bluuebunny/crossref_metadata_2025 huggingface dataset:
Alpha-synuclein increases in rodent and human spinal cord injury and promotes inflammation and tissue loss
Authors: Sauerbeck Andrew D. , Goldstein Evan Z. , Alfredo Anthony N. , Norenberg Michael , Marcillo Alexander , McTigue Dana M.
Published: June 2021

Synucleinopathies are neurodegenerative diseases in which α-synuclein protein accumulates in neurons and glia. In these diseases, α-synuclein forms dense intracellular aggregates that are disease hallmarks and actively contribute to tissue pathology. Interestingly, many pathological mechanisms, including iron accumulation and lipid peroxidation, are shared between classical synucleinopathies such as Alzheimer’s disease, Parkinson’s disease and traumatic spinal cord injury (SCI). However, to date, no studies have determined if α-synuclein accumulation occurs after human SCI. To examine this, cross-sections from injured and non-injured human spinal cords were immunolabeled for α-synuclein. This showed robust α-synuclein accumulation in profiles resembling axons and astrocytes in tissue surrounding the injury, revealing that α-synuclein markedly aggregates in traumatically injured human spinal cords. We also detected significant iron deposition in the injury site, a known catalyst for α-synuclein aggregation. Next a rodent SCI model mimicking the histological features of human SCI revealed aggregates and structurally altered monomers of α-synuclein are present after SCI. To determine if α-synuclein exacerbates SCI pathology, α-synuclein knockout mice were tested. Compared to wild type mice, α-synuclein knockout mice had significantly more spared axons and neurons and lower pro-inflammatory mediators, macrophage accumulation, and iron deposition in the injured spinal cord. Interestingly, locomotor analysis revealed that α-synuclein may be essential for dopamine-mediated hindlimb function after SCI. Collectively, the marked upregulation and long-lasting accumulation of α-synuclein and iron suggests that SCI may fit within the family of synucleinopathies and offer new therapeutic targets for promoting neuron preservation and improving function after spinal trauma.
The influence of high-efficiency particulate air filtration on mortality among multiple myeloma patients receiving autologous stem cell transplantation
Authors: Tsai Chun-Kuang , Yeh Chiu-Mei , Hong Ying-Chung , Chen Po-Min , Liu Jin-Hwang , Gau Jyh-Pyng , Liu Chia-Jen
Published: June 2021

Autologous stem cell transplantation (ASCT) continues to be the standard treatment for transplant-eligible multiple myeloma (MM) patients. A portion of MM patients received ASCT in an isolation room with high-efficiency particulate air (HEPA) filtration. The effectiveness of the HEPA filtration on reducing treatment-related mortality (TRM) is controversial. We enrolled patients with newly diagnosed MM in Taiwan between 2000 and 2017. The primary endpoint of the study was TRM, which was defined as death within 100 days after ASCT. A total of 961 MM patients received ASCT. Of them, 480 patients (49.9%) received ASCT in an isolation room with HEPA filtration (HEPA group). The median overall survival from ASCT was 7.52 years for the HEPA group and 5.88 years for the remaining patients (non-HEPA group) (p = 0.370). The 100-day mortality rate was 1.5% and 1.0% for the HEPA and non-HEPA groups, respectively. In the multivariate analysis, the 100-day mortality had no difference between the HEPA and non-HEPA groups (adjusted hazard ratio 1.65, 95% CI 0.52–5.23). The median cost for ASCT inpatient care was $13,777.6 and $6527.6 for the HEPA and non-HEPA groups, respectively (p < 0.001). Although half of MM patients in Taiwan received ASCT in HEPA room, it didn’t affect 100-day mortality.
Structural and optical properties of amorphous Si–Ge–Te thin films prepared by combinatorial sputtering
Authors: Mihai C. , Sava F. , Simandan I. D. , Galca A. C. , Burducea I. , Becherescu N. , Velea A.
Published: June 2021

The lack of order in amorphous chalcogenides offers them novel properties but also adds increased challenges in the discovery and design of advanced functional materials. The amorphous compositions in the Si–Ge–Te system are of interest for many applications such as optical data storage, optical sensors and Ovonic threshold switches. But an extended exploration of this system is still missing. In this study, magnetron co-sputtering is used for the combinatorial synthesis of thin film libraries, outside the glass formation domain. Compositional, structural and optical properties are investigated and discussed in the framework of topological constraint theory. The materials in the library are classified as stressed-rigid amorphous networks. The bandgap is heavily influenced by the Te content while the near-IR refractive index dependence on Ge concentration shows a minimum, which could be exploited in applications. A transition from a disordered to a more ordered amorphous network at 60 at% Te, is observed. The thermal stability study shows that the formed crystalline phases are dictated by the concentration of Ge and Te. New amorphous compositions in the Si–Ge–Te system were found and their properties explored, thus enabling an informed and rapid material selection and design for applications.
Long-term outcome of incidental cystic liver tumors in the general population
Authors: Blum S. F. U. , Ittermann T. , Kromrey M. L. , Dreyer C. M. , Seppelt D. , Hoffmann R. T. , Völzke H. , Kühn J. P.
Published: June 2021

Aim of this study was to investigate frequency, incidence and risk factors of liver cysts in the general population in a longitudinal survey. Cyst frequency was investigated in 607 adult volunteers (288 women, 319 men, mean age 55 years) using strong T2-weighted magnetic resonance imaging. Risk factors were investigated for occurrence, frequency and size of cystic lesions at baseline. Incidence and physiological growing of the lesions were observed in a 5-years follow-up. At baseline, 431 volunteers had 1,479 cysts (71.0%). The mean number of cysts per person was 3.4 ± 9.0. The mean size of cysts was 13.1 ± 11.7 mm. Women had a higher number of cysts than men (p = 0.026). Older and male volunteers demonstrated a higher cyst frequency (p = 0.002 and p = 0.025). Per one-year increase in age the chance for a liver cyst increased by 2%. Four-hundred seventeen volunteers had cysts in the follow-up, in 24.6% new lesions had occurred. Lesion size significantly increased in follow-up (p < 0.001). Age and male sex were associated with the occurrence of at least one liver cyst. Women had a higher average number of cysts. Cystic lesion progression is a physiological phenomenon in the long-term follow-up.
Comparative study on clinical efficacy of different methods for the treatment of intramural aortic hematoma
Authors: Luo Junfu , Zhao Wenpeng , Xu Jiasheng , Zou Rui , Zhang Kaihua , Wan Yanhua , Wan Shasha , Wang Riwei , Zeng Qingfu
Published: June 2021

To explore the difference of curative effect between different treatment modalities, in order to provide reference for the treatment of aortic intramural hematoma (IMH). 168 patients with aortic intramural hematoma diagnosed and treated from January 2010 to July 2020 were selected in the Second Affiliated Hospital of Nanchang University. Among them, 48 patients were diagnosed with Stanford A aortic intramural hematoma and 120 were diagnosed with Stanford B aortic intramural hematoma. According to the therapeutic methods, patients were divided into conservative treatment group and endovascular treatment group (TEVAR). For endovascular treatment group, according to the different timing of surgery, can be divided into acute phase group (onset within 72 h) and non-acute phase group (time of onset > 72 h).The clinical data and follow-up data were collected and analyzed by variance analysis and χ2 test. There were 168 patients diagnosed with aortic intramural hematoma 39 of them were (81.25%) Stanford A aortic intramural hematoma patients with pleural or pericardial effusion. For patient with Stanford A aortic intramural hematoma, endovascular treatment was performed in 15 patients (31.2%), and 33 cases (68.8%) for conservative treatment. The average follow-up (24.9 ± 13.9) was months. There were 120 patients with Stanford type B aortic intramural hematoma (71.4%), 60 patients received endovascular treatment (50%), and 60 patients (50%) received conservative treatment, with an average follow-up of (27.8 ± 14.6) months. For Stanford A type aortic intramural hematoma patients when the maximum aortic diameter ≥ 50 mm or hematoma thickness ≥ 11 mm, with high morbidity and mortality, positive endovascular treatment can reduce complications and death. For patients with Stanford type B aortic intramural hematoma, when the maximum aortic diameter ≥ 40 mm or hematoma thickness ≥ 10 mm, with high morbidity and mortality, positive endovascular treatment can reduce complications and death. Both Stanford type A and B aortic intramural hematoma patients could benefit from the endovascular treatment when the initial maximum aortic diameter is ≥ 50 mm or the hematoma thickness is ≥ 11 mm.
Transcriptomic landscape of early age onset of colorectal cancer identifies novel genes and pathways in Indian CRC patients
Authors: Singh Manish Pratap , Rai Sandhya , Singh Nand K. , Srivastava Sameer
Published: June 2021

Past decades of the current millennium have witnessed an unprecedented rise in Early age Onset of Colo Rectal Cancer (EOCRC) cases in India as well as across the globe. Unfortunately, EOCRCs are diagnosed at a more advanced stage of cancer. Moreover, the aetiology of EOCRC is not fully explored and still remains obscure. This study is aimed towards the identification of genes and pathways implicated in the EOCRC. In the present study, we performed high throughput RNA sequencing of colorectal tumor tissues for four EOCRC (median age 43.5 years) samples with adjacent mucosa and performed subsequent bioinformatics analysis to identify novel deregulated pathways and genes. Our integrated analysis identifies 17 hub genes (INSR, TNS1, IL1RAP, CD22, FCRLA, CXCL3, HGF, MS4A1, CD79B, CXCR2, IL1A, PTPN11, IRS1, IL1B, MET, TCL1A, and IL1R1). Pathway analysis of identified genes revealed that they were involved in the MAPK signaling pathway, hematopoietic cell lineage, cytokine–cytokine receptor pathway and PI3K-Akt signaling pathway. Survival and stage plot analysis identified four genes CXCL3, IL1B, MET and TNS1 genes (p = 0.015, 0.038, 0.049 and 0.011 respectively), significantly associated with overall survival. Further, differential expression of TNS1 and MET were confirmed on the validation cohort of the 5 EOCRCs (median age < 50 years and sporadic origin). This is the first approach to find early age onset biomarkers in Indian CRC patients. Among these TNS1 and MET are novel for EOCRC and may serve as potential biomarkers and novel therapeutic targets in future.
Nobiletin enhances the development and quality of bovine embryos in vitro during two key periods of embryonic genome activation
Authors: Cañón-Beltrán Karina , Cajas Yulia N. , Peréz-Cerezales Serafín , Leal Claudia L. V. , Agirregoitia Ekaitz , Gutierrez-Adán Alfonso , González Encina M. , Rizos Dimitrios
Published: June 2021

In vitro culture can alter the development and quality of bovine embryos. Therefore, we aimed to evaluate whether nobiletin supplementation during EGA improves embryonic development and blastocyst quality and if it affects PI3K/AKT signaling pathway. In vitro zygotes were cultured in SOF + 5% FCS (Control) or supplemented with 5, 10 or 25 µM nobiletin (Nob5, Nob10, Nob25) or with 0.03% dimethyl-sulfoxide (CDMSO) during minor (2 to 8-cell stage; MNEGA) or major (8 to 16-cell stage; MJEGA) EGA phase. Blastocyst yield on Day 8 was higher in Nob5 (42.7 ± 1.0%) and Nob10 (44.4 ± 1.3%) for MNEGAphase and in Nob10 (61.0 ± 0.8%) for MJEGAphase compared to other groups. Mitochondrial activity was higher and lipid content was reduced in blastocysts produced with nobiletin, irrespective of EGA phase. The mRNA abundance ofCDK2, H3-3B, H3-3A, GPX1, NFE2L2andPPARαtranscripts was increased in 8-cells, 16-cells and blastocysts from nobiletin groups. Immunofluorescence analysis revealed immunoreactive proteins for p-AKT forms (Thr308 and Ser473) in bovine blastocysts produced with nobiletin. In conclusion, nobiletin supplementation during EGA has a positive effect on preimplantation bovine embryonic development in vitro and corroborates on the quality improvement of the produced blastocysts which could be modulated by the activation of AKT signaling pathway.
Estimated glomerular filtration rate and cardiometabolic risk factors in a longitudinal cohort of children
Authors: Xargay-Torrent Sílvia , Puerto-Carranza Elsa , Marcelo Irene , Mas-Parés Berta , Gómez-Vilarrubla Ariadna , Martínez-Calcerrada Jose-Maria , de Zegher Francis , Ibáñez Lourdes , López-Bermejo Abel , Bassols Judit
Published: June 2021

Associations between glomerular filtration rate (GFR) and cardiometabolic risk factors have been reported in adult and pediatric patients with renal disease. We aimed to assess the relationship between the estimated GFR (eGFR) and cardiometabolic risk factors in apparently healthy children. A longitudinal study in 401 asymptomatic Caucasian children (mean age 8 years) followed up after 4 years (mean age 12 years). GFR was estimated using the pediatric form of the FAS-equation. Children were classified at baseline according to their obesity status (normal weight and overweight) and according to eGFR levels (lower, average, and higher). The association of eGFR with anthropometric data [body mass index (BMI) and waist], blood pressure [systolic (SBP) and diastolic (DBP)], metabolic parameters [glucose, insulin resistance (HOMA-IR) and serum lipids], and renal ultrasonography measurements were assessed at baseline and follow-up. Baseline eGFR associated with several cardiometabolic risk factors at follow-up including higher waist, SBP, HOMA-IR, and kidney size (all p < 0.0001) in both normal weight and overweight children. In multivariate analysis, baseline eGFR was independently associated with follow-up HOMA-IR and SBP in both normal weight and overweight subjects (model R2: 0.188–0.444), and with follow-up BMI and waist in overweight subjects (model R2: 0.367–0.477). Moreover, children with higher filtration rates at baseline showed higher waist, SBP, DBP, HOMA-IR and renal size both at baseline and follow-up. eGFR is related to insulin resistance, blood pressure and adiposity measures in school-age children. eGFR may help to profile the cardiometabolic risk of children.
In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα
Authors: Li Benjamin Xiaoyi , Dai Xiangrong , Xu Xiaohong Ruby , Adili Reheman , Neves Miguel Antonio Dias , Lei Xi , Shen Chuanbin , Zhu Guangheng , Wang Yiming , Zhou Hui , Hou Yan , Ni Tiffany , Pasman Yfke , Yang Zhongqiang , Qian Fang , Zhao Yanan , Gao Yongxiang , Liu Jing , Teng Maikun , Marshall Alexandra H. , Cerenzia Eric G. , Li Mandy Lokyee , Ni Heyu
Published: June 2021

The interaction of platelet GPIbα with von Willebrand factor (VWF) is essential to initiate platelet adhesion and thrombosis, particularly under high shear stress conditions. However, no drug targeting GPIbα has been developed for clinical practice. Here we characterized anfibatide, a GPIbα antagonist purified from snake (Deinagkistrodon acutus) venom, and evaluated its interaction with GPIbα by surface plasmon resonance and in silico modeling. We demonstrated that anfibatide interferds with both VWF and thrombin binding, inhibited ristocetin/botrocetin- and low-dose thrombin-induced human platelet aggregation, and decreased thrombus volume and stability in blood flowing over collagen. In a single-center, randomized, and open-label phase I clinical trial, anfibatide was administered intravenously to 94 healthy volunteers either as a single dose bolus, or a bolus followed by a constant rate infusion of anfibatide for 24 h. Anfibatide inhibited VWF-mediated platelet aggregation without significantly altering bleeding time or coagulation. The inhibitory effects disappeared within 8 h after drug withdrawal. No thrombocytopenia or anti-anfibatide antibodies were detected, and no serious adverse events or allergic reactions were observed during the studies. Therefore, anfibatide was well-tolerated among healthy subjects. Interestingly, anfibatide exhibited pharmacologic effects in vivo at concentrations thousand-fold lower than in vitro, a phenomenon which deserves further investigation.

Trial registration: Clinicaltrials.gov NCT01588132.
Capicua regulates the development of adult-born neurons in the hippocampus
Authors: Hourigan Brenna , Balay Spencer D. , Yee Graydon , Sharma Saloni , Tan Qiumin
Published: June 2021

New neurons continuously arise from neural progenitor cells in the dentate gyrus of the adult hippocampus to support ongoing learning and memory formation. To generate functional adult-born neurons, neural progenitor cells proliferate to expand the precursor cell pool and differentiate into neurons. Newly generated cells then undergo postmitotic maturation to migrate to their final destination and develop elaborate dendritic branching, which allows them to receive input signals. Little is known about factors that regulate neuronal differentiation, migration, and dendrite maturation during adult hippocampal neurogenesis. Here, we show that the transcriptional repressor protein capicua (CIC) exhibits dynamic expression in the adult dentate gyrus. Conditional deletion of Cic from the mouse dentate gyrus compromises the adult neural progenitor cell pool without altering their proliferative potential. We further demonstrate that the loss of Cic impedes neuronal lineage development and disrupts dendritic arborization and migration of adult-born neurons. Our study uncovers a previously unrecognized role of CIC in neurogenesis of the adult dentate gyrus.
Development of a prediction model for mortality and cardiovascular outcomes in older adults taking into account AZGP1
Authors: Huscher Dörte , Ebert Natalie , Soerensen-Zender Inga , Mielke Nina , Schaeffner Elke , Schmitt Roland
Published: June 2021

Zinc-alpha 2-glycoprotein (AZGP1) is a serum protein with postulated functions in metabolism, cancer and cardiovascular disease. We developed new prediction models for mortality or cardiovascular events investigating the predictive potential of serum AZGP1 in a community-based cohort of older adults. We measured AZGP1 (μg/ml) in stored serum samples of 930 individuals of the Berlin Initiative Study, a prospective, population-based cohort of adults aged ≥ 70. We determined the prognostic potential of 20 knowledge-based predictors including AZGP1 for the outcomes of mortality or the composite endpoint of death and cardiovascular events (stroke, myocardial infarction (MI)) using Cox models; their model fit was evaluated with calibration plots, goodness-of-fit tests and c-indices. During median follow-up of 48.3 months, 70 incident strokes, 38 incident MI and 234 deaths occurred. We found no associations or correlations between AZGP1 and other candidate variables. After multivariable Cox regression with backward-selection AZGP1 remained in both models for mortality (HR = 0.44, 95%CI: 0.24–0.80) and for the composite endpoint (HR = 0.43, 95%CI: 0.23–0.82). Within newly built prediction models, we found that increased AZGP1 levels were predictive for lower risk of mortality and the composite endpoint in older adults. AZGP1 as a predictor warrants further validation in older adults.
Pirfenidone modifies hepatic miRNAs expression in a model of MAFLD/NASH
Authors: Escutia-Gutiérrez Rebeca , Rodríguez-Sanabria J. Samael , Monraz-Méndez C. Alejandra , García-Bañuelos Jesús , Santos-García Arturo , Sandoval-Rodríguez Ana , Armendáriz-Borunda Juan
Published: June 2021

miRNAs are involved in the development of metabolic associated fatty liver disease (MAFLD) and nonalcoholic steatohepatitis (NASH). We aimed to evaluate modifications by prolonged-release pirfenidone (PR-PFD) on key hepatic miRNAs expression in a MAFLD/NASH model. First, male C57BL/6J mice were randomly assigned into groups and fed with conventional diet (CVD) or high fat and carbohydrate diet (HFD) for 16 weeks. At the end of the eighth week, HFD mice were divided in two and only one half was treated with 300 mg/kg/day of PR-PFD mixed with food. Hepatic expression of miRNAs and target genes that participate in inflammation and lipid metabolism was determined by qRT-PCR and transcriptome by microarrays. Increased hepatic expression of miR-21a-5p, miR-34a-5p, miR-122-5p and miR-103-3p in MAFLD/NASH animals was reduced with PR-PFD. Transcriptome analysis showed that 52 genes involved in lipid and collagen biosynthesis and inflammatory response were downregulated in PR-PFD group. The expression of Il1b, Tnfa, Il6, Tgfb1, Col1a1, and Srebf1 were decreased in PR-PFD treated animals. MAFLD/NASH animals compared to CVD group showed modifications in gene metabolic pathways implicated in lipid metabolic process, inflammatory response and insulin resistance; PR-PFD reversed these modifications.
Effects of emission trading schemes on corporate carbon productivity and implications for firm-level responses
Authors: Jung Hail , Song Seyeong , Ahn Young-Hwan , Hwang Ha , Song Chang-Keun
Published: June 2021

Since the South Korean government enacted the Emission Trading Scheme (ETS), companies have been striving to simultaneously improve productivity and reduce carbon emissions, which represent conflicting goals. We used firm-level emissions and corporate variables to investigate how ETS enactment has affected carbon productivity, which is a firm-level revenue created per unit of carbon emission. Results showed that firm-level carbon productivity increased significantly under the ETS, and such a trend was more evident for high-emission industries. We also found that companies with high carbon productivity were (1) profitable, (2) innovative, and (3) managed by CEOs with experience in environmental fields. These findings suggest that to achieve the conflicting goals of increasing corporate profits while reducing emissions, firms have to invest in green technologies, and such decisions are supported by green leadership. Our findings also have implications for corporate leadership; data highlight the importance of managing human resources and deploying investment policies to respond to ETS.
Glaucoma and mortality risk: findings from a prospective population-based study
Authors: Kühn Tilman , Rohrmann Sabine , Karavasiloglou Nena , Friedman David S. , Cassidy Aedin , Bärnighausen Till , Schuster Alexander K. , Nickels Stefan
Published: June 2021

Glaucoma is a neurodegenerative disease with a structural change of the optic nerve head, leading to visual field defects and ultimately blindness. It has been proposed that glaucoma is associated with increased mortality, but previous studies had methodological limitations (selective study samples, lack of data on potential confounders, self-reported or secondary data on glaucoma diagnoses). We evaluated the association between diagnosed glaucoma and mortality in the population-based National Health and Nutrition Examination Survey (NHANES), a representative health survey in the United States. The survey cycles 2005–2006 and 2007–2008 included an extensive ophthalmic examination with fundus photography, which were used to derive standardized glaucoma diagnoses. Risk of all-cause mortality was assessed with multivariable Cox proportional hazards regression models accounting for the complex survey design of NHANES. Time to death was calculated from the examination date to date of death or December 31, 2015 whichever came first. 5385 participants (52.5% women) were eligible, of which 138 had glaucoma at baseline, and 833 died during follow-up. Participants with glaucoma were more likely to be older than those without glaucoma (mean age 69.9 vs. 56.0 years). Mean follow-up time was 8.4 years for participants with glaucoma, and 8.6 years for participants without glaucoma. Glaucoma was associated with increased mortality in an unadjusted Cox regression model (hazard ratio 2.06, 95% confidence interval 1.16 to 3.66), but the association was no longer statistically significant after adjusting for age and sex (hazard ratio 0.74, 95% confidence interval 0.46 to 1.17). Additional adjustment for a range of potential confounders did not significantly change the results. In this representative population-based study, we found no evidence of increased mortality risk in glaucoma patients.
Molecular simulation of gases competitive adsorption in lignite and analysis of original CO desorption
Authors: Zhang Jing , Wang Jiren , Zhang Chunhua , Li Zongxiang , Zhu Jinchao , Lu Bing
Published: June 2021

To study the adsorption characteristics of CO, CO2, N2, O2, and their binary-components in lignite coal, reveal the influence of CO2 or N2 injection and air leakage on the desorption of CO in goafs, a lignite model (C206H206N2O44) was established, and the supercell structure was optimized under temperatures of 288.15–318.15 K for molecular simulation. Based on molecular dynamics, the Grand Canonical Monte Carlo method was used to simulate the adsorption characteristics and the Langmuir equation was used to fit the adsorption isotherms of gases. The results show that for single-components, the order of adsorption capacity is CO2 > CO > O2 > N2. For binary-components, the competitive adsorption capacities of CO2 and CO are approximate. In the low-pressure zone, the competitive adsorption capacity of CO2 is stronger than that of CO, and the CO is stronger than N2 or O2. From the simulation, it can be seen that CO2, N2 or O2 will occupy adsorption sites, causing CO desorption. Therefore, to prevent the desorption of the original CO in the goaf, it is not suitable to use CO2 or N2 injection for fire prevention, and the air leakage at the working faces need to be controlled.
Longer DNA exhibits greater potential for cell-free gene expression
Authors: Nishio Takashi , Yoshikawa Yuko , Yoshikawa Kenichi , Sato Shin-ichi
Published: June 2021

Cell-free gene expression systems have been valuable tools for understanding how transcription/translation can be regulated in living cells. Many studies have investigated the determining factors that affect gene expression. Here we report the effect of the length of linearized reporter DNAs encoding the firefly luciferase gene so as to exclude the influence of supercoiling. It is found that longer DNA molecules exhibit significantly greater potency in gene expression; for example, the expression level for DNA with 25.7 kbp is 1000-times higher than that for DNA of 1.7 kbp. AFM observation of the DNA conformation indicates that longer DNA takes shrunken conformation with a higher segment density in the reaction mixture for gene expression, in contrast to the stiff conformation of shorter DNA. We propose an underlying mechanism for the favorable effect of longer DNA on gene expression in terms of the enhancement of access of RNA polymerase to the shrunken conformation. It is expected that the enhancement of gene expression efficiency with a shrunken DNA conformation would also be a rather general mechanism in living cellular environments.
Football and team handball training postpone cellular aging in women
Authors: Hagman Marie , Fristrup Bjørn , Michelin Rémi , Krustrup Peter , Asghar Muhammad
Published: June 2021

Several hallmarks of aging have been identified and examined separately in previous exercise studies. For the first time, this study investigates the effect of lifelong regular exercise in humans on two of the central aging hallmarks combined. This cross-sectional study involved 129 healthy, non-smoking women, including young elite football players (YF, n = 29), young untrained controls (YC, n = 30), elderly team handball players (EH, n = 35) and elderly untrained controls (EC, n = 35). From a resting blood sample, mononuclear cells (MNCs) were isolated and sorted into monocytes and lymphocytes. Telomere length, mitochondrial (mtDNA) copy number and key regulators of mitochondrial biogenesis and function (PGC-1α and PGC-1β expression) were measured using quantitative polymerase chain reaction (qPCR). Overall, young women showed significantly longer telomeres and higher PGC-1α and PGC-1β expression, but lower mtDNA copy number compared to elderly subjects. A multivariate analysis showed that YF had 22–24% longer telomeres in lymphocytes and MNCs compared to YC. In addition, YF showed 19–20% higher mtDNA copy number in lymphocytes and MNCs compared to YC. The two young groups did not differ in PGC-1α and PGC-1β expression. EH showed 14% lower mtDNA copy number in lymphocytes compared to EC, but 3.4-fold higher lymphocyte PGC-1α expression compared to EC. In MNCs, EH also showed 1.4–1.6-fold higher PGC-1α and PGC-1β expression. The two elderly groups did not differ in telomere length. Elite football training and lifelong team handball training are associated with anti-aging mechanisms in leukocytes in women, including maintenance of telomere length and superior mitochondrial characteristics.
Differences in plasma microRNA content impair microRNA-based signature for breast cancer diagnosis in cohorts recruited from heterogeneous environmental sites
Authors: Uyisenga Jeanne P. , Debit Ahmed , Poulet Christophe , Frères Pierre , Poncin Aurélie , Thiry Jérôme , Mutesa Leon , Jerusalem Guy , Bours Vincent , Josse Claire
Published: June 2021

Circulating microRNAs are non-invasive biomarkers that can be used for breast cancer diagnosis. However, differences in cancer tissue microRNA expression are observed in populations with different genetic/environmental backgrounds. This work aims at checking if a previously identified diagnostic circulating microRNA signature is efficient in other genetic and environmental contexts, and if a universal circulating signature might be possible. Two populations are used: women recruited in Belgium and Rwanda. Breast cancer patients and healthy controls were recruited in both populations (Belgium: 143 primary breast cancers and 136 healthy controls; Rwanda: 82 primary breast cancers and 73 healthy controls; Ntot = 434), and cohorts with matched age and cancer subtypes were compared. Plasmatic microRNA profiling was performed by RT-qPCR. Random Forest was used to (1) evaluate the performances of the previously described breast cancer diagnostic tool identified in Belgian-recruited cohorts on Rwandan-recruited cohorts and vice versa; (2) define new diagnostic signatures common to both recruitment sites; (3) define new diagnostic signatures efficient in the Rwandan population. None of the circulating microRNA signatures identified is accurate enough to be used as a diagnostic test in both populations. However, accurate circulating microRNA signatures can be found for each specific population, when taken separately.
Potential adverse drug events and its predictors among hospitalized patients at medical center in Ethiopia: a prospective observational study
Authors: Sahilu Tamiru , Getachew Mestawet , Melaku Tsegaye , Sheleme Tadesse , Abu Duresa , Zewdu Tesfu
Published: June 2021

Potential adverse drug event (PADE) is a medication error with the potential to cause associate degree injury however that does not cause any injury, either due to specific circumstances, chance, or as a result of the error being intercepted and corrected. This study aimed to assess the incidence, contributing factors, predictors, severity, and preventability of PADEs among hospitalized adult patients at Jimma Medical Center. A prospective observational study was conducted among hospitalized adult patients at a tertiary hospital in Ethiopia. Logistic regression was performed to identify factors predicting PADE occurrence. P-value < 0.05 was considered for statistical significance. A total of 319 patients were included. About 50.5% of them were females. The mean ± SD age of the participants was 43 ± 17.6 years. Ninety-four PADEs were identified. Number of medications (adjusted OR = 5.12; 95% CI: 2.01–13.05; p = 0.001), anticoagulants (adjusted OR = 2.51; 95% CI: 1.22–5.19; p = 0.013), anti-seizures (adjusted OR = 21.96; 95% CI: 6.57–73.39; p < 0.0001), anti-tuberculosis (adjusted OR = 2.2; 95% CI: 1.002–4.59, p = 0.049), and Elixhauser comorbidity Index ≤ 15 (adjusted OR = 6.24; 95% CI: 1.48–26.25, p = 0.013) were independent predictors of PADEs occurrence. About one-third of patients admitted to the hospital experienced PADEs.
BET inhibitor suppresses migration of human hepatocellular carcinoma by inhibiting SMARCA4
Authors: Choi Hae In , An Ga Yeong , Baek Mina , Yoo Eunyoung , Chai Jin Choul , Lee Young Seek , Jung Kyoung Hwa , Chai Young Gyu
Published: June 2021

Hepatocellular carcinoma (HCC) is one of the most prevalent and poorly responsive cancers worldwide. Bromodomain and extraterminal (BET) inhibitors, such as JQ1 and OTX-015, inhibit BET protein binding to acetylated residues in histones. However, the physiological mechanisms and regulatory processes of BET inhibition in HCC remain unclear. To explore BET inhibitors’ potential role in the molecular mechanisms underlying their anticancer effects in HCC, we analyzed BET inhibitor-treated HCC cells’ gene expression profiles with RNA-seq and bioinformatics analysis. BET inhibitor treatment significantly downregulated genes related to bromodomain-containing proteins 4 (BRD4), such as ACSL5, SLC38A5, and ICAM2. Importantly, some cell migration-related genes, including AOC3, CCR6, SSTR5, and SCL7A11, were significantly downregulated. Additionally, bioinformatics analysis using Ingenuity Knowledge Base Ingenuity Pathway Analysis (IPA) revealed that SMARCA4 regulated migration response molecules. Furthermore, knockdown of SMARCA4 gene expression by siRNA treatment significantly reduced cell migration and the expression of migration-related genes. In summary, our results indicated that BET inhibitor treatment in HCC cell lines reduces cell migration through the downregulation of SMARCA4.
Validation of mathematical model with phosphate activation effect by batch (R)-phenylacetylcarbinol biotransformation process utilizing Candida tropicalis pyruvate decarboxylase in phosphate buffer
Authors: Khemacheewakul Julaluk , Taesuwan Siraphat , Nunta Rojarej , Techapun Charin , Phimolsiripol Yuthana , Rachtanapun Pornchai , Jantanasakulwong Kittisak , Porninta Kritsadaporn , Sommanee Sumeth , Mahakuntha Chatchadaporn , Chaiyaso Thanongsak , Seesuriyachan Phisit , Reungsang Alissara , Trinh Ngoc Thao Ngan , Wangtueai Sutee , Sommano Sarana Rose , Leksawasdi Noppol
Published: June 2021

The (R)-phenylacetylcarbinol (PAC) batch biotransformation kinetics for partially purified Candida tropicalis TISTR 5350 pyruvate decarboxylase (PDC) were determined to validate a comprehensive mathematical model in 250 mL scale with 250 mM phosphate buffer/pH 7.0.
PDC could convert initial 100/120 mM benzaldehyde/pyruvate substrates to the statistical significantly highest (p ≤ 0.05) maximum PAC concentration (95.8 ± 0.1 mM) and production rate (0.639 ± 0.001 mM min−1). A parameter search strategy aimed at minimizing overall residual sum of square (RSST) based on a system of six ordinary differential equations was applied to PAC biotransformation profiles with initial benzaldehyde/pyruvate concentration of 100/120 and 30/36 mM. Ten important biotransformation kinetic parameters were then elucidated including the zeroth order activation rate constant due to phosphate buffer species (ka) of (9.38 ±  < 0.01) ×  10–6% relative PDC activity min−1 mM−1. The validation of this model to independent biotransformation kinetics with initial benzaldehyde/pyruvate concentration of 50/60 mM resulted in relatively good fitting with RSST, mean sum of square error (MSE), and coefficient of determination (R2) values of 662, 17.4, and 0.9863, respectively.
Effect of dietary protein on energy metabolism including protein synthesis in the spiny lobster Sagmariasus verreauxi
Authors: Wang Shuangyao , Carter Chris G. , Fitzgibbon Quinn P. , Codabaccus Basseer M. , Smith Gregory G.
Published: June 2021

This is the first study in an aquatic ectotherm to combine a stoichiometric bioenergetic approach with an endpoint stochastic model to explore dietary macronutrient content. The combination of measuring respiratory gas (O2and CO2) exchange, nitrogenous (ammonia and urea) excretion, specific dynamic action (SDA), metabolic energy substrate use, and whole-body protein synthesis in spiny lobster,Sagmariasus verreauxi, was examined in relation to dietary protein. Three isoenergetic feeds were formulated with varying crude protein: 40%, 50% and 60%, corresponding to CP40, CP50and CP60treatments, respectively. Total CO2and ammonia excretion, SDA magnitude and coefficient, and protein synthesis in the CP60treatment were higher compared to the CP40treatment. These differences demonstrate dietary protein influences post-prandial energy metabolism. Metabolic use of each major energy substrate varied at different post-prandial times, indicating suitable amounts of high-quality protein with major non-protein energy-yielding nutrients, lipid and carbohydrate, are critical for lobsters. The average contribution of protein oxidation was lowest in the CP50treatment, suggesting mechanisms underlying the most efficient retention of dietary protein and suitable dietary inclusion. This study advances understanding of how deficient and surplus dietary protein affects energy metabolism and provides approaches for fine-scale feed evaluation to support sustainable aquaculture.
Long-term stability of computational parameters during approach-avoidance conflict in a transdiagnostic psychiatric patient sample
Authors: Smith Ryan , Kirlic Namik , Stewart Jennifer L. , Touthang James , Kuplicki Rayus , McDermott Timothy J. , Taylor Samuel , Khalsa Sahib S. , Paulus Martin P. , Aupperle Robin L.
Published: June 2021

Maladaptive behavior during approach-avoidance conflict (AAC) is common to multiple psychiatric disorders. Using computational modeling, we previously reported that individuals with depression, anxiety, and substance use disorders (DEP/ANX; SUDs) exhibited differences in decision uncertainty and sensitivity to negative outcomes versus reward (emotional conflict) relative to healthy controls (HCs). However, it remains unknown whether these computational parameters and group differences are stable over time. We analyzed 1-year follow-up data from a subset of the same participants (N = 325) to assess parameter stability and relationships to other clinical and task measures. We assessed group differences in the entire sample as well as a subset matched for age and IQ across HCs (N = 48), SUDs (N = 29), and DEP/ANX (N = 121). We also assessed 2–3 week reliability in a separate sample of 30 HCs. Emotional conflict and decision uncertainty parameters showed moderate 1-year intra-class correlations (.52 and .46, respectively) and moderate to excellent correlations over the shorter period (.84 and .54, respectively). Similar to previous baseline findings, parameters correlated with multiple response time measures (ps < .001) and self-reported anxiety (r = .30, p < .001) and decision difficulty (r = .44, p < .001). Linear mixed effects analyses revealed that patients remained higher in decision uncertainty (SUDs, p = .009) and lower in emotional conflict (SUDs, p = .004, DEP/ANX, p = .02) relative to HCs. This computational modelling approach may therefore offer relatively stable markers of transdiagnostic psychopathology.
Characterization of four mitochondrial genomes of family Neritidae (Gastropoda: Neritimorpha) and insight into its phylogenetic relationships
Authors: Feng Jian-tong , Xia Li-ping , Yan Cheng-rui , Miao Jing , Ye Ying-ying , Li Ji-ji , Guo Bao-ying , Lü Zhen-ming
Published: June 2021

Neritidae is one of the most diverse families of Neritimorpha and possesses euryhaline properties. Members of this family usually live on tropical and subtropical coasts and are mainly gregarious. The phylogenetic relationships between several subclasses of Gastropoda have been controversial for many years. With an increase in the number of described species of Neritidae, the knowledge of the evolutionary relationships in this family has improved. In the present study, we sequenced four complete mitochondrial genomes from two genera (ClithonandNerita) and compared them with available complete mitochondrial genomes of Neritidae. Gene order exhibited a highly conserved pattern among three genera in the Neritidae family. Our results improved the phylogenetic resolution within Neritidae, and more comprehensive taxonomic sampling of subclass Neritimorpha was proposed. Furthermore, we reconstructed the divergence among the main lineages of 19 Neritimorpha taxa under an uncorrelated relaxed molecular clock.
Electrical stimulation of the nucleus basalis of meynert: a systematic review of preclinical and clinical data
Authors: Nazmuddin Muhammad , Philippens Ingrid H. C. H. M. , van Laar Teus
Published: June 2021

Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been clinically investigated in Alzheimer’s disease (AD) and Lewy body dementia (LBD). However, the clinical effects are highly variable, which questions the suggested basic principles underlying these clinical trials. Therefore, preclinical and clinical data on the design of NBM stimulation experiments and its effects on behavioral and neurophysiological aspects are systematically reviewed here. Animal studies have shown that electrical stimulation of the NBM enhanced cognition, increased the release of acetylcholine, enhanced cerebral blood flow, released several neuroprotective factors, and facilitates plasticity of cortical and subcortical receptive fields. However, the translation of these outcomes to current clinical practice is hampered by the fact that mainly animals with an intact NBM were used, whereas most animals were stimulated unilaterally, with different stimulation paradigms for only restricted timeframes. Future animal research has to refine the NBM stimulation methods, using partially lesioned NBM nuclei, to better resemble the clinical situation in AD, and LBD. More preclinical data on the effect of stimulation of lesioned NBM should be present, before DBS of the NBM in human is explored further.
A conserved rhizobial peptidase that interacts with host-derived symbiotic peptides
Authors: Benedict Alex B. , Ghosh Prithwi , Scott Samuel M. , Griffitts Joel S.
Published: June 2021

In the Medicago truncatula-Sinorhizobium meliloti symbiosis, chemical signaling initiates rhizobial infection of root nodule tissue, where a large portion of the bacteria are endocytosed into root nodule cells to function in nitrogen-fixing organelles. These intracellular bacteria are subjected to an arsenal of plant-derived nodule-specific cysteine-rich (NCR) peptides, which induce the physiological changes that accompany nitrogen fixation. NCR peptides drive these intracellular bacteria toward terminal differentiation. The bacterial peptidase HrrP was previously shown to degrade host-derived NCR peptides and give the bacterial symbionts greater fitness at the expense of host fitness. The hrrP gene is found in roughly 10% of Sinorhizobium isolates, as it is carried on an accessory plasmid. The objective of the present study is to identify peptidase genes in the core genome of S. meliloti that modulate symbiotic outcome in a manner similar to the accessory hrrP gene. In an overexpression screen of annotated peptidase genes, we identified one such symbiosis-associated peptidase (sap) gene, sapA (SMc00451). When overexpressed, sapA leads to a significant decrease in plant fitness. Its promoter is active in root nodules, with only weak expression evident under free-living conditions. The SapA enzyme can degrade a broad range of NCR peptides in vitro.
Transmembrane adaptor protein PAG is a mediator of PD-1 inhibitory signaling in human T cells
Authors: Strazza Marianne , Azoulay-Alfaguter Inbar , Peled Michael , Adam Kieran , Mor Adam
Published: June 2021

The inhibitory receptor PD-1 is expressed on T cells to inhibit select functions when ligated. The complete signaling mechanism downstream of PD-1 has yet to be uncovered. Here, we discovered phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG) is phosphorylated following PD-1 ligation and associate this with inhibitory T cell function. Clinical cohort analysis correlates low PAG expression with increased survival from numerous tumor types. PAG knockdown in T cells prevents PD-1-mediated inhibition of cytokine secretion, cell adhesion, CD69 expression, and ERK204/187 phosphorylation, and enhances phosphorylation of SRC527 following PD-1 ligation. PAG overexpression rescues these effects. In vivo, PAG contributes greatly to the growth of two murine tumors, MC38 and B16, and limits T cell presence within the tumor. Moreover, PAG deletion sensitizes tumors to PD-1 blockade. Here PAG is established as a critical mediator of PD-1 signaling and as a potential target to enhance T cell activation in tumors.
The detection dogs test is more sensitive than real-time PCR in screening for SARS-CoV-2
Authors: Hag-Ali Mohammed , AlShamsi Abdul Salam , Boeijen Linda , Mahmmod Yasser , Manzoor Rashid , Rutten Harry , Mweu Marshal M. , El-Tholoth Mohamed , AlShamsi Abdullatif Alteraifi
Published: June 2021

In January 2020, the coronavirus disease was declared, by the World Health Organization as a global public health emergency. Recommendations from the WHO COVID Emergency Committee continue to support strengthening COVID surveillance systems, including timely access to effective diagnostics. Questions were raised about the validity of considering the RT-PCR as the gold standard in COVID-19 diagnosis. It has been suggested that a variety of methods should be used to evaluate advocated tests. Dogs had been successfully trained and employed to detect diseases in humans. Here we show that upon training explosives detection dogs on sniffing COVID-19 odor in patients’ sweat, those dogs were able to successfully screen out 3249 individuals who tested negative for the SARS-CoV-2, from a cohort of 3290 individuals. Additionally, using Bayesian analysis, the sensitivity of the K9 test was found to be superior to the RT-PCR test performed on nasal swabs from a cohort of 3134 persons. Given its high sensitivity, short turn-around-time, low cost, less invasiveness, and ease of application, the detection dogs test lends itself as a better alternative to the RT-PCR in screening for SARS-CoV-2 in asymptomatic individuals.
Three dimensional acoustic tweezers with vortex streaming
Authors: Li Junfei , Crivoi Alexandru , Peng Xiuyuan , Shen Lu , Pu Yunjiao , Fan Zheng , Cummer Steven A.
Published: June 2021

Acoustic tweezers use ultrasound for contact-free manipulation of particles from millimeter to sub-micrometer scale. Particle trapping is usually associated with either radiation forces or acoustic streaming fields. Acoustic tweezers based on single-beam focused acoustic vortices have attracted considerable attention due to their selective trapping capability, but have proven difficult to use for three-dimensional (3D) trapping without a complex transducer array and significant constraints on the trapped particle properties. Here we demonstrate a 3D acoustic tweezer in fluids that uses a single transducer and combines the radiation force for trapping in two dimensions with the streaming force to provide levitation in the third dimension. The idea is demonstrated in both simulation and experiments operating at 500 kHz, and the achieved levitation force reaches three orders of magnitude larger than for previous 3D trapping. This hybrid acoustic tweezer that integrates acoustic streaming adds an additional twist to the approach and expands the range of particles that can be manipulated.