bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retina-attached slice recording reveals light-triggered tonic GABA signaling in suprachiasmatic nucleus
Authors: Kwon Jea , Jang Minwoo Wendy , Lee C. Justin 
Published: November 2021

AbstractLight is a powerful external cue modulating the biological rhythm of internal clock neurons in the suprachiasmatic nucleus (SCN). GABA signaling in SCN is critically involved in this process. Both phasic and tonic modes of GABA signaling exist in SCN. Of the two modes, the tonic mode of GABA signaling has been implicated in light-mediated synchrony of SCN neurons. However, modulatory effects of external light on tonic GABA signalling are yet to be explored. Here, we systematically characterized electrophysiological properties of the clock neurons and determined the spatio-temporal profiles of tonic GABA current. Based on the whole-cell patch-clamp recordings from 76 SCN neurons, the cells with large tonic GABA current (>15 pA) were more frequently found in dorsal SCN. Moreover, tonic GABA current in SCN was highly correlated with the frequency of spontaneous inhibitory postsynaptic current (sIPSC), raising a possibility that tonic GABA current is due to spill-over from synaptic release. Interestingly, tonic GABA current was inversely correlated with slice-to-patch time interval, suggesting a critical role of retinal light exposure in intact brain for an induction of tonic GABA current in SCN. To test this possibility, we obtained meticulously prepared retina-attached SCN slices and successfully recorded tonic and phasic GABA signaling in SCN neurons. For the first time, we observed an early-onset, long-lasting tonic GABA current, followed by a slow-onset, short-lasting increase in the phasic GABA frequency, upon direct light-illumination of the attached retina. This result provides the first evidence that external light cue can directly trigger both tonic and phasic GABA signaling in SCN cell. In conclusion, we propose tonic GABA as the key mediator of external light in SCN.
Amplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma
Authors: Lu Jia-Cheng , Zhang Peng-Fei , Huang Xiao-Yong , Guo Xiao-Jun , Gao Chao , Zeng Hai-Ying , Zheng Yi-Min , Wang Si-Wei , Cai Jia-Bin , Sun Qi-Man , Shi Ying-Hong , Zhou Jian , Ke Ai-Wu , Shi Guo-Ming , Fan Jia 
Published: November 2021

Abstract
Background
Immune checkpoint blockade resistance narrows the efficacy of cancer immunotherapies, but the underlying mechanism remains elusive. Delineating the inherent mechanisms of anti-PD1 resistance is important to improve outcome of patients with advanced HCC.

Method
The level of cricTMEM181 was measured in HCC patients with anti-PD1 therapy by RNA sequencing and then confirmed by qPCR and Sanger sequencing. Immune status in tumor microenvironment of HCC patients or mice models was evaluated by flow cytometry and IHC. Exosomes from HCC cell lines were isolated by ultracentrifugation, and their internalization by macrophage was confirmed by immunofluorescence. The underlying mechanism of HCC-derived exosomal circTMEM181 to macrophage was confirmed by SILAC, RNA FISH and RNA immunoprecipitation. The ATP–ADO pathway amplified by HCC–macrophage interaction was evaluated through ATP, AMP and ADO measurement and macrophage-specific CD39 knockout mice. The role of circTMEM181 in anti-PD1 therapy and its clinical significance were also determined in our retrospective HCC cohorts.

Results
Here, we found that circTMEM181 was elevated in hepatocellular carcinoma (HCC) patients responding poorly to anti-PD1 therapy and in HCC patients with a poor prognosis after operation. Moreover, we also found that high exosomal circTMEM181 favored the immunosuppressive microenvironment and endowed anti-PD1 resistance in HCC. Mechanistically, exosomal circTMEM181 sponged miR-488-3p and upregulated CD39 expression in macrophages. Using macrophage-specific CD39 knockout mice and pharmacologic approaches, we revealed a novel mode of anti-PD1 resistance in HCC. We discovered that cell-specific CD39 expression in macrophages and CD73 expression in HCC cells synergistically activated the eATP–adenosine pathway and produced more adenosine, thereby impairing CD8+ T cell function and driving anti-PD1 resistance.

Conclusion
In summary, HCC-derived exosomal circTMEM181 contributes to immunosuppression and anti-PD1 resistance by elevating CD39 expression, and inhibiting the ATP–adenosine pathway by targeting CD39 on macrophages can rescue anti-PD1 therapy resistance in HCC.

Graphical Abstract
Dispatcher instructions for bystander cardiopulmonary resuscitation and neurologically intact survival after bystander-witnessed out-of-hospital cardiac arrests: a nationwide, population-based observational study
Authors: Goto Yoshikazu , Funada Akira , Maeda Tetsuo , Goto Yumiko 
Published: November 2021

AbstractBackgroundThe International Liaison Committee on Resuscitation recommends that dispatchers provide instructions to perform compression-only cardiopulmonary resuscitation (CPR) to callers responding to adults with out-of-hospital cardiac arrest (OHCA). This study aimed to determine the optimal dispatcher-assisted CPR (DA-CPR) instructions for OHCA.MethodsWe analysed the records of 24,947 adult patients (aged ≥ 18 years) who received bystander DA-CPR after bystander-witnessed OHCA. Data were obtained from a prospectively recorded Japanese nationwide Utstein-style database for a 2-year period (2016–2017). Patients were divided into compression-only DA-CPR (n = 22,778) and conventional DA-CPR (with a compression-to-ventilation ratio of 30:2,n = 2169) groups. The primary outcome measure was 1-month neurological intact survival, defined as a cerebral performance category score of 1–2 (CPC 1–2).ResultsThe 1-month CPC 1–2 rate was significantly higher in the conventional DA-CPR group than in the compression-only DA-CPR group (before propensity score (PS) matching, 7.5% [162/2169] versus 5.8% [1309/22778],p < 0.01; after PS matching, 7.5% (162/2169) versus 5.7% (123/2169),p < 0.05). Compared with compression-only DA-CPR, conventional DA-CPR was associated with increased odds of 1-month CPC 1–2 (before PS matching, adjusted odds ratio 1.39, 95% confidence interval [CI] 1.14–1.70,p < 0.01; after PS matching, adjusted odds ratio 1.34, 95% CI 1.00–1.79,p < 0.05).ConclusionWithin the limitations of this retrospective observational study, conventional DA-CPR with a compression-to-ventilation ratio of 30:2 was preferable to compression-only DA-CPR as an optimal DA-CPR instruction for coaching callers to perform bystander CPR for adult patients with bystander-witnessed OHCAs.
Perceived study-induced influence on the control group in a randomized controlled trial evaluating a complex intervention to promote psychosocial well-being after stroke: a process evaluation
Authors: Mangset Margrete , Kitzmüller Gabriele , Evju Anne S. , Angel Sanne , Aadal Lena , Martinsen Randi , Bronken Berit Arnesveen , Kvigne Kari J. , Bragstad Line K. , Hjelle Ellen Gabrielsen , Sveen Unni , Kirkevold Marit 
Published: November 2021

Abstract
Background
A commonly applied control condition in trials evaluating complex interventions in rehabilitation research is “usual care.” The main challenge is to ensure that the control group receives genuine usual care as delivered in everyday clinical practice. The assessment interviews and dialogues with the data collectors may influence the control group participants’ reflections on their condition and adjustments. This represents a threat to the internal validity of the trial. Thus, the aim of this study was to explore the perceived study-induced influence of assessment interviews on the adjustment of the members of a control group in a randomized clinical trial. The aim of the trial was to test a dialogue-based psychosocial intervention aiming at promoting the psychosocial well-being and adjustment of stroke survivors.

Methods
Fifteen participants in the control group of a multicenter stroke rehabilitation trial participated in narrative semi-structured interviews. Ricoeur’s interpretation theory guided the analysis.

Results
The perceived study-induced influence of the assessment interviews on the adjustment process of members of the control group varied considerably. The results demonstrated that the assessment interviews facilitated some participants’ feelings of control and their ability to cope. Other participants’ statements indicate that they relied on their existing personal capacity to cope and adjust and that the assessment interviews did not make any difference either on their coping ability or on their process of adjustment.
Five themes were identified that described the perceived study-induced influence of the assessment interviews in the control group. The themes illustrated that the assessments served as a safety net, enhanced awareness and understanding, encouraged seeking support, allowed the opportunity to vent disappointment, or did not make any difference either way.

Conclusions
RCT assessment interviews may influence the adjustment process and represent a serious problem in measuring interventions over time in trials of complex interventions in rehabilitation research. To uphold rigor and stringency, the usual care control conditions should be thoroughly assessed and described. Informing participants only about the treatment they were allocated to receive might counteract the potential to dilute the difference between the two arms of the trial.

Trial registration
ClinicalTrials.gov NCT02338869. Registered on October 4, 2014
The place of S-ketamine in fibromyalgia treatment (ESKEFIB): study protocol for a prospective, single-center, double-blind, randomized, parallel-group, dose-escalation controlled trial
Authors: Javorcikova Zuzana , Dangoisse Michel , Nikis Stéphane , Lechat Jean-Paul , Gillain Aline , Fils Jean-François , Van der Linden Philippe 
Published: November 2021

AbstractBackgroundFibromyalgia is a chronic multidimensional pain disease with no curative treatment currently available. Its management relies on a multimodal approach involving pharmacologic and non-pharmacologic elements. Because a suggested factor in its etiology is a central sensitization phenomenon involving the N-methyl-D-aspartate receptor (NMDAR), NMDAR antagonists have been proposed as a treatment target. Ketamine and its levogyre form, S-ketamine, have been used to treat chronic pain for many years without consensus about their therapeutic efficiency. We aim to assess the efficacy of S-ketamine as a co-treatment for fibromyalgia.MethodsThis prospective, randomized, single-center, double-blind, parallel-group, dose-escalation trial will compare a co-treatment with S-ketamine (intervention) to a control treatment without S-ketamine (control). It will consist of two successive cohorts with 2:1 randomization ratio (S-ketamine at two different doses: control) with 105 participants in each cohort. The protocol follow-up time will be 12 weeks, including 3 visits for the treatment (week 0, week 2, and week 4) and 3 visits for follow-up (week 6, week 9, and week 12). Our primary outcome, pain relief and/or better patient function, will be assessed with the Brief Pain Inventory questionnaire. The statistical analysis will be performed on an intention-to-treat basis. If the primary outcome is reached at the end of follow-up in the first cohort with low-dose S-ketamine (0.2 mg/kg), the trial will end. If not, the trial will continue with the second cohort and high-dose S-ketamine (0.4 mg/kg).DiscussionThe challenge of our trial is the inclusion of a large number of participants in comparison to other trials involving ketamine or S-ketamine infusions for chronic pain management. The originality of our protocol is to include functionality in addition to pain relief as a primary outcome because these two endpoints are not linked in a linear way. For some patients, functional status is more important than pain relief.Trial registrationEudraCT reference: 2020-000473-25,ClinicalTrials.gov: NCT04436250, first posted June 18, 2020; last updated July 21, 2020. Protocol version 2.2 issued on September 30, 2020, after a revision by the ethics committee.https://clinicaltrials.gov/ct2/show/NCT04436250
Synergistic effects of multiple enzymes from industrial Aspergillus niger strain O1 on starch saccharification
Authors: Guo Wenzhu , Yang Jianhua , Huang Tianchen , Liu Dandan , Liu Qian , Li Jingen , Sun Wenliang , Wang Xingji , Zhu Leilei , Tian Chaoguang 
Published: November 2021

Abstract
Background
Starch is one of the most important renewable polysaccharides in nature for production of bio-ethanol. The starch saccharification step facilitates the depolymerization of starch to yield glucose for biofuels production. The filamentous fungus Aspergillus niger (A. niger) is the most used microbial cell factory for production of the commercial glucoamylase. However, the role of each component in glucoamylases cocktail of A. niger O1 for starch saccharification remains unclear except glucoamylase.

Results
In this study, we identified the key enzymes contributing to the starch saccharification process are glucoamylase, α-amylase and acid α-amylase out of 29 glycoside hydrolases from the 6-day fermentation products of A. niger O1. Through the synergistic study of the multienzymes for the starch saccharification in vitro, we found that increasing the amount of α-amylase by 5-10 times enhanced the efficiency of starch saccharification by 14.2-23.2%. Overexpression of acid α-amylase in strain O1 in vivo increased the total glucoamylase activity of O1 cultures by 15.0%.

Conclusions
Our study clarifies the synergistic effects among the components of glucoamylases cocktail, and provides an effective approach to optimize the profile of saccharifying enzymes of strain O1 for improving the total glucoamylase activity.
Spawning behavior of Aedini (Diptera: Culicidae) in a remnant of Atlantic Forest in the state of Rio de Janeiro
Authors: Bastos Amanda Queiroz , Leite Paulo José , dos Santos-Mallet Jacenir Reis , de Mello Cecilia Ferreira , Serdeiro Michele , dos Silva Júlia Santos , Figueiró Ronaldo , Docile Tatiana , Alencar Jeronimo 
Published: November 2021

AbstractBackgroundMosquito assemblages are organized along an ecological gradient, including small habitats where interspecific competition predominates and large permanent habitats where predation predominates. This study aimed to analyze the oviposition behavior of mosquitoes regarding the preference for traps installed at two different heights with regard to ground level and the tendency to share spawning sites in an Atlantic Forest fragment in Nova Iguaçu, State of Rio de Janeiro, Brazil.MethodsThe eggs were collected from April 2018 to March 2019. Twelve ovitraps were used, randomly distributed in trees at ground level and at a height of 3 m in a forest environment.ResultsThey were sequentially numbered, monitored, and replaced every 2 weeks. Among the 5818 eggs collected, 3941 hatched, 3756 reached the pupa stage, and 2370 reached the adult stage. The most abundant species wereAedes albopictus(63%) andHaemagogus leucocelaenus(35%), followed byAedes terrens(2%) andHaemagogus janthinomys(1%). Analyses showed a significant difference of (P = 0.02) between the number of mosquito species collected in the palettes at ground level and the number collected at the height of 3 m. Cluster analysis of species abundance showed that the eggs collected in the palettes at ground level were more abundant than those collected in the palettes at the height of 3 m. We detected co-occurrence of species in the oviposition palettes; according to the null model, such species distribution was not random.ConclusionsThe exploitation of oviposition sites by mosquito species can represent an event forced by population density facilitated by the ecological valence of individuals of one species. Understanding the aggregate distribution of larvae at the oviposition site allows us to conduct more in-depth studies of the oviposition behavior of female mosquitoes.Graphical Abstract
Whole-genome analysis reveals the contribution of non-coding de novo transposon insertions to autism spectrum disorder
Authors: Borges-Monroy Rebeca , Chu Chong , Dias Caroline , Choi Jaejoon , Lee Soohyun , Gao Yue , Shin Taehwan , Park Peter J. , Walsh Christopher A. , Lee Eunjung Alice 
Published: November 2021

Abstract
Background
Retrotransposons have been implicated as causes of Mendelian disease, but their role in autism spectrum disorder (ASD) has not been systematically defined, because they are only called with adequate sensitivity from whole genome sequencing (WGS) data and a large enough cohort for this analysis has only recently become available.

Results
We analyzed WGS data from a cohort of 2288 ASD families from the Simons Simplex Collection by establishing a scalable computational pipeline for retrotransposon insertion detection. We report 86,154 polymorphic retrotransposon insertions—including > 60% not previously reported—and 158 de novo retrotransposition events. The overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 117, and 206 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 21 births total. However, ASD cases showed more de novo L1 insertions than expected in ASD genes. Additionally, we observed exonic insertions in loss-of-function intolerant genes, including a likely pathogenic exonic insertion in CSDE1, only in ASD individuals.

Conclusions
These findings suggest a modest, but important, impact of intronic and exonic retrotransposon insertions in ASD, show the importance of WGS for their analysis, and highlight the utility of specific bioinformatic tools for high-throughput detection of retrotransposon insertions.
Optimizing high-flow nasal cannula flow settings in adult hypoxemic patients based on peak inspiratory flow during tidal breathing
Authors: Li Jie , Scott J. Brady , Fink James B. , Reed Brooke , Roca Oriol , Dhand Rajiv 
Published: November 2021

Abstract
Background
Optimal flow settings during high-flow nasal cannula (HFNC) therapy are unknown. We investigated the optimal flow settings during HFNC therapy based on breathing pattern and tidal inspiratory flows in patients with acute hypoxemic respiratory failure (AHRF).

Methods
We conducted a prospective clinical study in adult hypoxemic patients treated by HFNC with a fraction of inspired oxygen (FIO2) ≥ 0.4. Patient’s peak tidal inspiratory flow (PTIF) was measured and HFNC flows were set to match individual PTIF and then increased by 10 L/min every 5–10 min up to 60 L/min. FIO2 was titrated to maintain pulse oximetry (SpO2) of 90–97%. SpO2/FIO2, respiratory rate (RR), ROX index [(SpO2/FIO2)/RR], and patient comfort were recorded after 5–10 min on each setting. We also conducted an in vitro study to explore the relationship between the HFNC flows and the tracheal FIO2, peak inspiratory and expiratory pressures.

Results
Forty-nine patients aged 58.0 (SD 14.1) years were enrolled. At enrollment, HFNC flow was set at 45 (38, 50) L/min, with an FIO2 at 0.62 (0.16) to obtain an SpO2/FIO2 of 160 (40). Mean PTIF was 34 (9) L/min. An increase in HFNC flows up to two times of the individual patient’s PTIF, incrementally improved oxygenation but the ROX index plateaued with HFNC flows of 1.34–1.67 times the individual PTIF. In the in vitro study, when the HFNC flow was set higher than PTIF, tracheal peak inspiratory and expiratory pressures increased as HFNC flow increased but the FIO2 did not change.

Conclusion
Mean PTIF values in most patients with AHRF were between 30 and 40 L/min. We observed improvement in oxygenation with HFNC flows set above patient PTIF. Thus, a pragmatic approach to set optimal flows in patients with AHRF would be to initiate HFNC flow at 40 L/min and titrate the flow based on improvement in ROX index and patient tolerance.
Trial registration: ClinicalTrials.gov (NCT03738345). Registered on November 13th, 2018. https://clinicaltrials.gov/ct2/show/NCT03738345?term=NCT03738345&draw=2&rank=1
Research on college English teaching based on data mining technology
Authors: Duan Jinhui , Gao Rui 
Published: November 2021

AbstractTo improve the efficiency and quality of college English teaching, we analyzed the feasibility and application process of data mining technology in college English teaching. The entire process of data classification mining was fully realized. A new teaching program was proposed. The object and target of data mining were determined. Online surveys were used to collect data. Data integration, data cleaning, data conversion, data reduction and other pre-processing technologies were adopted. The decision tree was generated by using the C4.5 algorithm, and the pruning was carried out. The result analysis decision tree model was completed. A detailed survey of the students' English learning in University was made in detail. The results showed that the qualified rate of students' English performance was increased from 20–30% to 50–60%. Therefore, the classification rules provide theoretical support for the school teaching decision. This method can improve the quality of English teaching.
Biochemical characterization of a family IV esterase with R-form enantioselectivity from a compost metagenomic library
Authors: Park Jong Eun , Jeong Geum Seok , Lee Hyun Woo , Kim Hoon 
Published: November 2021

AbstractA novel family IV esterase (hormone-sensitive lipase, HSL) gene, est15L, was isolated from a compost metagenomic library. Encoded Est15L comprised 328 amino acids with a molecular weight of 34,770 kDa and was an intracellular esterase without a signal peptide. The multiple sequence alignment (MSA) of Est15L with other family IV esterases showed conserved regions such as HGG, DYR, GXSXG, DPL, and GXIH. Native Est15L was a dimeric form from the results of size exclusion chromatography. It was optimally active at 50 ℃ and pH 9.0, indicating alkaline esterase. However, it showed a low thermostability with half-lives of 30.3 at 30 ℃ and 2.7 min at 40 ℃. It preferred p-nitrophenyl butyrate (C4) with Km and Vmax values of 0.28 mM and 270.8 U/mg, respectively. Est15L was inhibited by organic solvents such as 30% methanol, isopropanol, and acetonitrile with residual activities of 12.5, 0.9, and 0.3%, respectively. It was also inhibited by 1% SDS and 1% PMSF; however, Est15L maintained its activity at 1% Triton X-100 and EDTA. Est15L was inhibited by Cu2+, Zn2+, Mn2+, Co2+, Fe2+, and Na+. In addition, Est15L hydrolyzed glyceryl tributyrate with a residual substrate amount of 43.7% at 60 min but could not hydrolyze the oils (fish and olive) and glyceryl trioleate. Interestingly, Est15L showed significant enantioselectivity toward the R-form with a residual substrate amount of 44.6%, lower than that of the S-form (83.5%). Considering its properties, Est15L can be a potential candidate for chemical reactions, such as the synthesis of pharmaceutical compounds.