bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of plasma mitochondrial DNA with COPD severity and progression in the SPIROMICS cohort
Authors: Zhang William Z. , Hoffman Katherine L. , Schiffer Kristen T. , Oromendia Clara , Rice Michelle C. , Barjaktarevic Igor , Peters Stephen P. , Putcha Nirupama , Bowler Russell P. , Wells J. Michael , Couper David J. , Labaki Wassim W. , Curtis Jeffrey L. , Han Meilan K. , Paine Robert , Woodruff Prescott G. , Criner Gerard J. , Hansel Nadia N. , Diaz Ivan , Ballman Karla V. , Nakahira Kiichi , Choi Mary E. , Martinez Fernando J. , Choi Augustine M. K. , Cloonan Suzanne M. 
Published: April 2021

Abstract
Background
There is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures.

Methods
P-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up.

Results
P-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up.

Conclusion
In this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies.
Trial Registration: ClinicalTrials.gov NCT01969344 (SPIROMICS)
Single-cell characterization of a model of poly I:C-stimulated peripheral blood mononuclear cells in severe asthma
Authors: Chen Ailu , Diaz-Soto Maria P. , Sanmamed Miguel F. , Adams Taylor , Schupp Jonas C. , Gupta Amolika , Britto Clemente , Sauler Maor , Yan Xiting , Liu Qing , Nino Gustavo , Cruz Charles S. Dela , Chupp Geoffrey L. , Gomez Jose L. 
Published: April 2021

AbstractBackgroundAsthma has been associated with impaired interferon response. Multiple cell types have been implicated in such response impairment and may be responsible for asthma immunopathology. However, existing models to study the immune response in asthma are limited by bulk profiling of cells. Our objective was to Characterize a model of peripheral blood mononuclear cells (PBMCs) of patients with severe asthma (SA) and its response to the TLR3 agonist Poly I:C using two single-cell methods.MethodsTwo complementary single-cell methods, DropSeq for single-cell RNA sequencing (scRNA-Seq) and mass cytometry (CyTOF), were used to profile PBMCs of SA patients and healthy controls (HC). Poly I:C-stimulated and unstimulated cells were analyzed in this study.ResultsPBMCs (n = 9414) from five SA (n = 6099) and three HC (n = 3315) were profiled using scRNA-Seq. Six main cell subsets, namely CD4 + T cells, CD8 + T cells, natural killer (NK) cells, B cells, dendritic cells (DCs), and monocytes, were identified. CD4 + T cells were the main cell type in SA and demonstrated a pro-inflammatory profile characterized by increased JAK1 expression. Following Poly I:C stimulation, PBMCs from SA had a robust induction of interferon pathways compared with HC. CyTOF profiling of Poly I:C stimulated and unstimulated PBMCs (n = 160,000) from the same individuals (SA = 5; HC = 3) demonstrated higher CD8 + and CD8 + effector T cells in SA at baseline, followed by a decrease of CD8 + effector T cells after poly I:C stimulation.ConclusionsSingle-cell profiling of an in vitro model using PBMCs in patients with SA identified activation of pro-inflammatory pathways at baseline and strong response to Poly I:C, as well as quantitative changes in CD8 + effector cells. Thus, transcriptomic and cell quantitative changes are associated with immune cell heterogeneity in this model to evaluate interferon responses in severe asthma.
Current and future treatment strategies in chronic lymphocytic leukemia
Authors: Patel Krish , Pagel John M. 
Published: April 2021

AbstractTreatment decisions for patients with chronic lymphocytic leukemia (CLL) are dependent on symptoms and classification into high-, medium-, or low-risk categories. The prognosis for CLL hinges, in part, on the presence or absence of less-favorable genetic aberrations, including del(17p), del(11q), TP53 dysfunction, and IGHV mutations, as these markers are associated with worse treatment response. Promising results from multiple clinical trials show emerging therapies targeting Burton tyrosine kinase, B-cell leukemia/lymphoma 2, and phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta result in better outcomes and prolonged progression-free survival for patients both with and without certain high-risk aberrations. Favorable outcomes using these novel oral targeted therapies, either alone or in combination with other treatments such as anti-CD20 antibodies, has led to their use almost entirely supplanting chemoimmunotherapy in the treatment of CLL. In this narrative review, we summarize the current clinical evidence for the use of targeted mono- and combination therapies for CLL, discuss new and next-generation treatment approaches currently in development, and provide insight into areas of unmet need for the treatment of patients with CLL.
Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine
Authors: Buettner Ralf , Nguyen Le Xuan Truong , Morales Corey , Chen Min-Hsuan , Wu Xiwei , Chen Lisa S. , Hoang Dinh Hoa , Hernandez Vargas Servando , Pullarkat Vinod , Gandhi Varsha , Marcucci Guido , Rosen Steven T. 
Published: April 2021

Abstract
Background
BCL‐2 inhibition through venetoclax (VEN) targets acute myeloid leukemia (AML) blast cells and leukemic stem cells (LSCs). Although VEN-containing regimens yield 60–70% clinical response rates, the vast majority of patients inevitably suffer disease relapse, likely because of the persistence of drug-resistant LSCs. We previously reported preclinical activity of the ribonucleoside analog 8-chloro-adenosine (8-Cl-Ado) against AML blast cells and LSCs. Moreover, our ongoing phase I clinical trial of 8-Cl-Ado in patients with refractory/relapsed AML demonstrates encouraging clinical benefit. Of note, LSCs uniquely depend on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. VEN inhibits OXPHOS in LSCs, which eventually may escape the antileukemic activity of this drug. FAO is activated in LSCs isolated from patients with relapsed AML.

Methods
Using AML cell lines and LSC-enriched blast cells from pre-treatment AML patients, we evaluated the effects of 8-Cl-Ado, VEN and the 8-Cl-Ado/VEN combination on fatty acid metabolism, glycolysis and OXPHOS using liquid scintillation counting, a Seahorse XF Analyzer and gene set enrichment analysis (GSEA). Western blotting was used to validate results from GSEA. HPLC was used to measure intracellular accumulation of 8-Cl-ATP, the cytotoxic metabolite of 8-Cl-Ado. To quantify drug synergy, we created combination index plots using CompuSyn software. The log-rank Kaplan–Meier survival test was used to compare the survival distributions of the different treatment groups in a xenograft mouse model of AML.

Results
We here report that VEN and 8-Cl-Ado synergistically inhibited in vitro growth of AML cells. Furthermore, immunodeficient mice engrafted with MV4-11-Luc AML cells and treated with the combination of VEN plus 8-Cl-Ado had a significantly longer survival than mice treated with either drugs alone (p ≤ 0.006). We show here that 8-Cl-Ado in the LSC-enriched population suppressed FAO by downregulating gene expression of proteins involved in this pathway and significantly inhibited the oxygen consumption rate (OCR), an indicator of OXPHOS. By combining 8-Cl-Ado with VEN, we observed complete inhibition of OCR, suggesting this drug combination cooperates in targeting OXPHOS and the metabolic homeostasis of AML cells.

Conclusion
Taken together, the results suggest that 8-Cl-Ado enhances the antileukemic activity of VEN and that this combination represents a promising therapeutic regimen for treatment of AML.
Online questionnaire, clinical and biomechanical measurements for outcome prediction of plantar heel pain: feasibility for a cohort study
Authors: Gulle Halime , Prior Trevor , Miller Stuart , Birn‐Jeffery Aleksandra V. , Morrissey Dylan 
Published: April 2021

AbstractBackgroundPlantar heel pain (PHP) accounts for 11–15% of foot symptoms requiring professional care in adults. Recovery is variable, with no robust prognostic guides for sufferers, clinicians or researchers. Therefore, we aimed to determine the validity, reliability and feasibility of questionnaire, clinical and biomechanical measures selected to generate a prognostic model in a subsequent cohort study.MethodsThirty‐six people (19 females & 17 males; 20–63 years) were recruited with equal numbers in each of three groups: people with PHP (PwPHP), other foot pain (PwOP) and healthy (H) controls. Eighteen people performed a questionnaire battery twice in a randomised order to determine online and face‐to‐face agreement. The remaining 18 completed the online questionnaire once, plus clinical measurements including strength and range of motion, mid‐foot mobility, palpation and ultrasound assessment of plantar fascia. Nine of the same people underwent biomechanical assessment in the form of a graded loaded challenge augmenting walking with added external weight and amended step length on two occasions. Outcome measures were (1) feasibility of the data collection procedure, measurement time and other feedback; (2) establishing equivalence to usual procedures for the questionnaire battery; known‐group validity for clinical and imaging measures; and initial validation and reliability of biomechanical measures.ResultsThere were no systematic differences between online and face‐to‐face administration of questionnaires (p‐values all > .05) nor an administration order effect (d = − 0.31–0.25). Questionnaire reliability was good or excellent (ICC2,1_absolute)(ICC 0.86–0.99), except for two subscales. Full completion of the survey took 29 ± 14 min. Clinically, PwPHP had significantly less ankle‐dorsiflexion and hip internal‐rotation compared to healthy controls [mean (±SD) for PwPHP‐PwOP‐H = 14°(±6)‐18°(±8)‐28°(±10); 43°(±4)‐ 45°(±9)‐57°(±12) respectively; p < .02 for both]. Plantar fascia thickness was significantly higher in PwPHP (3.6(0.4) mm vs 2.9(0.4) mm, p = .01) than the other groups. The graded loading challenge demonstrated progressively increasing ground reaction forces.ConclusionOnline questionnaire administration was valid therefore facilitating large cohort recruitment and being relevant to remote service evaluation and research. The physical and ultrasound examination revealed the expected differences between groups, while the graded loaded challenge progressively increases load and warrants future research. Clinician and researchers can be confident about these methodological approaches and the cohort study, from which useful clinical tools should result, is feasible.Level of evidenceIV
The characteristics of insoluble softwood substrates affect fungal morphology, secretome composition, and hydrolytic efficiency of enzymes produced by Trichoderma reesei
Authors: Novy Vera , Nielsen Fredrik , Cullen Daniel , Sabat Grzegorz , Houtman Carl J. , Hunt Christopher G. 
Published: April 2021

Abstract
Background
On-site enzyme production using Trichoderma reesei can improve yields and lower the overall cost of lignocellulose saccharification by exploiting the fungal gene regulatory mechanism that enables it to continuously adapt enzyme secretion to the substrate used for cultivation. To harness this, the interrelation between substrate characteristics and fungal response must be understood. However, fungal morphology or gene expression studies often lack structural and chemical substrate characterization. Here, T. reesei QM6a was cultivated on three softwood substrates: northern bleached softwood Kraft pulp (NBSK) and lodgepole pine pretreated either by dilute-acid-catalyzed steam pretreatment (LP-STEX) or mild alkaline oxidation (LP-ALKOX). With different pretreatments of similar starting materials, we presented the fungus with systematically modified substrates. This allowed the elucidation of substrate-induced changes in the fungal response and the testing of the secreted enzymes’ hydrolytic strength towards the same substrates.

Results
Enzyme activity time courses correlated with hemicellulose content and cellulose accessibility. Specifically, increased amounts of side-chain-cleaving hemicellulolytic enzymes in the protein produced on the complex substrates (LP-STEX; LP-ALKOX) was observed by secretome analysis. Confocal laser scanning micrographs showed that fungal micromorphology responded to changes in cellulose accessibility and initial culture viscosity. The latter was caused by surface charge and fiber dimensions, and likely restricted mass transfer, resulting in morphologies of fungi in stress. Supplementing a basic cellulolytic enzyme mixture with concentrated T. reesei supernatant improved saccharification efficiencies of the three substrates, where cellulose, xylan, and mannan conversion was increased by up to 27, 45, and 2800%, respectively. The improvement was most pronounced for proteins produced on LP-STEX and LP-ALKOX on those same substrates, and in the best case, efficiencies reached those of a state-of-the-art commercial enzyme preparation.

Conclusion
Cultivation of T. reesei on LP-STEX and LP-ALKOX produced a protein mixture that increased the hydrolytic strength of a basic cellulase mixture to state-of-the-art performance on softwood substrates. This suggests that the fungal adaptation mechanism can be exploited to achieve enhanced performance in enzymatic hydrolysis without a priori knowledge of specific substrate requirements.
Unilateral and bilateral training competitive archers differ in some potentially unhealthy neck-shoulder region movement behaviour characteristics
Authors: Schmitt Mareike , Vogt Lutz , Wilke Jan , Niederer Daniel 
Published: April 2021

Abstract
Background
Excessive unilateral joint loads may lead to overuse disorders. Bilateral training in archery is only performed as a supportive coordination training and as a variation of typical exercise. However, a series of studies demonstrated a crossover transfer of training-induced motor skills to the contralateral side, especially in case of mainly unilateral skills. We compared the cervical spine and shoulder kinematics of unilateral and bilateral training archers.

Methods
In this cross-sectional study, 25 (5 females, 48 ± 14 years) bilaterally training and 50 age-, sex- and level-matched (1:2; 47.3 ± 13.9 years) unilaterally training competitive archers were included. Cervical range of motion (RoM, all planes) and glenohumeral rotation were assessed with an ultrasound-based 3D motion analysis system. Upward rotation of the scapula during abduction and elevation of the arm were measured by means of a digital inclinometer and active shoulder mobility by means of an electronic caliper. All outcomes were compared between groups (unilaterally vs. bilaterally) and sides (pull-hand- vs. bow-hand-side).

Results
Unilateral and bilateral archers showed no between group and no side-to-side-differences in either of the movement direction of the cervical spine. The unilateral archers had higher pull-arm-side total glenohumeral rotation than the bilateral archers (mean, 95% CI), (148°, 144–152° vs. 140°, 135°-145°). In particular, internal rotation (61°, 58–65° vs. 56°, 51–61°) and more upward rotation of the scapula at 45 degrees (12°, 11–14° vs. 8°, 6–10°), 90 degrees (34°, 31–36° vs. 28°, 24–32°), 135 degrees (56°, 53–59° vs. 49°, 46–53°), and maximal (68°, 65–70° vs. 62°, 59–65°) arm abduction differed. The bow- and pull-arm of the unilateral, but not of the bilateral archers, differed in the active mobility of the shoulder (22 cm, 20–24 cm vs. 18 cm, 16–20 cm).

Conclusions
Unilaterally training archers display no unphysiologic movement behaviour of the cervical spine, but show distinct shoulder asymmetris in the bow- and pull-arm-side when compared to bilateral archers in glenohumeral rotation, scapula rotation during arm abduction, and active mobility of the shoulder. These asymmetries in may exceed physiological performance-enhancing degrees. Bilateral training may seems appropriate in archery to prevent asymmetries.
PCJ Java library as a solution to integrate HPC, Big Data and Artificial Intelligence workloads
Authors: Nowicki Marek , Górski Łukasz , Bała Piotr 
Published: April 2021

AbstractWith the development of peta- and exascale size computational systems there is growing interest in running Big Data and Artificial Intelligence (AI) applications on them. Big Data and AI applications are implemented in Java, Scala, Python and other languages that are not widely used in High-Performance Computing (HPC) which is still dominated by C and Fortran. Moreover, they are based on dedicated environments such as Hadoop or Spark which are difficult to integrate with the traditional HPC management systems. We have developed the Parallel Computing in Java (PCJ) library, a tool for scalable high-performance computing and Big Data processing in Java. In this paper, we present the basic functionality of the PCJ library with examples of highly scalable applications running on the large resources. The performance results are presented for different classes of applications including traditional computational intensive (HPC) workloads (e.g. stencil), as well as communication-intensive algorithms such as Fast Fourier Transform (FFT). We present implementation details and performance results for Big Data type processing running on petascale size systems. The examples of large scale AI workloads parallelized using PCJ are presented.
A vacuum-driven rubber-band gripper
Authors: Yamada Ko , Mitsuda Takashi 
Published: April 2021

AbstractRobotic grippers that gently handle objects of various shapes are required for various applications these days. Conventional finger-shaped grippers are multifunctional and can grip various objects; however, grasping an item without slippage requires planning the positioning of the fingers at appropriate locations on the item. Hence, a ring-shaped soft gripper that coils itself around objects like a rubber band is suggested in this paper. The proposed gripper comprises a soft tube containing laminated sponges interleaved with plastic sheets. Evacuation of the air within the sponges shrinks them and decreases the diameter of the ring, thereby allowing the gripper to firmly hold objects. The gripper is therefore flexible enough to coil around objects of various shapes without gaps. Furthermore, the rigidity of the compressed sponges inside the gripper prevents wobbling of the gripped objects. The air within the gripper can be used to adjust the gripping force. The minimum diameter of the gripper after evacuating the air within the sponges is approximately one-fourth of the original diameter. Thus, the proposed gripper is expected to be used in various applications as it automatically conforms to the different shapes while simply gripping objects gently and securely.
Qualitative study: burden of menopause-associated vasomotor symptoms (VMS) and validation of PROMIS Sleep Disturbance and Sleep-Related Impairment measures for assessment of VMS impact on sleep
Authors: English Marci , Stoykova Boyka , Slota Christina , Doward Lynda , Siddiqui Emad , Crawford Rebecca , DiBenedetti Dana 
Published: April 2021

Abstract
Purpose
We evaluated the impact of menopause-associated vasomotor symptoms (VMS) on sleep. We also sought to establish the content validity of Patient-Reported Outcomes Measurement Information System (PROMIS) short form Sleep-Related Impairment and Sleep Disturbance measures in postmenopausal women with moderate to severe VMS.

Methods
Cross-sectional, in-person, qualitative interviews were conducted in the United States (Texas, Illinois) and European Union (UK, France) with women aged 40–64 years experiencing moderate to severe VMS (≥35/wk). Main outcomes were impact of VMS on sleep based on concept elicitation and content validity of PROMIS Sleep-Related Impairment and Sleep Disturbance short forms via cognitive debriefing.

Results
Thirty-two women (US: n = 16; EU: n = 16) participated. A majority (US: 93.8%; EU: 93.8%) said VMS affected sleep; specifically, they had sleep interrupted by sweating or overheating and had difficulty returning to sleep. Sleep disturbance was the most bothersome aspect of VMS (US: 75%; EU: 50%). VMS-associated sleep disturbance affected next-day work productivity, mood, relationships, daily activities, concentration, social activities, and physical health. Participants found both PROMIS sleep measures relevant and easy to answer; the Sleep Disturbance measure was considered the most relevant. Participants had no difficulty remembering their experiences over the 7-day recall period and found the response options to be distinct.

Conclusion
VMS associated with menopause significantly interferes with sleep and next-day functioning (e.g., work productivity), supporting assessment of sleep outcomes in studies evaluating treatment of VMS. Women with moderate to severe VMS found that the PROMIS Sleep-Related Impairment and Sleep Disturbance short forms assessed constructs important to understanding sleep in the context of menopause-associated VMS.