bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vagus nerve stimulation enhances the cholinergic anti-inflammatory pathway to reduce lung injury in acute respiratory distress syndrome via STAT3
Authors: Li Sheng , Qi Di , Li Jia-ni , Deng Xin-yu , Wang Dao-xin 
Published: March 2021

AbstractThe cholinergic anti-inflammatory pathway (CAIP) is important for antagonizing inflammation and treating several diseases, including acute respiratory distress syndrome (ARDS), and is related to vagus nerve integrity. However, its underlying pathophysiological mechanism is still unclear. We hypothesized that CAIP regulates lung injury repair after ARDS through the STAT3 signaling pathway, which is an important downstream effector of α7nAchR. We enhanced CAIP activity by subjecting rats to vagus nerve stimulation (VNS), and administered the α-7 acetylcholine receptor (α7nAchR) agonist and antagonist to determine whether VNS can reduce lung injury by regulating the pulmonary inflammatory response through CAIP. After being subjected to VNS, the secretion of TNF-α and IL-1β was decreased, while the level of IL-10 was increased in the rat model of ARDS. Moreover, VNS treatment reduced lung mRNA levels of M1 macrophage markers, while increased those of M2 macrophage markers. The expression of Caspase-1 decreased, while that of STAT3 increased in lung tissue after VNS treatment. The aforementioned effects of VNS were reversed by cutting the cervical vagus efferent branch and blocking α7nAchR. These findings suggest that VNS inhibits the ARDS inflammatory response by promoting CAIP activity. Next, we used lentivirus knockdown of STAT3 expression to explore the mechanism of VNS through CAIP on lung inflammation in ARDS model rats. VNS activates α7nAchR, increases STAT3 expression, reduces Caspase-1 expression, suppresses inflammation by inhibiting inflammatory pyroptosis and M1 to M2 macrophage transformation, which may constitute the main mechanism of VNS action in ARDS.
Germline mutations in apoptosis pathway genes in ovarian cancer; the functional role of a TP53I3 (PIG3) variant in ROS production and DNA repair
Authors: Chaudhry Sophia R. , Lopes Jaime , Levin Nancy K. , Kalpage Hasini , Tainsky Michael A. 
Published: March 2021

AbstractApproximately 25% of all cases of ovarian cancer (OVCA) cases are associated with inherited risk. However, accurate risk assessment is limited by the presence of variants of unknown significance (VUS). Previously, we performed whole-exome sequencing on 48 OVCA patients with familial predisposition, yet negative for pathogenic BRCA1/2 mutations. In our cohort, we uncovered thirteen truncating mutations in genes associated with apoptosis (~35% of our patient cohort). The TP53I3 p.S252X premature stop gain was identified in two unrelated patients. TP53I3 is transcriptionally activated by p53 and believed to play a role in DNA damage response and reactive oxygen species-induced apoptosis. In addition, nonsense variants in apoptosis-related genes TP53AIP1, BCLAF1, and PIK3C2G were identified in our cohort; highlighting the potential relevance of genes involved in apoptotic processes to hereditary cancer. In the current study, we employed functional assays and demonstrated that cells expressing TP53I3 p.S252X displayed decreased homologous recombination repair efficiency and increased sensitivity to chemotherapeutic drugs bleomycin, mitomycin c, and etoposide. In addition, in the presence of oxidative stress from hydrogen peroxide or etoposide we observed a reduction in the formation of reactive oxygen species, an important precursor to apoptosis with this variant. Our findings suggest that the combination of in silico and wet laboratory approaches can better evaluate VUSs, establish novel germline predisposition genetic loci, and improve individual cancer risk estimates.
In vivo self-assembled small RNAs as a new generation of RNAi therapeutics
Authors: Fu Zheng , Zhang Xiang , Zhou Xinyan , Ur-Rehman Uzair , Yu Mengchao , Liang Hongwei , Guo Hongyuan , Guo Xu , Kong Yan , Su Yuanyuan , Ye Yangyang , Hu Xiuting , Cheng Wei , Wu Jinrong , Wang Yanbo , Gu Yayun , Lu Sheng-feng , Wu Dianqing , Zen Ke , Li Jing , Yan Chao , Zhang Chen-Yu , Chen Xi 
Published: March 2021

AbstractRNAi therapy has undergone two stages of development, direct injection of synthetic siRNAs and delivery with artificial vehicles or conjugated ligands; both have not solved the problem of efficient in vivo siRNA delivery. Here, we present a proof-of-principle strategy that reprogrammes host liver with genetic circuits to direct the synthesis and self-assembly of siRNAs into secretory exosomes and facilitate the in vivo delivery of siRNAs through circulating exosomes. By combination of different genetic circuit modules, in vivo assembled siRNAs are systematically distributed to multiple tissues or targeted to specific tissues (e.g., brain), inducing potent target gene silencing in these tissues. The therapeutic value of our strategy is demonstrated by programmed silencing of critical targets associated with various diseases, including EGFR/KRAS in lung cancer, EGFR/TNC in glioblastoma and PTP1B in obesity. Overall, our strategy represents a next generation RNAi therapeutics, which makes RNAi therapy feasible.
Whole-exome sequencing identifies two novel ALMS1 mutations in Indian patients with Leber congenital amaurosis
Authors: Srikrupa Natarajan N. , Sripriya Sarangapani , Pavithra Suriyanarayanan , Sen Parveen , Gupta Ravi , Mathavan Sinnakaruppan 
Published: March 2021

AbstractLeber congenital amaurosis (LCA) is a severe autosomal recessive retinal degenerative disease. The current study describes exome sequencing results for two unrelated Indian LCA patients carrying novel nonsense p.(Glu636*) and frameshift p.(Pro2281Leufs*63) mutations in the ALMS1 gene. Although ALMS1 gene mutations are associated with Alstrom syndrome (AS), the current patients did not exhibit typical syndromic features of AS. These data suggest that ALMS1 should be included in the candidate gene panel for LCA to improve diagnostic efficiency.
A haemagglutination test for rapid detection of antibodies to SARS-CoV-2
Authors: Townsend Alain , Rijal Pramila , Xiao Julie , Tan Tiong Kit , Huang Kuan-Ying A. , Schimanski Lisa , Huo Jiandong , Gupta Nimesh , Rahikainen Rolle , Matthews Philippa C. , Crook Derrick , Hoosdally Sarah , Dunachie Susanna , Barnes Eleanor , Street Teresa , Conlon Christopher P. , Frater John , Arancibia-Cárcamo Carolina V. , Rudkin Justine , Stoesser Nicole , Karpe Fredrik , Neville Matthew , Ploeg Rutger , Oliveira Marta , Roberts David J. , Lamikanra Abigail A. , Tsang Hoi Pat , Bown Abbie , Vipond Richard , Mentzer Alexander J. , Knight Julian C. , Kwok Andrew J. , Screaton Gavin R. , Mongkolsapaya Juthathip , Dejnirattisai Wanwisa , Supasa Piyada , Klenerman Paul , Dold Christina , Baillie J. Kenneth , Moore Shona C. , Openshaw Peter J. M. , Semple Malcolm G. , Turtle Lance C. W. , Ainsworth Mark , Allcock Alice , Beer Sally , Bibi Sagida , Skelly Donal , Stafford Lizzy , Jeffrey Katie , O’Donnell Denise , Clutterbuck Elizabeth , Espinosa Alexis , Mendoza Maria , Georgiou Dominique , Lockett Teresa , Martinez Jose , Perez Elena , Gallardo Sanchez Veronica , Scozzafava Giuseppe , Sobrinodiaz Alberto , Thraves Hannah , Joly Etienne 
Published: March 2021

AbstractSerological detection of antibodies to SARS-CoV-2 is essential for establishing rates of seroconversion in populations, and for seeking evidence for a level of antibody that may be protective against COVID-19 disease. Several high-performance commercial tests have been described, but these require centralised laboratory facilities that are comparatively expensive, and therefore not available universally. Red cell agglutination tests do not require special equipment, are read by eye, have short development times, low cost and can be applied at the Point of Care. Here we describe a quantitative Haemagglutination test (HAT) for the detection of antibodies to the receptor binding domain of the SARS-CoV-2 spike protein. The HAT has a sensitivity of 90% and specificity of 99% for detection of antibodies after a PCR diagnosed infection. We will supply aliquots of the test reagent sufficient for ten thousand test wells free of charge to qualified research groups anywhere in the world.
Bomb 137Cs in modern honey reveals a regional soil control on pollutant cycling by plants
Authors: Kaste J. M. , Volante P. , Elmore A. J. 
Published: March 2021

Abstract137Cs is a long-lived (30-year radioactive half-life) fission product dispersed globally by mid-20th century atmospheric nuclear weapons testing. Here we show that vegetation thousands of kilometers from testing sites continues to cycle137Cs because it mimics potassium, and consequently, bees magnify this radionuclide in honey. There were no atmospheric weapons tests in the eastern United States, but most honey here has detectable137Cs at >0.03 Bq kg−1, and in the southeastern U.S., activities can be >500 times higher. By measuring honey, we show regional patterns in the biogeochemical cycling of137Cs and conclude that plants and animals receive disproportionally high exposure to ionizing radiation from137Cs in low potassium soils. In several cases, the presence of137Cs more than doubled the ionizing radiation from gamma and x-rays in the honey, indicating that despite its radioactive half-life, the environmental legacy of regional137Cs pollution can persist for more than six decades.
Reversed evolution of grazer resistance to cyanobacteria
Authors: Isanta-Navarro Jana , Hairston Nelson G. , Beninde Jannik , Meyer Axel , Straile Dietmar , Möst Markus , Martin-Creuzburg Dominik 
Published: March 2021

AbstractExploring the capability of organisms to cope with human-caused environmental change is crucial for assessing the risk of extinction and biodiversity loss. We study the consequences of changing nutrient pollution for the freshwater keystone grazer, Daphnia, in a large lake with a well-documented history of eutrophication and oligotrophication. Experiments using decades-old genotypes resurrected from the sediment egg bank revealed that nutrient enrichment in the middle of the 20th century, resulting in the proliferation of harmful cyanobacteria, led to the rapid evolution of grazer resistance to cyanobacteria. We show here that the subsequent reduction in nutrient input, accompanied by a decrease in cyanobacteria, resulted in the re-emergence of highly susceptible Daphnia genotypes. Expression and subsequent loss of grazer resistance occurred at high evolutionary rates, suggesting opposing selection and that maintaining resistance was costly. We provide a rare example of reversed evolution of a fitness-relevant trait in response to relaxed selection.
UXT chaperone prevents proteotoxicity by acting as an autophagy adaptor for p62-dependent aggrephagy
Authors: Yoon Min Ji , Choi Boyoon , Kim Eun Jin , Ohk Jiyeon , Yang Chansik , Choi Yeon-Gil , Lee Jinyoung , Kang Chanhee , Song Hyun Kyu , Kim Yoon Ki , Woo Jae-Sung , Cho Yongcheol , Choi Eui-Ju , Jung Hosung , Kim Chungho 
Published: March 2021

Abstractp62/SQSTM1 is known to act as a key mediator in the selective autophagy of protein aggregates, or aggrephagy, by steering ubiquitinated protein aggregates towards the autophagy pathway. Here, we use a yeast two-hybrid screen to identify the prefoldin-like chaperone UXT as an interacting protein of p62. We show that UXT can bind to protein aggregates as well as the LB domain of p62, and, possibly by forming an oligomer, increase p62 clustering for its efficient targeting to protein aggregates, thereby promoting the formation of the p62 body and clearance of its cargo via autophagy. We also find that ectopic expression of human UXT delays SOD1(A4V)-induced degeneration of motor neurons in a Xenopus model system, and that specific disruption of the interaction between UXT and p62 suppresses UXT-mediated protection. Together, these results indicate that UXT functions as an autophagy adaptor of p62-dependent aggrephagy. Furthermore, our study illustrates a cooperative relationship between molecular chaperones and the aggrephagy machinery that efficiently removes misfolded protein aggregates.
Expanding the scope of plant genome engineering with Cas12a orthologs and highly multiplexable editing systems
Authors: Zhang Yingxiao , Ren Qiurong , Tang Xu , Liu Shishi , Malzahn Aimee A. , Zhou Jianping , Wang Jiaheng , Yin Desuo , Pan Changtian , Yuan Mingzhu , Huang Lan , Yang Han , Zhao Yuxin , Fang Qing , Zheng Xuelian , Tian Li , Cheng Yanhao , Le Ysa , McCoy Bailey , Franklin Lidiya , Selengut Jeremy D. , Mount Stephen M. , Que Qiudeng , Zhang Yong , Qi Yiping 
Published: March 2021

AbstractCRISPR-Cas12a is a promising genome editing system for targeting AT-rich genomic regions. Comprehensive genome engineering requires simultaneous targeting of multiple genes at defined locations. Here, to expand the targeting scope of Cas12a, we screen nine Cas12a orthologs that have not been demonstrated in plants, and identify six, ErCas12a, Lb5Cas12a, BsCas12a, Mb2Cas12a, TsCas12a and MbCas12a, that possess high editing activity in rice. Among them, Mb2Cas12a stands out with high editing efficiency and tolerance to low temperature. An engineered Mb2Cas12a-RVRR variant enables editing with more relaxed PAM requirements in rice, yielding two times higher genome coverage than the wild type SpCas9. To enable large-scale genome engineering, we compare 12 multiplexed Cas12a systems and identify a potent system that exhibits nearly 100% biallelic editing efficiency with the ability to target as many as 16 sites in rice. This is the highest level of multiplex edits in plants to date using Cas12a. Two compact single transcript unit CRISPR-Cas12a interference systems are also developed for multi-gene repression in rice and Arabidopsis. This study greatly expands the targeting scope of Cas12a for crop genome engineering.
Effects of long sleep time and irregular sleep–wake rhythm on cognitive function in older people
Authors: Okuda Masato , Noda Akiko , Iwamoto Kunihiro , Nakashima Honoka , Takeda Kozue , Miyata Seiko , Yasuma Fumihiko , Ozaki Norio , Shimouchi Akito 
Published: March 2021

AbstractSleep disturbances and cognitive decline are common in older adults. We aimed to investigate the effects of the total sleep time (TST) and sleep–wake rhythm on executive function and working memory in older adults. In 63 older participants, we measured the TST, wake after sleep onset (WASO), and sleep timing (midpoint between bedtime and wake-up time) using actigraphy. Executive function was evaluated with the trail making test B (TMT-B) and Wisconsin card sorting test (WCST). The number of back task (N-back task) was used to measure working memory. Participants with a TST ≥ 8 h had a significantly lower percentage of correct answers (% correct) on the 1-back task than those with a TST < 8 h. The % correct on the 1-back task was significantly correlated with the TST, WASO, and sleep timing. Multiple regression analyses revealed that the TST and sleep timing were significant factors of the % correct on the 1-back task. The TMT-B score was significantly correlated with the sleep timing. Category achievement on the WCST was significantly correlated with the standard deviation of the sleep timing. Therefore, a long sleep time and an irregular sleep–wake rhythm could have adverse effects on executive function and working memory in older people.
A smart viral vector for targeted delivery of hydrophobic drugs
Authors: Ghosh Sukanya , Banerjee Manidipa 
Published: March 2021

AbstractTargeted delivery of hydrophobic chemotherapeutic drugs to tumor cells remains a fundamental problem in cancer therapy. Effective encapsulation of hydrophobic drugs in nano-vehicles can improve their pharmacokinetics, bioavailability and prevent off-target localization. We have devised a method for easy chemical conjugation and multivalent display of a tumor-homing peptide to virus-like particles of a non-mammalian virus, Flock House Virus (FHV), to engineer it into a smart vehicle for targeted delivery of hydrophobic drugs. This conjugation method provides dual functionalization to the VLPs, first, a 2 kDa PEG spacer arm shields VLPs from immune reactivity, and second, attachment of the tumor homing peptide tLyP-1 chauffeurs the encapsulated hydrophobic drugs to target cells. The fortuitous affinity of the FHV capsid towards hydrophobic molecules, and dependence on Ca2+ for maintaining a stable capsid shell, were utilized for incorporation of hydrophobic drugs—doxorubicin and ellipticine—in tLyP-1 conjugated VLPs. The drug release profile from the VLP was observed to be gradual, and strictly endosomal pH dependent. We propose that this accessible platform empowers surface functionalization of VLP with numerous ligands containing terminal cysteines, for generating competent delivery vehicles, antigenic display and other biomedical applications.
Impact of climate change and management strategies on water and salt balance of the polders and islands in the Ganges delta
Authors: Mainuddin Mohammed , Karim Fazlul , Gaydon Donald S. , Kirby John M. 
Published: March 2021

AbstractEnhancing crop production, particularly by growing a crop in the typically-fallow dry season is a key strategy for alleviating poverty in the Ganges delta region. We used a polder water and salt balance model to examine the impact of several crop management, salt management and climate change scenarios on salinity and crop evapotranspiration at Dacope and Amtali in Bangladesh and Gosaba in India. A key (and unsurprising) finding is that salt management is very important, particularly at the two drier sites, Dacope and Gosaba. Good salt management lowers salinity in the shallow groundwater, soil and water storage ponds, and leads to more irrigation. Climate change is projected to alter rainfall, and this in turn leads to modelled increases or decreases in runoff from the polders, and thence affect salt concentrations in the soil and ponds and canals. Thus, the main impacts of climate change are through the indirect impacts on salt concentrations, rather than the direct impacts of the amount of water supplied as rainfall. Management practices to remove salt from polders are therefore likely to be effective in combatting the impacts of projected climate change particularly at Dacope and Gosaba.
Revisiting single cell analysis in forensic science
Authors: Watkins Davis R. L. , Myers Dan , Xavier Hannah E. , Marciano Michael A. 
Published: March 2021

AbstractForensic science has yet to take full advantage of single cell analysis. Its greatest benefit is the ability to alleviate the challenges associated with DNA mixture analysis, which remains a significant hurdle in forensic science. Many of the factors that cause complexity in mixture interpretation are absent in single cell analyses—multiple contributors, varied levels of contribution, and allele masking. This study revisits single cell analyses in the context of forensic identification, introducing previously unseen depth to the characterization of data generated from single cells using a novel pipeline that includes recovery of single cells using the DEPArray NxT and amplification using the PowerPlex Fusion 6c kit with varied PCR cycles (29, 30, and 31). The resulting allelic signal was assessed using analytical thresholds of 10, 100, and 150RFU. The mean peak heights across the sample sets generally increased as cycle number increased, 75.0 ± 85.3, 147.1 ± 172.6, and 226.1 ± 298.2 RFU, for 29, 30, and 31 cycles, respectively. The average proportion of allele/locus dropout was most significantly impacted by changes in the detection threshold, whereas increases in PCR cycle number had less impact. Overall data quality improved notably when increasing PCR from 29 to 30 cycles, less improvement and more volatility was introduced at 31 cycles. The average random match probabilities for the 29, 30, and 31 cycle sets at 150RFU are 1 in 2.4 × 1018 ± 1.46 × 1019, 1 in 1.49 × 1025 ± 5.8 × 1025, and 1 in 1.83 × 1024 ± 8.09 × 1024, respectively. This demonstrates the current power of single cell analysis in removing the need for complex mixture analysis.
Clinical and genetic spectrum of glycogen storage disease in Iranian population using targeted gene sequencing
Authors: Beyzaei Zahra , Ezgu Fatih , Geramizadeh Bita , Imanieh Mohammad Hadi , Haghighat Mahmood , Dehghani Seyed Mohsen , Honar Naser , Zahmatkeshan Mojgan , Jassbi Amirreza , Mahboubifar Marjan , Alborzi Alireza 
Published: March 2021

AbstractGlycogen storage diseases (GSDs) are known as complex disorders with overlapping manifestations. These features also preclude a specific clinical diagnosis, requiring more accurate paraclinical tests. To evaluate the patients with particular diagnosis features characterizing GSD, an observational retrospective case study was designed by performing a targeted gene sequencing (TGS) for accurate subtyping. A total of the 14 pediatric patients were admitted to our hospital and referred for molecular genetic testing using TGS. Seven genes namely SLC37A4, AGL, GBE1, PYGL, PHKB, PGAM2, and PRKAG2 were detected to be responsible for the onset of the clinical symptoms. A total number of 15 variants were identified i.e. mostly loss-of-function (LoF) variants, of which 10 variants were novel. Finally, diagnosis of GSD types Ib, III, IV, VI, IXb, IXc, X, and GSD of the heart, lethal congenital was made in 13 out of the 14 patients. Notably, GSD-IX and GSD of the heart-lethal congenital (i.e. PRKAG2 deficiency) patients have been reported in Iran for the first time which shown the development of liver cirrhosis with novel variants. These results showed that TGS, in combination with clinical, biochemical, and pathological hallmarks, could provide accurate and high-throughput results for diagnosing and sub-typing GSD and related diseases.
Biofabrication of chitosan/chitosan nanoparticles/polycaprolactone transparent membrane for corneal endothelial tissue engineering
Authors: Tayebi Tahereh , Baradaran-Rafii Alireza , Hajifathali Abbas , Rahimpour Azam , Zali Hakimeh , Shaabani Alireza , Niknejad Hassan 
Published: March 2021

AbstractWe aimed to construct a biodegradable transparent scaffold for culturing corneal endothelial cells by incorporating chitosan nanoparticles (CSNPs) into chitosan/polycaprolactone (PCL) membranes. Various ratios of CSNP/PCL were prepared in the presence of constant concentration of chitosan and the films were constructed by solvent casting method. Scaffold properties including transparency, surface wettability, FTIR, and biocompatibility were examined. SEM imaging, H&E staining, and cell count were performed to investigate the HCECs adhesion. The phenotypic maintenance of the cells during culture was investigated by flow cytometry. Transparency and surface wettability improved by increasing the CSNP/PCL ratio. The CSNP/PCL 50/25, which has the lowest WCA, showed comparable transparency with human acellular corneal stroma. The scaffold was not cytotoxic and promoted the HCECs proliferation as evaluated by MTT assay. Cell counting, flow cytometry, SEM, and H&E results showed appropriate attachment of HCECs to the scaffold which formed a compact monolayer. The developed scaffold seems to be suitable for use in corneal endothelial regeneration in terms of transparency and biocompatibility.