bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-dose rapamycin exerts a temporary impact on T. reesei RUT-C30 through gene trFKBP12
Authors: Pang Ai-Ping , Wang Haiyan , Zhang Funing , Hu Xin , Wu Fu-Gen , Zhou Zhihua , Wang Wei , Lu Zuhong , Lin Fengming 
Published: March 2021

Abstract
Background
Knowledge with respect to regulatory systems for cellulase production is prerequisite for exploitation of such regulatory networks to increase cellulase production, improve fermentation efficiency and reduce the relevant production cost. The target of rapamycin (TOR) signaling pathway is considered as a central signaling hub coordinating eukaryotic cell growth and metabolism with environmental inputs. However, how and to what extent the TOR signaling pathway and rapamycin are involved in cellulase production remain elusive.

Result
At the early fermentation stage, high-dose rapamycin (100 μM) caused a temporary inhibition effect on cellulase production, cell growth and sporulation of Trichoderma reesei RUT-C30 independently of the carbon sources, and specifically caused a tentative morphology defect in RUT-C30 grown on cellulose. On the contrary, the lipid content of T. reesei RUT-C30 was not affected by rapamycin. Accordingly, the transcriptional levels of genes involved in the cellulase production were downregulated notably with the addition of rapamycin. Although the mRNA levels of the putative rapamycin receptor trFKBP12 was upregulated significantly by rapamycin, gene trTOR (the downstream effector of the rapamycin–FKBP12 complex) and genes associated with the TOR signaling pathways were not changed markedly. With the deletion of gene trFKBP12, there is no impact of rapamycin on cellulase production, indicating that trFKBP12 mediates the observed temporary inhibition effect of rapamycin.

Conclusion
Our study shows for the first time that only high-concentration rapamycin induced a transient impact on T. reesei RUT-C30 at its early cultivation stage, demonstrating T. reesei RUT-C30 is highly resistant to rapamycin, probably due to that trTOR and its related signaling pathways were not that sensitive to rapamycin. This temporary influence of rapamycin was facilitated by gene trFKBP12. These findings add to our knowledge on the roles of rapamycin and the TOR signaling pathways play in T. reesei.
OncoGEMINI: software for investigating tumor variants from multiple biopsies with integrated cancer annotations
Authors: Nicholas Thomas J. , Cormier Michael J. , Huang Xiaomeng , Qiao Yi , Marth Gabor T. , Quinlan Aaron R. 
Published: March 2021

Abstract
Background
DNA sequencing has unveiled extensive tumor heterogeneity in several different cancer types, with many exhibiting diverse subclonal populations. Identifying and tracing mutations throughout the expansion and progression of a tumor represents a significant challenge. Furthermore, prioritizing the subset of such mutations most likely to contribute to tumor evolution or that could serve as potential therapeutic targets represents an ongoing problem.

Results
Here, we describe OncoGEMINI, a new tool designed for exploring the complex patterns and trajectory of somatic and inherited variation observed in heterogeneous tumors biopsied over the course of treatment. This is accomplished by creating a searchable database of variants that includes tumor sampling time points and allows for filtering methods that reflect specific changes in variant allele frequencies over time. Additionally, by incorporating existing annotations and resources that facilitate the interpretation of cancer mutations (e.g., CIViC, DGIdb), OncoGEMINI enables rapid searches for, and potential identification of, mutations that may be driving subclonal evolution.

Conclusions
By combining relevant genomic annotations alongside specific filtering tools, OncoGEMINI provides powerful and customizable approaches that enable the quick identification of individual tumor variants that meet specified criteria. It can be applied to a wide range of tumor-derived sequence data, but is especially designed for studies with multiple samples, including longitudinal datasets. It is available under an MIT license at github.com/fakedrtom/oncogemini.
Development of double-positive thymocytes at single-cell resolution
Authors: Li Young , Li Kun , Zhu Lianbang , Li Bin , Zong Dandan , Cai Pengfei , Jiang Chen , Du Pengcheng , Lin Jun , Qu Kun 
Published: March 2021

Abstract
Background
T cells generated from thymopoiesis are essential for the immune system, and recent single-cell studies have contributed to our understanding of the development of thymocytes at the genetic and epigenetic levels. However, the development of double-positive (DP) T cells, which comprise the majority of thymocytes, has not been well investigated.

Methods
We applied single-cell sequencing to mouse thymocytes and analyzed the transcriptome data using Seurat. By applying unsupervised clustering, we defined thymocyte subtypes and validated DP cell subtypes by flow cytometry. We classified the cell cycle phases of each cell according to expression of cell cycle phase-specific genes. For immune synapse detection, we used immunofluorescent staining and ImageStream-based flow cytometry. We studied and integrated human thymocyte data to verify the conservation of our findings and also performed cross-species comparisons to examine species-specific gene regulation.

Results
We classified blast, rearrangement, and selection subtypes of DP thymocytes and used the surface markers CD2 and Ly6d to identify these subtypes by flow cytometry. Based on this new classification, we found that the proliferation of blast DP cells is quite different from that of double-positive cells and other cell types, which tend to exit the cell cycle after a single round. At the DP cell selection stage, we observed that CD8-associated immune synapses formed between thymocytes, indicating that CD8sp selection occurred among thymocytes themselves. Moreover, cross-species comparison revealed species-specific transcription factors (TFs) that contribute to the transcriptional differences of thymocytes from humans and mice.

Conclusions
Our study classified DP thymocyte subtypes of different developmental stages and provided new insight into the development of DP thymocytes at single-cell resolution, furthering our knowledge of the fundamental immunological process of thymopoiesis.
Microglial PGC-1α protects against ischemic brain injury by suppressing neuroinflammation
Authors: Han Bin , Jiang Wei , Cui Pan , Zheng Kai , Dang Chun , Wang Junjie , Li He , Chen Lin , Zhang Rongxin , Wang Qing Mei , Ju Zhenyu , Hao Junwei 
Published: March 2021

Abstract
Background
Neuroinflammation and immune responses occurring minutes to hours after stroke are associated with brain injury after acute ischemic stroke (AIS). PPARγ coactivator-1α (PGC-1α), as a master coregulator of gene expression in mitochondrial biogenesis, was found to be transiently upregulated in microglia after AIS. However, the role of microglial PGC-1α in poststroke immune modulation remains unknown.

Methods
PGC-1α expression in microglia from human and mouse brain samples following ischemic stroke was first determined. Subsequently, we employed transgenic mice with microglia-specific overexpression of PGC-1α for middle cerebral artery occlusion (MCAO). The morphology and gene expression profile of microglia with PGC-1α overexpression were evaluated. Downstream inflammatory cytokine production and NLRP3 activation were also determined. ChIP-Seq analysis was performed to detect PGC-1α-binding sites in microglia. Autophagic and mitophagic activity was further monitored by immunofluorescence staining. Unc-51-like autophagy activating kinase 1 (ULK1) expression was evaluated under the PGC-1α interaction with ERRα. Finally, pharmacological inhibition and genomic knockdown of ULK1 were performed to estimate the role of ULK1 in mediating mitophagic activity after ischemic stroke.

Results
PGC-1α expression was shortly increased after ischemic stroke, not only in human brain samples but also in mouse brain samples. Microglia-specific PGC-1α overexpressing mice exhibited significantly decreased neurologic deficits after ischemic injury, with reduced NLRP3 activation and proinflammatory cytokine production. ChIP-Seq analysis and KEGG pathway analysis revealed that mitophagy was significantly enhanced. PGC-1α significantly promoted autophagic flux and induced autolysosome formation. More specifically, the autophagic clearance of mitochondria was enhanced by PGC-1α regulation, indicating the important role of mitophagy. Pharmacological inhibition or knockdown of ULK1 expression impaired autophagic/mitophagic activity, thus abolishing the neuroprotective effects of PGC-1α.

Conclusions
Mechanistically, in AIS, PGC-1α promotes autophagy and mitophagy through ULK1 and reduces NLRP3 activation. Our findings indicate that microglial PGC-1α may be a promising therapeutic target for AIS.
Phenome-wide investigation of the causal associations between childhood BMI and adult trait outcomes: a two-sample Mendelian randomization study
Authors: Dong Shan-Shan , Zhang Kun , Guo Yan , Ding Jing-Miao , Rong Yu , Feng Jun-Cheng , Yao Shi , Hao Ruo-Han , Jiang Feng , Chen Jia-Bin , Wu Hao , Chen Xiao-Feng , Yang Tie-Lin 
Published: March 2021

AbstractBackgroundChildhood obesity is reported to be associated with the risk of many diseases in adulthood. However, observational studies cannot fully account for confounding factors. We aimed to systematically assess the causal associations between childhood body mass index (BMI) and various adult traits/diseases using two-sample Mendelian randomization (MR).MethodsAfter data filtering, 263 adult traits genetically correlated with childhood BMI (P < 0.05) were subjected to MR analyses. Inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods were used to estimate the causal effects. Multivariable MR analysis was performed to test whether the effects of childhood BMI on adult traits are independent from adult BMI.ResultsWe identified potential causal effects of childhood obesity on 60 adult traits (27 disease-related traits, 27 lifestyle factors, and 6 other traits). Higher childhood BMI was associated with a reduced overall health rating (β = − 0.10, 95% CI − 0.13 to − 0.07,P = 6.26 × 10−11). Specifically, higher childhood BMI was associated with increased odds of coronary artery disease (OR = 1.09, 95% CI 1.06 to 1.11,P = 4.28 × 10−11), essential hypertension (OR = 1.12, 95% CI 1.08 to 1.16,P = 1.27 × 10−11), type 2 diabetes (OR = 1.36, 95% CI 1.30 to 1.43,P = 1.57 × 10−34), and arthrosis (OR = 1.09, 95% CI 1.06 to 1.12,P = 8.80 × 10−9). However, after accounting for adult BMI, the detrimental effects of childhood BMI on disease-related traits were no longer present (P > 0.05). For dietary habits, different from conventional understanding, we found that higher childhood BMI was associated with low calorie density food intake. However, this association might be specific to the UK Biobank population.ConclusionsIn summary, we provided a phenome-wide view of the effects of childhood BMI on adult traits. Multivariable MR analysis suggested that the associations between childhood BMI and increased risks of diseases in adulthood are likely attributed to individuals remaining obese in later life. Therefore, ensuring that childhood obesity does not persist into later life might be useful for reducing the detrimental effects of childhood obesity on adult diseases.
Diet and gut microbiome interactions of relevance for symptoms in irritable bowel syndrome
Authors: Tap Julien , Störsrud Stine , Le Nevé Boris , Cotillard Aurélie , Pons Nicolas , Doré Joël , Öhman Lena , Törnblom Hans , Derrien Muriel , Simrén Magnus 
Published: March 2021

Abstract
Background
While several studies have documented associations between dietary habits and microbiota composition and function in healthy individuals, no study explored these associations in patients with irritable bowel syndrome (IBS), and especially with symptoms.

Methods
Here, we used a novel approach that combined data from a 4-day food diary, integrated into a food tree, together with gut microbiota (shotgun metagenomic) for individuals with IBS (N = 149) and healthy controls (N = 52). Paired microbiota and food-based trees allowed us to detect new associations between subspecies and diet. Combining co-inertia analysis and linear regression models, exhaled gas levels and symptom severity could be predicted from metagenomic and dietary data.

Results
We showed that individuals with severe IBS are characterized by a higher intake of poorer-quality food items during their main meals. Our analysis suggested that covariations between gut microbiota at subspecies level and diet could be explained with IBS symptom severity, exhaled gas, glycan metabolism, and meat/plant ratio. We provided evidence that IBS severity is associated with altered gut microbiota hydrogen function in correlation with microbiota enzymes involved in animal carbohydrate metabolism.

Conclusions
Our study provides an unprecedented resolution of diet-microbiota-symptom interactions and ultimately guides new interventional studies that aim to identify gut microbiome-based nutritional recommendations for the management of gastrointestinal symptoms.

Trial registration
This trial was registered on the ClinicalTrials.gov, with the registration number NCT01252550, on 3rd December 2010.
A small-molecule pan-class I glucose transporter inhibitor reduces cancer cell proliferation in vitro and tumor growth in vivo by targeting glucose-based metabolism
Authors: Shriwas Pratik , Roberts Dennis , Li Yunsheng , Wang Liyi , Qian Yanrong , Bergmeier Stephen , Hines Jennifer , Adhicary Subhodip , Nielsen Corinne , Chen Xiaozhuo 
Published: March 2021

AbstractBackgroundCancer cells drastically increase the uptake of glucose and glucose metabolism by overexpressing class I glucose transporters (GLUT1-4) to meet their energy and biomass synthesis needs and are very sensitive and vulnerable to glucose deprivation. Although targeting glucose uptake via GLUTs has been an attractive anticancer strategy, the relative anticancer efficacy of multi-GLUT targeting or single GLUT targeting is unclear. Here, we report DRB18, a synthetic small molecule, is a potent anticancer compound whose pan-class I GLUT inhibition is superior to single GLUT targeting.MethodsGlucose uptake and MTT/resazurin assays were used to measure DRB18’s inhibitory activities of glucose transport and cell viability/proliferation in human lung cancer and other cancer cell lines. Four HEK293 cell lines expressing GLUT1-4 individually were used to determine the IC50values of DRB18’s inhibitory activity of glucose transport. Docking studies were performed to investigate the potential direct interaction of DRB18 with GLUT1-4. Metabolomics analysis was performed to identify metabolite changes in A549 lung cancer cells treated with DRB18. DRB18 was used to treat A549 tumor-bearing nude mice. TheGLUT1gene was knocked out to determine how the KO of the gene affected tumor growth.ResultsDRB18 reduced glucose uptake mediated via each of GLUT1-4 with different IC50s, which match with the docking glidescores with a correlation coefficient of 0.858. Metabolomics analysis revealed that DRB18 altered energy-related metabolism in A549 cells by changing the abundance of metabolites in glucose-related pathways in vitro and in vivo. DRB18 eventually led to G1/S phase arrest and increased oxidative stress and necrotic cell death. IP injection of DRB18 in A549 tumor-bearing nude mice at 10 mg/kg body weight thrice a week led to a significant reduction in the tumor volume compared with mock-treated tumors. In contrast, the knockout of theGLUT1gene did not reduce tumor volume.ConclusionsDRB18 is a potent pan-class I GLUT inhibitor in vitro and in vivo in cancer cells. Mechanistically, it is likely to bind the outward open conformation of GLUT1-4, reducing tumor growth through inhibiting GLUT1-4-mediated glucose transport and metabolisms. Pan-class I GLUT inhibition is a better strategy than single GLUT targeting for inhibiting tumor growth.
Association of transcranial Doppler blood flow velocity slow waves with delayed cerebral ischemia in patients suffering from subarachnoid hemorrhage: a retrospective study
Authors: Papaioannou Vasilios E. , Budohoski Karol P. , Placek Michal M. , Czosnyka Zofia , Smielewski Peter , Czosnyka Marek 
Published: March 2021

Abstract
Background
Cerebral vasospasm (VS) and delayed cerebral ischemia (DCI) constitute major complications following subarachnoid hemorrhage (SAH). A few studies have examined the relationship between different indices of cerebrovascular dynamics with the occurrence of VS. However, their potential association with the development of DCI remains elusive. In this study, we investigated the pattern of changes of different transcranial Doppler (TCD)-derived indices of cerebrovascular dynamics during vasospasm in patients suffering from subarachnoid hemorrhage, dichotomized by the presence of delayed cerebral ischemia.

Methods
A retrospective analysis was performed using recordings from 32 SAH patients, diagnosed with VS. Patients were divided in two groups, depending on development of DCI. Magnitude of slow waves (SWs) of cerebral blood flow velocity (CBFV) was measured. Cerebral autoregulation was estimated using the moving correlation coefficient Mxa. Cerebral arterial time constant (tau) was expressed as the product of resistance and compliance. Complexity of CBFV was estimated through measurement of sample entropy (SampEn).

Results
In the whole population (N = 32), magnitude of SWs of ipsilateral to VS side CBFV was higher during vasospasm (4.15 ± 1.55 vs before: 2.86 ± 1.21 cm/s, p < 0.001). Ipsilateral SWs of CBFV before VS had higher magnitude in DCI group (N = 19, p < 0.001) and were strongly predictive of DCI, with area under the curve (AUC) = 0.745 (p = 0.02). Vasospasm caused a non-significant shortening of ipsilateral values of tau and increase in SampEn in all patients related to pre-VS measurements, as well as an insignificant increase of Mxa in DCI related to non-DCI group (N = 13).

Conclusions
In patients suffering from subarachnoid hemorrhage, TCD-detected VS was associated with higher ipsilateral CBFV SWs, related to pre-VS measurements. Higher CBFV SWs before VS were significantly predictive of delayed cerebral ischemia.
Comparison of length and dynamics of wood pieces in streams covered with coniferous and broadleaf forests mapped using orthophotos acquired by an unmanned aerial vehicle
Authors: Tsunetaka Haruka , Mtibaa Slim , Asano Shiho , Okamoto Takashi , Kurokawa Ushio 
Published: March 2021

AbstractAs wood pieces supplied by landslides and debris flows are one of the main components of ecological and geomorphic systems, the importance of quantifying the dimensions of the wood pieces is evident. However, the low accessibility of disturbed channels after debris flows generally impedes accurate and quick wood-piece investigations. Thus, remote-sensing measurements for wood pieces are necessitated. Focusing on sub-watersheds in coniferous and broadleaf forests in Japan (the CF and BF sites, respectively), we measured the lengths of wood pieces supplied by landslides (> 0.2 m length and > 0.03 m diameter) from orthophotos acquired using a small unmanned aerial vehicle (UAV). The measurement accuracy was analyzed by comparing the lengths derived from the UAV method with direct measurements. The landslides at the CF and BF sites were triggered by extremely heavy rainfalls in 2017 and 2018, respectively. UAV flights were operated during February and September 2019 at the CF site and during November 2018 and December 2019 at the BF site. Direct measurements of wood pieces were carried out on the date of the respective second flight date in each site. When both ends of a wood piece are satisfactorily extracted from an orthophoto acquired by the UAV, the wood-piece lengths at the CF site can be measured with an accuracy of approximately ±0.5 m. At the BF site, most of the extracted lengths were shorter than the directly measured lengths, probably because the complex structures of the root wad and tree crown reduced the visibility. Most wood pieces were discharged from landslide scars at the BF site, but at the CF site, approximately 750 wood pieces remained in the landslide scars approximately 19 months after the landslide occurrence. The number of wood pieces in the landslide scars of the CF site increased with increasing landslide area, suggesting that some wood pieces can be left even if large landslides occur. The lengths and locations of the entrapped wood pieces at both sites were not significantly changed between the two UAV flight dates. However, during this period, the rainfall intensities around the CF site measured by the closest rain-gauge of the Japan Meteorological Agency reached their second highest values from 1976 to 2019, which exceeded the 30-year return period. This suggests that most of the entrapped wood pieces rarely migrated even under intense rainfall.
Dexamethasone to decrease post-anesthesia sore throat (POST) and hoarseness-which is the most effective route: intravenous, topical, or nebulization? A prospective randomized trial
Authors: Sharma Shalini , Bhardwaj Vatika , Sharma Shailja , Rana Shelly 
Published: March 2021

Abstract
Background and Aims
Postoperative sore throat (POST) is common after endotracheal intubation making patients uncomfortable and anxious in postoperative period. The present study was undertaken to compare efficacy of equal dose of dexamethasone in preventing POST via three different routes, i.e., intravenous, topical, and nebulization before surgery.

Methods and Results
The present prospective double-blind randomized parallel group trial included 190 patients of either sex above 18 years, American Society of Anesthesiologists (ASA) physical status I–II posted for laparoscopic cholecystectomy. The patients were divided into three groups. Patients in group N were nebulized with 8 mg dexamethasone prior to surgery, patients in group I received intravenous dexamethasone (8 mg) before induction of anesthesia, while patients in group C were intubated with endotracheal tube which was pretreated (cuff soaked in dexamethasone 8 mg). The severity of POST and hoarseness of voice was determined by interviewing patients after 24-h of completion of surgery. Incidence of POST decreased in all patients with maximum decrease in group N (18%), while 30.8% in group I and 30.4% in group C. This decrease was not statistically significant when compared to group I (p 0.14) as well as group C (p 0.15). Incidence of hoarseness significantly decreased in group N (15.6%) as compared to group I (40.3%) as well as group C (39.1%). This decrease was statistically significant when compared to group I (p 0.005) as well as group C (p 0.009).

Conclusions
Topical dexamethasone (group C) is as effective as intravenous dexamethasone in decreasing incidence of POST, while both the techniques are not effective in decreasing hoarseness of voice. Nebulization is most effective method in decreasing POST as well as hoarseness.

Trial Registration
CTRI/2017/08/009524 dated 29 August 2017 prospectively.