bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Expression Analysis Reveals Age and Ethnicity Signatures Between Young and Old Adults in Human PBMC
Authors: Hu Yang , Xu Yudai , Mao Lipeng , Lei Wen , Xiang Jan Jian , Zhu Guodong , Hu Yutian , Niu Haitao , Gao Feng , Gao Lijuan , Huang Li`an , Luo Oscar Junhong , Duan Jinhai , Chen Guobing 
Published: August 2021

Abstract
Background: Human immune system functions over an entire lifetime, yet how and why the immune system becomes less effective with age are not well understood. Therefore, the aim of this study is to exploit a large-scale population-based strategy to systematically identify genes and pathways differentially expressed as a function of chronological age. Despite the importance of age and race in shaping immune cell numbers and functions, it is unclear whether Asian and Caucasian immune systems go through similar gene expression changes throughout their lifespan, and to what extent these aging-associated variations are shared among ethnicities. Results: Here, we characterize peripheral blood mononuclear cells transcriptome from 19 healthy adults of RNA-seq data and 153 healthy subjects of micoarray data with 21~90 years of age using the weighted gene correlation network analyses (WGCNA). These data reveal a set of insightful gene expression modules and representative gene biomarkers for human immune system aging from Asian and Caucasian ancestry, respectively. Among them, the aging-specific modules may show an age-related gene expression variation spike around early-seventies. In addition, we find the top hub genes including NUDT7, CLPB, OXNAD1 and MLLT3 are shared between Asian and Caucasian aging related modules and further validated in human PBMCs from different age groups. Conclusion: Overall, our findings reveal how age and race differentially affect the immune systems between Asian and Caucasian, as well as discovered a common genetic variant that greatly impacts normal PBMC aging between Asian and Caucasian.
Parietal-Hippocampal rTMS Improves Cognitive Function in Alzheimer's Disease by Inducing Increased Dynamic Functional Connectivity of Default Mode Network
Authors: Wei Lili , Zhang Yingchun , Wang Jintao , Xu Luoyi , Yang Kehua , Lv Xinghui , Zhu Zhenwei , Gong Qian , Hu Weiming , Li Xia , Qian Mincai , Shen Yuedi , Chen Wei 
Published: August 2021

Abstract
Background

Alzheimer’s disease, a neurodegenerative disease with significant social and economic impact, is mainly treated by focusing on decelerating cognition decline. Parietal-hippocampal repetitive transcranial magnetic stimulation (rTMS) improves memory and cognitive function in Alzheimer’s disease, however, the underlying therapeutic mechanism has not been elucidated.
Methods

A double-blind, randomized, sham-controlled parietal-hippocampal rTMS trial of mild-to-moderate Alzheimer's disease patients was conducted in the current study. High-frequency rTMS was applied to a subject-specific left lateral parietal region with the highest functional connectivity with the hippocampus based on resting-state fMRI. Patients were randomized to either rTMS or sham treatment (five sessions/week for a total of 10 sessions). A multimodal MRI scan and a complete neuropsychological battery of tests were conducted at baseline, immediately after the intervention and 12-week follow-up after the rTMS treatment. Primary outcomes were differences in the Mini Mental State Examination (MMSE) and Philadelphia Verbal Learning Test (PVLT) scores between the groups and between pre- and post-treatment. Moreover, flexible least squares (FLS) method was used to calculate the dynamic functional connectivity (dFC) of the default mode network (DMN), and dFC changes were compared between the groups and between pre- and post-treatment.
Results

Patients undergoing active rTMS treatment (n = 31) for two weeks showed higher MMSE, PVLT-Immediate recall, and PVLT-Short Delay recall scores, whereas those who underwent sham rTMS (n = 27) treatment did not show significant changes in these measures. Dynamic functional connectivity (dFC) magnitude of the default mode network (DMN) was significantly higher after two weeks of rTMS treatment in the patients who underwent active-rTMS treatment, however, no significant changes were observed in patients who received sham-rTMS treatment. dFC magnitude reduced to baseline level at 12-week follow-up, which resembled the trajectory of the cognitive measures. A significant positive correlation was observed between changes in MMSE and changes in the dFC magnitude of DMN in patients who underwent active-rTMS treatment, but not in those who received sham-rTMS treatment.
Conclusions

The findings of the current study indicate that fMRI-guided rTMS treatment improves memory and cognitive function of Alzheimer's disease patients. In addition, the findings indicate that the DMN functional connectivity contributes to therapeutic effectiveness of rTMS.
Trial registration:
China National Medical Research Platform (http://114.255.48.20/login, No:MR-33-20-004217), retrospectively registered 2020-12-23.
APOE Genetics Influence Murine Gut Microbiome
Authors: Zajac Diana J. , Green Stefan J. , Johnson Lance A. , Estus Steven 
Published: August 2021

Abstract
Background: Apolipoprotein E (APOE) alleles impact pathogenesis and risk for multiple human diseases, making them primary targets for disease treatment and prevention. Previously, we and others reported an association between APOE alleles and the gut microbiome. Here, we tested whether these results are confirmed by using mice that were maintained under ideal conditions for microbiome analyses. Methods: To model human APOE alleles, this study used APOE targeted replacement (TR) mice on a C57Bl/6 background. To minimize genetic drift, APOE3 mice were crossed to APOE2 or APOE4 mice prior to the study, and the resulting heterozygous progeny crossed further to generate the study mice. To maximize environmental homogeneity, mice with mixed genotypes were housed together and used bedding from the cages was mixed and added back as a portion of new bedding. Fecal samples were obtained from mice at three-, five- and seven-months of age, and microbiota analyzed by 16S ribosomal RNA gene amplicon sequencing. APOE2/E2 and APOE2/E3 mice were categorized as APOE2, APOE3/E4 and APOE4/E4 mice were categorized as APOE4, and APOE3/E3 mice were categorized as APOE3. Linear discriminant analysis of Effect Size (LefSe) identified taxa associated with APOE status, depicted as cladograms to show phylogenetic relatedness. The influence of APOE status was tested onalpha-diversity (Shannon H index) and beta-diversity (principal coordinate analyses and PERMANOVA). Individual taxa associated with APOE status were identified by classical univariate analysis. Whether findings in the APOE mice were replicated in humans was evaluated by using published microbiome genome wide association data. Results: Cladograms revealed robust differences with APOE in male mice and limited differences in female mice. The richness and evenness (alpha-diversity) and microbial community composition (beta-diversity) of the fecal microbiome was robustly associated with APOE status in male but not female mice. Classical univariate analysis revealed individual taxa that were significantly increased or decreased with APOE, illustrating a stepwise APOE2-APOE3-APOE4 pattern of association. The Clostridia class, Clostridiales order, Ruminococacceae family and related genera increased with APOE2 status. The Erysipelotrichia phylogenetic branch increased with APOE4 status, a finding that extended to humans.Conclusions: In this study wherein mice were maintained in an ideal fashion for microbiome studies, gut microbiome profiles were strongly and significantly associated with APOE status in male APOE-TR mice. Erysipelotrichia in particular appears to increase with APOE4 in both mice and humans. Further evaluation of these findings in humans, as well as studies evaluating the impact of the APOE-associated microbiota on disease-relevant phenotypes, will be necessary to determine if alterations in the gut microbiome represents a novel mechanism whereby APOE alleles impact disease.
Increased Fasting Serum Level of Arsenic Caused by Intake of Fish Meat Promotes a Potential Risk of Hypertension
Authors: He Tingchao , Ohgami Nobutaka , Ohnuma Shoko , Naito Hisao , Yajima Ichiro , Tazaki Akira , Tamura Takashi , Kondo Takaaki , Wakai Kenji , Kato Masashi 
Published: August 2021

Abstract
Despite identification of arsenic intake from well drinking water in developing countries as a crucial hazard for health, the health effects of diet-mediated intake of arsenic on health in developed countries have remained unclear. The Japanese diet, which is regarded as a healthy diet, includes a high intake of seafoods that contain high levels of arsenic. The associations among intake of Japanese food including 54 food items classified into 6 categories, arsenic exposure and hypertension were investigated in 2,709 adults in Japan. Logistic regression analysis including serum sodium and potassium levels as confounders indicated a positive association between fasting serum level of arsenic (fsl-As) and prevalence of hypertension. Seaweed, bone-edible small fish and fish meat in seafoods were strong contributors to the increased fsl-As among the food items examined. Fish meat intake was identified as the greatest contributor to prevalence of hypertension. Since 94% of arsenic has been reported to be caused by dietary intake in Japan, our results suggest that increased fsl-As caused by intake of fish meat could be a potential risk for hypertension. Considering the worldwide trend of increased fish meat intake, arsenic in fish meat might be a new global hazardous material.
The Role of Indian Ocean Warming on Extreme Rainfall in Central China During Early Summer 2020: Without El Niño Influence
Authors: Cai Yinan , Chen Zesheng , Du Yan 
Published: August 2021

Abstract
This study investigates the role of water vapor transport and sea surface temperature (SST) warming in the tropical Indian Ocean (TIO) on the heavy rainfall in central China during boreal early summer. In the past four decades, four significant rainfall events, in 1983, 1998, 2016, and 2020, occured in central China and caused severe floods, in which the year 2020 has the most extreme event. All four events are associated with significant TIO SST warming, associated with a strong and westward extending anomalous anticyclone on the western North Pacific (WNPAC). The anomalous winds in the northwestern flank of the WNPAC bring excess water vapor into central China. The water vapor, mainly carried from the central tropical Pacific, converges in central China and result in heavy rainfall. A theory of regional ocean-atmosphere interaction can well explain the processes, called the Indo-Western Pacific Ocean Capacitor (IPOC) effect. The WNPAC is usually associated with strong El Niño-Southern Oscillation (ENSO), except for the 2020 case. The 2020 event is extraordinary, without ensuring El Niño occurred in the previous winter. In 2020, the significant TIO warming sustained the anomalous WNPAC, inducing the most significant extreme rainfall event in central China. This study reveals that the IPOC effect can dramatically influence the East Asian climate even without involving the ENSO in the Pacific.
Variability of α/β Ratios for Prostate Cancer With the Fractionation Schedule: Caution Against Using the Linear-Quadratic Model for Hypofractionated Radiotherapy
Authors: Cui Ming , Gao Xianshu , Li Xiaoying , Ma Mingwei , Qi Xin , Shibamoto Yuta 
Published: August 2021

Abstract
Background: Prostate cancer (PCa) is known to be suitable for hypofractionated radiotherapy due to the very low α/β ratio (about 1.5-3 Gy). However, several randomized controlled trials have not shown the superiority of hypofractionated radiotherapy over conventionally fractionated radiotherapy. Besides, in vivo and in vitro experimental results show that the linear-quadratic (LQ) model may not be appropriate for hypofractionated radiotherapy, and we guess it may be due to the influence of fractionation schedules on the α/β ratio. Therefore, this study attempted to estimate the α/β ratio in different fractionation schedules and evaluate the applicability of the LQ model in hypofractionated radiotherapy. Methods: The maximum likelihood principle in mathematical statistics was used to fit the parameters: k, α and β values in the tumor control probability (TCP) formula derived from the LQ model. In addition, the fitting results were substituted into the original TCP formula to calculate 5-year biochemical relapse-free survival for further verification.Results: Information necessary for fitting could be extracted from a total of 23,281 PCa patients. A total of 16,442 PCa patients were grouped according to fractionation schedules. We found that, for patients who received conventionally fractionated radiotherapy, moderately hypofractionated radiotherapy, and stereotactic body radiotherapy, the average α/β ratios were 1.78 Gy (95% CI: 1.59-1.98, P < 0.001), 3.46 Gy (95% CI: 3.08-3.83, P < 0.001), and 4.24 Gy (95% CI: 4.10-4.39, P < 0.001), respectively. Hence, the calculated α/β ratios for PCa tended to become higher when the dose per fraction increased. Among all PCa patients, 14,641 could be grouped according to the risks of PCa in patients receiving radiotherapy with different fractionation schedules. The results showed that as the risk increased, the k and α values decreased, indicating that the number of effective target cells decreased and the radioresistance increased.Conclusions: The LQ model appeared to be inappropriate for high doses per fraction owing to α/β ratios tending to become higher when the dose per fraction increased. Therefore, to convert the conventionally fractionated radiation doses to equivalent high doses per fraction using the standard LQ model, a higher α/β ratio should be used for calculation.
Magnetic-resonance-guided Radiation Therapy With Simultaneous Integrated Boost at Mid-bladder Volume for Bladder Cancer
Authors: Petsuksiri Janjira , Sathitwatthanawirot Chanida , Puangragsa Utumporn , Phongprapun Wisawa , Dankulchai Pittaya , Apiwarodom Nantakan 
Published: August 2021

Abstract
Background and Purpose: To report the workflow and dose accumulation for bladder preservation for a bladder cancer patient, using magnetic-resonance-guided radiation therapy (MRgRT) and the simultaneous integrated boost (SIB) technique at mid-bladder volume.Materials and Methods: A muscle-invasive bladder cancer patient was treated with MRgRT. The patient was treated with the SIB technique at mid-bladder volume, with 45 Gy to the whole bladder (CTV WB) and 55 Gy to the tumor bed (CTV boost) in 20 fractions. Daily re-optimization with an adapt-to-position (ATP) strategy was utilized for dose adjustment to encompass the bladder within anisotropic planning target volume (PTV WB and PTV boost). Results: The mean daily treatment time was 55 minutes (range, 35–73). The actual whole-bladder and tumor-bed-boost doses were 45.74 ± 5.91 and 54.1 ± 4.62 Gy, respectively. PTV WB encompassing CTV WB was 95.69% ± 5.36%. PTV boost encompassing CTV boost was 97.52% ± 6.05%. The actual rectal and bowel doses were below the reference plan doses.Conclusions: The use of MRgRT with the SIB and ATP strategy proved feasible for bladder cancer treatment. Mid-bladder volume allowed treatment with the SIB technique under MR monitoring.
The Prognostic Value of Cardiac Biomarkers and Echocardiography in Critical COVID-19
Authors: Zwaenepoel Bert , Dhont Sebastiaan , Hoste Eric , Gevaert Sofie , Schaubroeck Hannah 
Published: August 2021

Abstract
Background Early risk stratification is crucial in critically ill COVID-19 patients. Myocardial injury is associated with worse outcome. This study aimed to evaluate cardiac biomarkers and echocardiographic findings in critically ill COVID-19 patients and to assess their association with 30-day mortality in comparison to other biomarkers, risk factors and clinical severity scores.Methods Prospective, single-center, cohort study in patients with PCR-confirmed, critical COVID-19. Laboratory assessment included high sensitive troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) on admission to ICU: a hs-cTnT ≥ 14 pg/mL and a NT-proBNP ≥ 450 pg/mL were considered as elevated. Transthoracic echocardiographic evaluation was performed within the first 48 hours of ICU admission. The primary outcome was 30-day all-cause mortality. Predictive markers for mortality were assessed by ROC analysis and cut-off values by the Youden Index.Results A total of 100 patients were included. The median age was 63.5 years, the population was predominantly male (66%). At the time of ICU admission, 47% of patients had elevated hs-cTnT and 39% had elevated NT-proBNP. Left ventricular ejection fraction was below 50% in 19.1%. Elevated cardiac biomarkers (hs-cTnT P-value < 0.001, NT-proBNP P-value = 0.001) and impaired left ventricular function (P-value 0.011) were significantly associated with mortality, while other biomarkers (D-dimers, ferritin, C-reactive protein) and clinical scores (SOFA) did not differ significantly between survivors and non-survivors. An optimal cut-off value to predict increased risk for 30-day all-cause mortality was 16.5 pg/mL for hs-cTnT (OR 8.5, 95% CI: 2.9, 25.0) and 415.5 pg/ml for NT-proBNP (OR 5.1, 95% CI: 1.8, 14.7).Conclusion Myocardial injury in COVID-19 is common. Early detection of elevated hs-cTnT and NT-proBNP are predictive for 30-day mortality in patients with critical COVID-19. These markers outperform other routinely used biomarkers, as well as clinical indices of disease severity in ICU. The additive value of routine transthoracic echocardiography is disputable and should only be considered if it is likely to impact therapeutic management.
m⁶A Demethylase ALKBH5 Promotes Tumor Cell Proliferation by Destabilizing IGF2BPs Target Genes and Worsens the Prognosis of Patients with Non-Small Cell Lung Cancer
Authors: Tsuchiya Kazuo , Yoshimura Katsuhiro , Iwashita Yuji , Inoue Yusuke , Ohta Tsutomu , Watanabe Hirofumi , Yamada Hidetaka , Kawase Akikazu , Tanahashi Masayuki , Ogawa Hiroshi , Funai Kazuhito , Shinmura Kazuya , Suda Takafumi , Sugimura Haruhiko 
Published: August 2021

Abstract
Background: The modification of N6-methyladenosine (m6A) in RNA and its eraser ALKBH5, an m6A demethylase, play important roles across various steps of human carcinogenesis. However, the involvement of ALKBH5 in non-smallcell lung cancer (NSCLC) development remains to be completely elucidated.Methods: The current study investigated the involvement of ALKBH5 in NSCLC development using immunostaining of clinical NSCLC specimens as well as cancer-related cellular functions (cell proliferation, migration ability, cell cycle, and apoptosis) in ALKBH5-knockdown lung cancer cell lines. Moreover, a microarray was utilized to comprehensively analyze mRNA and m6A in ALKBH5-knockdown cells. m6A target genes were identified using the methylated RNA immunoprecipitation (MeRIP) assay with m6A antibody. Furthermore, mRNA stability and protein expression owing to m6A modification (the target genes) were examined.Results: Clinicopathological analysis revealed that increased ALKBH5 expression was an independent prognostic factor associated with unfavorable overall survival in NSCLC (hazard ratios, 1.468; 95% confidence interval, 1.039–2.073). In vitro study revealed that ALKBH5 knockdown suppressed cell proliferation ability of PC9 and A549 cells as well as promoted G1 arrest and increased the number of apoptotic cells. Furthermore, ALKBH5 overexpression increased the cell proliferation ability of the immortalized cell lines BEAS2B and HEK293. Comprehensive analysis of microarray and MeRIP quantitative-polymerase chain reaction revealed that 3′ untranslated regions (3′ UTRs) of CDKN1A, TIMP3, E2F1, and CCNG2 mRNA were potential targets of ALKBH5. Depending on the lung cancer cell lines, increased expression of CDKN1A or TIMP3 and decreased cell proliferation were observed by ALKBH5 knockdown.These alterations were offset by a double knockdown of both ALKBH5 and one of the IGF2BPs. The decline of mRNAs was, at least partly, owing to the destabilization of these mRNAs by one of the IGF2BPs.Conclusions:Upregulation of ALKBH5 in NSCLC reduces m6A modifications on the 3′ UTR of specific genes. Loss of m6A causes a decrease in opportunity for recognition by IGF2BPs and destabilizes the target transcript, such as CDKN1A (p21) and TIMP3. Downregulation of CDKN1A (p21) and TIMP3 induces cell cycle alteration and inhibits apoptosis. The ALKBH5–IGF2BPs axis promotes cell proliferation and tumorigenicity, which in turn causes the unfavorable prognosis of NSCLC.
Effects of Acupuncture for Anorexia and Dietary Intake Loss in Cachexia Patients With Advanced Respiratory Illness (Pilot Study)
Authors: Maekura Tomonori , Maekura Ryoji , Miki Keisuke , Miki Mari , Kitada Seigo 
Published: August 2021

Abstract
Background: Weight loss and low body mass index with cachexia are serious and refractory clinical conditions in patients with advanced chronic respiratory disease. This pilot study aimed to determine whether acupuncture improves dietary intake through increased appetite stimulation, and nutritional biomarkers, in cachectic patients with advanced respiratory illness.Methods: This study used a single-arm, open experimental design, and was conducted among hospitalized patients whose dietary intake was extremely decreased due to poor appetite. Food intake, and biomarkers were evaluated before and after acupuncture (3 times a week for 3 weeks). Results: Ten patients (age: 70.5 years [interquartile range (IQR): 68.7–75.8 years], 50% females) completed the acupuncture treatment. Significant improvements in appetite loss (visual analog scale [VAS]: 58.6 mm [42–83 mm] to 37.2 mm [19.5–50.8 mm], p = 0.0039), amount of food intake (1461 Kcal/day [1204–1620 Kcal/day] to 1696 Kcal/day [1443–2047 Kcal/day], p = 0.0039), and serum nutritional biomarker (albumin: 3.3 g/dL [3–3.8 g/dL] to 3.5 [3.3–3.7 g/dL], p = 0.0293; pre-albumin: 14.4 mg/dL [10–19.5 mg/dL] to 16.7 mg/dL [11.1–21.6 mg/dL], p = 0.0137) were observed after acupuncture. Body weight loss (0 kg [-1.4 to 1.75 kg], p = 0.0078, 0% [-3.25% to 4.7%], p = 0.0078) 6 months after acupuncture was significantly improved versus 6 months before acupuncture (-3.8 kg [-6.4 to -0.3 kg], -5.2% [-11.8% to -0.83%]). Conclusions: Short-term acupuncture may be a novel and safe treatment for improving the appetite and nutritional status of cachectic patients with advanced chronic respiratory illness. Trial registration: UMIN000044859; Date of registration: July 14, 2021-Retrospectively registered; https://www.umin.ac.jp/
A gluten-free biscuit fortified with lemon IntegroPectin
Authors: Nuzzo Domenico , Scurria Antonino , Picone Pasquale , Guiducci Alessandro , Pagliaro Mario , Pantaleo Giuseppe , Albanese Lorenzo , Meneguzzo Francesco , Ciriminna Rosaria 
Published: August 2021

Abstract
We report the first outcomes of producing a gluten-free biscuit by replacing 2.5 wt% of the rice flour used in the preparation of the cookie with lemon IntegroPectin, a new citrus pectin obtained from lemon processing waste via hydrodynamic cavitation showing exceptional antioxidant properties and (in vitro) high neuroprotective activity. The cookie’s friability, palate adhesion, flavor persistency and compactness remain virtually unchanged. Only the sweetness and the smell (flavor) of the functionalized cookie are lower than those of the commercial biscuit. Production of biscuits fortified with this new pectin might result not only in gluten-free and low-calorie cookies but also in a fortified cookie capable to aid in the prevention of chronic disease such as neuronal disorders.