes associated with providing care. OBJECTIVE: The aim of this study was to examine the effect of internet-based interventions on the mental health outcomes of family caregivers of PwD and to explore which components of the Web-based interventions play an important role. METHODS: A comprehensive literature search was conducted in PubMed, Excerpta Medica dataBASE, PsycINFO, Cochrane Database, and the Cumulative Index to Nursing and Allied Health Literature using relevant terms such as Web-based and caregiver as keywords, covering all studies published before June 2018. A total of 2 reviewers independently reviewed all published abstracts, according to established inclusion and exclusion criteria. We extracted information about the participants, interventions, and results and reviewed article quality in terms of the randomized trial methods, using the approach recommended by the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: A total of 815 caregivers participated in 6 studies, with 4 of the studies using depression as an outcome. The analysis found that depression scores dropped an average of 0.23 (95% CI -0.38 to -0.07; P<.01) after Web-based interventions. In 2 studies of caregivers who were experiencing anxiety symptoms, the average score for anxiety dropped by 0.32 points (95% CI -0.50 to -0.14; P<.01). However, in terms of coping, pain, and stress, the Web-based interventions showed a poor effect. On the whole, the addition of professional psychological support on the basis of education can improve caregivers' mental health. CONCLUSIONS: Internet-based interventions were generally effective at reducing anxiety and depression in dementia caregivers, although negative results were found in some studies. As for burden and stress, further research is required.