bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolomic analysis of spontaneous neutrophil apoptosis reveals the potential involvement of glutathione depletion
Authors: Yuyun Xiong , Fan Yu , Weiping Wei , Qing Yin , Bingwei Sun
Published: September 2020

Spontaneous apoptosis of neutrophils plays a key role in maintaining immune homeostasis and resolving inflammation. However, the mechanism triggering this apoptosis remains obscure. In the present study, we performed a global metabolomics analysis of neutrophils undergoing spontaneous apoptosis by using hydrophilic interaction chromatography ultra-high-performance liquid chromatography-tandem quadrupole/time-of-flight mass spectrometry and found 23 metabolites and 42 related pathways that were altered in these cells. Among them, glutathione, which is known to be involved in apoptosis, was particularly interesting. We found that L-pyroglutamic acid, glutamate, and their glutathione-mediated embolic pathways were all changed. Our findings confirmed the glutathione levels decreased in apoptotic neutrophils. Exogenous glutathione and LPS treatment delayed neutrophil apoptosis and decreased the levels of pro-apoptotic protein caspase-3. γ-glutamylcyclotransferase, 5-oxoprolinase, and ChaC1, which participated in glutathione degradation, were all activated. At the same time, the down-regulation of ATP production suggested the activity of glutathione biosynthesis may be attenuated even if glutamate-cysteine ligase and glutathione synthase, which are two ATP-dependent enzymes participating in glutathione biosynthesis, were enhanced. To our knowledge, this is the first report highlighting a global metabolomics analysis using hydrophilic interaction chromatography ultra-high-performance liquid chromatography-tandem quadrupole/time-of-flight mass spectrometry and the potential involvement of glutathione depletion in spontaneous apoptosis of neutrophils demonstrating that LPS could delay this process.
Vitamin D: Testing and supplementation in adults
Authors: MacRae Clare , Pearson-Stuttard Ben , Ralston Stuart H
Published: September 2020

Vitamin D is essential for the maintenance of musculoskeletal health through the regulation of calcium and phosphate homeostasis. Severe prolonged deficiency of vitamin D can lead to rickets in children and osteomalacia in adults. Both conditions are now rare in the UK, except in high-risk groups such as those with malabsorption and reduced exposure to sunlight. A much more common situation is ‘biochemical’ vitamin D deficiency, where circulating 25(OH)D concentrations fall below pre-defined thresholds in the absence of osteomalacia or rickets, making vitamin D deficiency and insufficiency very common in the UK particularly during the winter months and early spring. Biochemical vitamin D deficiency has been associated with various non-skeletal disorders, but it seems likely that the low vitamin D levels in these situations are the result of the underlying condition, rather than the cause.
Cystic echinococcosis causing thrombosis of the inferior vena cava in a patient with multiple sclerosis treated with alemtuzumab
Authors: Kantorová Ema , Vajdová Veronika , Hnilicová Petra , Tarčák Marek , Turčanová Monika , Kurča Egon , Zeleňák Kamil
Published: September 2020

Alemtuzumab, one of the very effective immunomodulatory forms of treatment for patients with highly active multiple sclerosis, can also have unexpected side effects. We present a case of cystic echinococcosis causing thrombosis of the inferior vena cava in a female patient after two cycles of alemtuzumab.
On Being Gifted at University: Academic, Social, Emotional, and Institutional Adjustment in Kazakhstan
Authors: Almukhambetova Ainur , Hernández-Torrano Daniel
Published: September 2020

Globally, universities have an interest in recruiting the most talented students; however, limited attention has been given to how these students experience their transition and adjustment to university life. This mixed-methods study analyzes the academic, social, emotional, and institutional dimensions of gifted students’ adjustment to university in the context of post-Soviet Kazakhstan, a country characterized by a strong emphasis on the education of gifted students. The findings of the study confirm that the process of gifted students’ adjustment to university is a complex phenomenon, and all the aspects of students’ first-year experiences should be carefully taken into consideration when studying the transition to postsecondary education. The results of the study are useful for understanding the issues that gifted students face in the transition to higher education and have important implications for research on gifted students’ postsecondary experiences internationally.
Pandanus conoideus Lamk Oil Protects Against Inflammation Through Regulating Reactive Oxygen Species in LPS-Induced Murine Macrophages
Authors: Rhee Yun-Hee , Park Ye Kyu , Kim Jong-Soo
Published: September 2020

The aim of this study was to investigate the anti-inflammatory properties of Pandanus conoideus Lamk (red fruit oil [RFO]) and establish the signal pathway of the leading compounds. RAW 264.7 murine macrophage cells were used with lipopolysaccharide (LPS). Cell viability and the pro-inflammatory factors were investigated using MTT assay, real-time polymerase chain reaction (PCR), western blot analysis, and enzyme-linked immunosorbent assay. The quantification of leading compounds in RFO was performed using high-performance liquid chromatography (HPLC). RFO did not reduce RAW 264.7 cell viability. RFO significantly reduced the production of nitric oxide (NO), cyclooxygenase-2, and prostaglandin E2, and both the protein level and mRNA level of inducible NO synthase in LPS-induced macrophages. RFO also regulated the reactive oxygen species (ROS) in LPS-induced macrophages. RFO attenuated the translocation of the nuclear factor κB (NF-κB) p65 subunit, phosphorylation of I-κB, p38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase (JNK) in a dose-dependent manner. HPLC analysis determined that 1 g of RFO had 14.05 ± 0.8 mg of β-cryptoxanthin and 7.4 ± 0.7 mg of β-carotene. In conclusion, RFO provides an anti-inflammatory effect by regulating ROS and NF-κB through mitogen-activated protein kinase due to antioxidant activity.
The Influence of Occupancy Change on Hotel Market Equilibrium
Authors: Denton Gregory , Sandstrom Jennifer
Published: September 2020

Supply and demand imbalances in hotel markets are known to cause short-term growth or declines in rate and are largely (but inefficiently) self-correcting over the long term. However, looking at aggregated monthly supply and demand shifts for a market overlooks the dramatic shifts that typically occur daily within a market. Building on natural occupancy rate theory and using daily performance over a 5-year period for the Seattle Metropolitan Statistical Area (MSA) and submarkets, this study shows that examining daily occupancy patterns provides important insights into average rate growth. Furthermore, the analysis shows that the real average rate growth is a function of not only absolute occupancy levels relative to the market’s natural occupancy rate but also relative changes in occupancy, and that change in occupancy moderates the relationship between occupancy and average rate growth. In addition, submarkets within the MSA have significantly different attributes, including different natural occupancy levels and different responses to changes in occupancy. Implications for hotel investors, managers, and policy planners are then presented.
Building Capacity for Medication Assisted Treatment in Rural Primary Care Practices: The IT MATTTRs Practice Team Training
Authors: Zittleman Linda , Curcija Kristen , Sutter Christin , Dickinson L. Miriam , Thomas John , de la Cerda Dionisia , Nease Donald E. , Westfall John M.
Published: September 2020

Objectives:

In response to rural communities and practice concerns related to opioid use disorder (OUD), the Implementing Technology and Medication Assisted Treatment Team Training in Rural Colorado study (IT MATTTRs) developed a training intervention for full primary care practice (PCP) teams in MAT for OUD. This evaluation reports on training implementation, participant satisfaction, and impact on perceived ability to deliver MAT.

Methods:

PCPs in the High Plains Research Network and Colorado Research Network were randomized to receive team training either in-person or through virtual tele-mentoring. Training attendance logs recorded the number of participants and their roles. Participants completed a survey within one month of the last training session to evaluate satisfaction and ability to deliver components of MATs.

Results:

441 team members at 42 PCPs were trained, including 22% clinicians, 47% clinical support staff, 24% administrative support staff. Survey respondents reported high levels of satisfaction, including 82% reporting improved understanding of the topic, and 68% identifying actions to apply information. Self-rated ability was significantly higher after training for all items ( P < .0001), including ability to identify patients for MAT and to manage patients receiving MAT. Mean change scores, adjusted for role, were significantly greater for all measures ( P < .001) in SOuND practices compared to ECHO practices.

Conclusions:

The IT MATTTRs Practice Team Training successfully engaged PCP team members in diverse roles in MAT for OUD training and increased self-efficacy to deliver MAT. Results support the training as a resource for a team-based approach to build rural practices’ capacity to deliver MAT.
Spinal Cord Injury With Tetraplegia in Young Persons After Diving Into Shallow Water: What Has Changed in the Past 10 to 15 Years?
Authors: Ull Christopher , Yilmaz Emre , Jansen Oliver , Lotzien Sebastian , Schildhauer Thomas A. , Aach Mirko , Königshausen Matthias
Published: September 2020

Study Design:

Retrospective, monocentric, observational study in a tertiary health care center.

Objectives:

To analyze prehospital and clinical findings, complications, neurological improvement and follow-up in a young person cohort with spinal cord injury (SCI) and tetraplegia according to the American Spinal Injury Association (ASIA) Impairment Scale (AIS) A to D after diving into shallow water.

Methods:

Included were all persons younger than 50 years with SCI after head-first diving into shallow water between June 2001 and June 2019. All persons with SCI were divided into complete tetraplegia (AIS A) and incomplete tetraplegia (AIS B, C, and D) to test differences.

Results:

A total of 59 males (98.7%) and 1 female with a mean age of 27.7 years suffered an SCI. Alcohol use was documented in 25 cases (41.7%). At the time of admission, 33 people (55%) showed a complete tetraplegia (AIS A) and 27 showed an incomplete tetraplegia with 8 AIS B (13.3%), 15 AIS C (25%), and 4 AIS D (6.7%). At the time of discharge, people with initially complete tetraplegia showed a significant improvement from admission to discharge ( P ≤ .004). Persons with incomplete tetraplegia were more likely to improve their neurological status compared with complete tetraplegia patients ( P ≤ .001). Especially persons with complete tetraplegia suffered from typical SCI-related problems and complications.

Conclusions:

People with SCI and tetraplegia at the time admission show neurological improvement in 50% of the cases with an overall better outcome in persons with incomplete tetraplegia. The surgical treatment of SCI within 24 hours seems to be associated with a better neurological outcome and a lower level of tetraplegia. The incidence of SCI caused by diving into shallow water remains stable without a significant change, especially in high-risk groups. More education and prevention programs are necessary to avoid these injuries.
Superior mesenteric artery syndrome: A rare complication of scoliosis corrective surgery
Authors: Chung Weng Hong , Anuar Amir Arif , Lee Keong Joo , Hasan Mohd Shahnaz , Chiu Chee Kidd , Chan Chris Yin Wei , Kwan Mun Keong
Published: September 2020

Superior mesenteric artery (SMA) syndrome is a rare but serious complication following scoliosis surgery. Early diagnosis and management are key factors for successful conservative treatment to avoid the need for emergency laparotomies which causes higher morbidity or even mortality. We report two adolescent idiopathic scoliosis patients with Cobb angle of 49° and 132°, respectively, and low body mass index who presented with SMA syndrome following posterior spinal fusion from T2 to L3 and were treated successfully with conservative management. Abdominal radiographs showed distended gastric shadow. Computed tomography angiography of the abdomen showed decreased aortomesenteric angle and SMA-aorta distance. Both patients were treated successfully with conservative treatment which included three principles: gastric decompression with nasogastric tube, correction of electrolytes imbalance, and nutritional support with low volume, high calorie nutritional supplement. Both patients were started with small but frequent meals. Surgeries were not required in both cases. Early diagnosis and management are the key factors to successful treatment in SMA syndrome. Patients with SMA can be treated successfully with conservative treatment comprising of nasogastric decompression, electrolyte correction, and nutritional support with small but frequent meals.
Reliability of the radiographic views in supine position for evaluation of displaced midshaft clavicle fracture length
Authors: Kongmalai Pinkawas , Chiaprasert Peeraput , Rungsinaporn Visit
Published: September 2020

Purpose:

To analyze the agreement of the displaced midshaft clavicle fracture length measurement between each of the supine radiographic position (chest anteroposterior (AP), both clavicle AP, and 20° cephalic tilt clavicle AP view) and computed tomography (CT) scan of the clavicle. Furthermore, the inter- and intraobserver reliability of each radiographic position was analyzed.

Methods:

Prospective cross-sectional study was performed with patients diagnosed with displaced midshaft clavicle fracture treated conservatively. Three views of radiographs and CT scan of clavicle were obtained in supine position after informed consent. The measurement of fractured clavicle length was done by three observers at the time and after 4 weeks interval.

Results:

Thirty-three patients (25 males and 8 females), with a mean age of 45, were recruited. The agreement between each of the radiographic measurement and CT scan was good. The interobserver reliability was moderate to good for radiographic measurement. The highest intraclass correlation coefficient (ICC) of 0.80–0.81 was shown between the 20° cephalic tilt and the CT scan, followed by the both clavicle AP (0.75–0.77) and the chest AP (0.69–0.75), respectively. There was an excellent intraobserver reliability for all of the radiographic measurement with the ICC 0.92–0.99.

Conclusion:

The supine radiographs could be a useful option to measure the displaced midshaft clavicle fracture length. The recommended view was the 20° cephalic tilt clavicle AP view in supine position to best evaluate the fractured clavicle length.
Augmented, virtual and mixed reality in spinal surgery: A real-world experience
Authors: Sakai Daisuke , Joyce Kieran , Sugimoto Maki , Horikita Natsumi , Hiyama Akihiko , Sato Masato , Devitt Aiden , Watanabe Masahiko
Published: September 2020

This review aims to identify the role of augmented, virtual or mixed reality (AR, VR or MR) technologies in setting of spinal surgery. The authors address the challenges surrounding the implementation of this technology in the operating room. A technical standpoint addresses the efficacy of these imaging modalities based on the current literature in the field. Ultimately, these technologies must be cost-effective to ensure widespread adoption. This may be achieved through reduced surgical times and decreased incidence of post-operative complications and revisions while maintaining equivalent safety profile to alternative surgical approaches. While current studies focus mainly on the successful placement of pedicle screws via AR-guided instrumentation, a wider scope of procedures may be assisted using AR, VR or MR technology once efficacy and safety have been validated. These emerging technologies offer a significant advantage in the guidance of complex procedures that require high precision and accuracy using minimally invasive interventions.
The Structuration of Identification on Organizational Members’ Social Media
Authors: Piercy Cameron W. , Carr Caleb T.
Published: September 2020

The structurational model of identification is applied to test structures that may lead to sharing organizational membership on social media and increased organizational identification. We propose and test how antecedents (e.g., social media use, organizational prestige) relate to acts of identification on social media and promote organizational identification. United States working adults ( N = 303) responded to an online survey about hypothesized motivational structures, online disclosures of organizational affiliation, and organizational identification. Results show three specific structures significantly predicted one’s willingness to share her or his organizational affiliation across social media: personae overlap, social media use, and organizational prestige. Commitment and turnover intentions were, surprisingly, not direct predictors of organizational affiliation disclosure. Implications for individuals, organizations, and both organizational and computer-mediated theory are presented.
Augustus Granville Dill: A Case Study in the Conceptualization of a Black Public Sociology
Authors: Brooks Marcus A. , Wright Earl
Published: September 2020

Black sociology developed as a response to mainstream, white sociology’s failures to address the condition of Black people in the Unites States. Central to the practice of Black sociology is that it necessitates sociological work be used, where possible, for the benefit of Black people. The contemporary practice of public sociology has similar aims of bringing sociological knowledges to various publics to address their particular issues. The public sociology literature, though, fails to conceptualize or articulate praxes of public sociology that are constructed to address the unique needs of various communities. Using the biography of the little-known Black, queer sociologist Augustus Granville Dill (1881–1956) as a case study, the authors conceptualize a practice of Black public sociology as one of many public sociologies. Like Black sociology before, Black public sociology is a rearticulation of established sociological practice that centers on Black people and Black communities. Using the most comprehensive biography of Dill published to date, the authors examine how he transitioned from knowledge producer to knowledge disseminator via the practice of Black public sociology. This article, then, serves to highlight a Black, queer foreparent of the discipline and to use his forgotten story to inform the practice of contemporary public sociology.
People With Lived Experience at the Centre of Canadian Stroke Best Practice Recommendations: A Model for Guideline Developers
Authors: Lindsay M Patrice , Gierman Natalie , Harris Jocelyn E , Arthur Gavin , Teed Moira E , Mountain Anita , Gubitz Gordon , Smith Eric E , Dowlatshahi Dar , de Jong Andrea , Botly Leigh C P
Published: September 2020

Actively engaging people with lived experience (PWLE) in stroke-related clinical practice guideline development has not been effectively implemented. This pilot project evaluated the feasibility, perceived value, and effectiveness of the Community Consultation and Review Panel (CCRP), a new model to engage PWLE in the writing and review of Canadian Stroke Best Practice Recommendations. Responses to a standardized evaluation tool indicated that participants perceived the CCRP as valued, impactful, effective, and beneficial to stroke care. This project successfully demonstrated that values, experiences, and recommendations of PWLE can be effectively incorporated into guideline content and is applicable to all guideline development processes.
Blood Transfusion: Knowledge, Perspectives, and Experience of Individuals With Sickle Cell Disease
Authors: Lawrence Raymona H , Singleton Ashley , Branscomb Jane
Published: September 2020

Patient voice and perspective were needed to inform effective, comprehensive strategies for reducing preventable transfusion-associated complications. This report presents the results of interviews with sickle cell disease (SCD) patients and implications for strategies to reduce transfusion complications in this population. Twenty-two participants were recruited from 2 comprehensive SCD treatment centers in Georgia and interviewed regarding knowledge about transfusions and potential complications, attitudes about data storage and sharing, and the transfusion experience. Participants had general knowledge of physiology, blood products, and blood transfusions, including knowing the risk of complications, but varied in comprehension of complex health information and level of misinformation. Patients also varied in preferences for how they would like their transfusion information stored. They saw both advantages and disadvantages to wallet cards, smartphone applications, and registries. There is a need for a patient-centered approach that involves transfusion education and shared decision-making. Education should range from essential and simple to more in-depth to accommodate varying education and comprehension levels. Multiple tracking methods should be offered to store sensitive patient information.
Impaired episodic simulation in a patient with visual memory deficit amnesia
Authors: Easton Alexander , Cockcroft Jamie P. , Ameen-Ali Kamar E. , Eacott Madeline J.
Published: September 2020

For the first time, we assess episodic simulation in a patient with visual memory deficit amnesia, following damage to visual association cortices. Compared to control participants, the patient with visual memory deficit amnesia shows severely restricted responses when asked to simulate different types of future episodic scenarios. Surprisingly, the patient’s responses are more limited in cases where the scenarios require less reliance on visual information. We explain this counterintuitive finding through discussing how the severe retrograde amnesia in visual memory deficit amnesia limits the patient’s access to episodic memories in which vision has not been a focus of their life. As a result, we argue that the deficits in visual memory deficit amnesia continue to distinguish it from amnesia after direct damage to the hippocampus.
Polycentric urban development and urban amenities: Evidence from Chinese cities
Authors: Wang Mingshu
Published: September 2020

The recent literature on the “consumer city” and the “love of variety” argues that the provision of urban amenities makes a city more attractive. Meanwhile, polycentric urban development has been highlighted by academics and policymakers as a sustainable urban development regime, although its purported benefits need to be further investigated. Against this background, this paper empirically examines the relationship between polycentricity and the provision of urban amenities in 309 Chinese cities. After controlling for the size, population density, wage, and human capital, this paper finds that a higher degree of intra-urban polycentricity is associated with a larger number of urban amenities. Additionally, when all the covariates above are held, a higher degree of intra-urban polycentricity is associated with a greater diversity of urban amenities. Robust checks show that these findings are consistent with different polycentricity indices and diversity measures. Finally, possible explanations of the relationship between intra-urban polycentricity and urban amenities are provided from both the producer and consumer perspectives.
Spatial clustering: Influence of urban street networks on retail sales volumes
Authors: Yoshimura Yuji , Santi Paolo , Arias Juan Murillo , Zheng Siqi , Ratti Carlo
Published: September 2020

As is often believed that the more centrally located a shop, the higher its sales volume, this paper analyzed relationships between the spatial clustering of retail stores, their respective transaction volumes, and the urban street networks to determine whether, and to what extent, the accessibility and density of a store’s location was correlated with its transaction volume. While this hypothesis is widely accepted, its veracity is underexplored and rarely validated using large-scale empirical datasets, possibly owing to the lack of access. Therefore, transaction datasets and accessibility indicators were first examined; a clear, positive correlation between density and revenue was found for specialty stores wherein people do “comparison shopping,” and for stores that complemented each other for activities such as “one-trip shopping,” the revenues were positively correlated when the stores were clustered. Generally, daily-use stores’ revenues were more sensitive to local access and those of non-daily-use stores were more sensitive to global access. In conclusion, these findings would not have been found using conventional methodology focused on the retail sector as a whole, because aggregate market mechanisms would have hidden the observed effects on specific store categories. Therefore, upon disaggregating the data, we found a distinct heterogeneity across the different store types for what concerns the relationship between revenue and location.
Reverse Sural Flap for Repair of Foot and Ankle Defects: Our Cases, Modifications, and a Literature Review
Authors: Anlatici Recep
Published: September 2020

Introduction:

Reverse-flow sural flap is a valuable option in cases of lower extremity repair. In this study, we aimed to present our sural flap applications and modifications for the treatment of ankle and foot defects and to evaluate our results in the light of historical process and current literature.

Materials and Methods:

A reverse-flow fasciocutaneous flap was performed in 14 patients to repair foot and ankle defects. In 6 cases (42.86%), we chose to perform interpolation sural flaps where we aimed to repair the distal defects of the foot and/or in order to prevent patients from having trouble wearing shoes due to bulkiness of the flap pedicle at the ankle. In other cases (tunnel flap group, 57.14%), the pedicle of the flap was passed through the subcutaneous tunnel. Wide and meticulous dissection of the tunnel, nitroglycerine application on the flap, and close flap monitoring were our protective measures. Our results were analyzed statistically. The literature review was performed from Medline and PubMed.

Results:

Sural flap repair was performed in 14 patients. The mean age was 32.75 years. Etiologic factors were traffic accidents, spinal cord injuries, and hyperkeratotic lesions. The defects were localized in the ankle or proximal foot in 12 (85.71%) patients and the distal foot in the remaining patients (14.29%). The mean area of the defects was 46.75 cm2. Partial necrosis at the distal flap developed in 2 (25%) cases in the tunnel group and in 1 (16.67%) in the interpolation group (3 cases in total, 21.43% in the study population). No statistical difference was found between the flap groups in terms of patient distribution and complications.

Conclusion:

Wide dissection of the subcutaneous tunnel through which the pedicle is passed (in the tunnel group), application of nitroglycerin, meticulous hemostasis, and postoperative follow-ups are important factors for a successful reverse sural flap application. Sural interpolation modification is advantageous in several cases as the flap can reach farther and does not cause bulkiness in the ankle that would impair shoe wear. However, the disadvantage is that it requires 2 sessions.
BCL6 maintains survival and self-renewal of primary human acute myeloid leukemia cells
Authors: Kawabata Kimihito C. , Zong Hongliang , Meydan Cem , Wyman Sarah , Wouters Bas J. , Sugita Mayumi , Goswami Srinjoy , Albert Michael , Yip Winnie , Roboz Gail J. , Chen Zhengming , Delwel Ruud , Carroll Martin , Mason Christopher E. , Melnick Ari , Guzman Monica L.
Published: September 2020

B-cell lymphoma 6 (BCL6) is a transcription repressor and proto-oncogene that plays a crucial role in the innate and adaptive immune system and lymphoid neoplasms. However, its role in myeloid malignancies remains unclear. Here, we explored the role of BCL6 in acute myeloid leukemia (AML). BCL6 was expressed at variable and often high levels in AML cell lines and primary AML samples. AMLs with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors, with the exception of those with monocytic differentiation. Gene expression profiling of AML cells treated with a BCL6 inhibitor revealed induction of BCL6-repressed target genes and transcriptional programs linked to DNA damage checkpoints and downregulation of stem cell genes. Ex vivo treatment of primary AML cells with BCL6 inhibitors induced apoptosis and decreased colony-forming capacity, which correlated with the levels of BCL6 expression. Importantly, inhibition or knockdown of BCL6 in primary AML cells resulted in a significant reduction of leukemia-initiating capacity in mice, suggesting ablation of leukemia repopulating cell functionality. In contrast, BCL6 knockout or inhibition did not suppress the function of normal hematopoietic stem cells. Treatment with cytarabine further induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to cytarabine. Treatment of AML patient-derived xenografts with BCL6 inhibitor plus cytarabine suggested enhanced antileukemia activity with this combination. Hence, pharmacologic inhibition of BCL6 might provide a novel therapeutic strategy for ablation of leukemia-repopulating cells and increased responsiveness to chemotherapy.
An intact gut microbiome protects genetically predisposed mice against leukemia
Authors: Vicente-Dueñas Carolina , Janssen Stefan , Oldenburg Marina , Auer Franziska , González-Herrero Inés , Casado-García Ana , Isidro-Hernández Marta , Raboso-Gallego Javier , Westhoff Philipp , Pandyra Aleksandra A. , Hein Daniel , Gössling Katharina L. , Alonso-López Diego , De Las Rivas Javier , Bhatia Sanil , García-Criado Francisco Javier , García-Cenador María Begoña , Weber Andreas P. M. , Köhrer Karl , Hauer Julia , Fischer Ute , Sánchez-García Isidro , Borkhardt Arndt
Published: September 2020

The majority of childhood leukemias are precursor B-cell acute lymphoblastic leukemias (pB-ALLs) caused by a combination of prenatal genetic predispositions and oncogenic events occurring after birth. Although genetic predispositions are frequent in children (>1% to 5%), fewer than 1% of genetically predisposed carriers will develop pB-ALL. Although infectious stimuli are believed to play a major role in leukemogenesis, the critical determinants are not well defined. Here, by using murine models of pB-ALL, we show that microbiome disturbances incurred by antibiotic treatment early in life were sufficient to induce leukemia in genetically predisposed mice, even in the absence of infectious stimuli and independent of T cells. By using V4 and full-length 16S ribosomal RNA sequencing of a series of fecal samples, we found that genetic predisposition to pB-ALL (Pax5 heterozygosity or ETV6-RUNX1 fusion) shaped a distinct gut microbiome. Machine learning accurately (96.8%) predicted genetic predisposition using 40 of 3983 amplicon sequence variants as proxies for bacterial species. Transplantation of either wild-type (WT) or Pax5+/– hematopoietic bone marrow cells into WT recipient mice revealed that the microbiome is shaped and determined in a donor genotype–specific manner. Gas chromatography-mass spectrometry (GC-MS) analyses of sera from WT and Pax5+/– mice demonstrated the presence of a genotype-specific distinct metabolomic profile. Taken together, our data indicate that it is a lack of commensal microbiota rather than the presence of specific bacteria that promotes leukemia in genetically predisposed mice. Future large-scale longitudinal studies are required to determine whether targeted microbiome modification in children predisposed to pB-ALL could become a successful prevention strategy.
Ibrutinib added to 10-day decitabine for older patients with AML and higher risk MDS
Authors: Huls Gerwin , Chitu Dana A. , Pabst Thomas , Klein Saskia K. , Stussi Georg , Griskevicius Laimonas , Valk Peter J. M. , Cloos Jacqueline , van de Loosdrecht Arjan A. , Breems Dimitri , van Lammeren-Venema Danielle , van Zeventer Isabelle , Boersma Rinske , Jongen-Lavrencic Mojca , Fehr Martin , Hoogendoorn Mels , Manz Markus G. , Söhne Maaike , van Marwijk Kooy Rien , Deeren Dries , van der Poel Marjolein W. M. , Legdeur Marie Cecile , Tick Lidwine , Chalandon Yves , Ammatuna Emanuele , Blum Sabine , Löwenberg Bob , Ossenkoppele Gert J.
Published: September 2020

The treatment of older, unfit patients with acute myeloid leukemia (AML) is challenging. Based on preclinical data of Bruton tyrosine kinase expression/phosphorylation and ibrutinib cytotoxicity in AML blasts, we conducted a randomized phase 2 multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in unfit (ie, Hematopoietic Cell Transplantation Comorbidity Index ≥3) AML patients and higher risk myelodysplasia patients (HOVON135/SAKK30/15 trial). In total, 144 eligible patients were randomly (1:1) assigned to either 10-day decitabine combined with ibrutinib (560 mg; sequentially given, starting the day after the last dose of decitabine) (n = 72) or to 10-day decitabine (n = 72). The addition of ibrutinib was well tolerated, and the number of adverse events was comparable for both arms. In the decitabine plus ibrutinib arm, 41% reached complete remission/complete remission with incomplete hematologic recovery (CR/CRi), the median overall survival (OS) was 11 months, and 2-year OS was 27%; these findings compared with 50% CR/CRi, median OS of 11.5 months, and 2-year OS of 21% for the decitabine group (not significant). Extensive molecular profiling at diagnosis revealed that patients with STAG2, IDH2, and ASXL1 mutations had significantly lower CR/CRi rates, whereas patients with mutations in TP53 had significantly higher CR/CRi rates. Furthermore, multicolor flow cytometry revealed that after 3 cycles of treatment, 28 (49%) of 57 patients with available bone marrow samples had no measurable residual disease. In this limited number of cases, measurable residual disease revealed no apparent impact on event-free survival and OS. In conclusion, the addition of ibrutinib does not improve the therapeutic efficacy of decitabine. This trial was registered at the Netherlands Trial Register (NL5751 [NTR6017]) and has EudraCT number 2015-002855-85.
Mental health and related influencing factors among rural elderly in 14 poverty state counties of Chongqing, Southwest China: a cross-sectional study
Authors: Yang Yin , Deng Hui , Yang Qingqing , Ding Xianbin , Mao Deqiang , Ma Xiaosong , Xiao Bangzhong , Zhong Zhaohui
Published: September 2020

Background

China has the largest elderly population in the world; little attention has been paid to the mental health of elderly in areas of extreme poverty. This is the first study to investigate the mental health of the rural elderly in poverty state counties in Chongqing and was part of the Chongqing 2018 health literacy promotion project.

Methods

In 2019, a cross-sectional study was conducted to investigate the mental health status of the rural elderly in fourteen poverty state counties of Chongqing, in which a total of 1400 elderly aged ≥ 65 years were interviewed, where mental health status was measured by the ten-item Kessler10 (K10) scale. Ordered multivariate logistic regression was performed to evaluate the influencing factors related to mental health of the elderly in these areas.

Results

The average score of K10 in 14 poverty state counties was 17.40 ± 6.31, 47.6% was labeled as good, 30.2% was moderate, 17.0% was poor, and lastly 5.1% was bad, and the mental health status of the elderly in the northeastern wing of Chongqing was better than the one in the southeastern wing of Chongqing. A worse self-rated health was the risk factor for mental health both in the northeastern and southeastern wings of Chongqing (all P < 0.001). Lower education level (OR (95% CI) = 1.45 (1.12–1.87), P = 0.004) was a risk factor in the northeastern wing, whereas older age (OR (95% CI) = 1.33 (1.13–1.56), P = 0.001) was a risk factors in the southeastern wing.

Conclusions

The results showed that mental health of the elderly in poverty state counties was poor, especially in the southeastern wing of Chongqing. Particular attention needs to be paid to the males who were less educated, older, and single; female with lower annual per capital income; and especially the elderly with poor self-rated health.
A Cyclophilin OsCYP20–2 Interacts with OsSYF2 to Regulate Grain Length by Pre-mRNA Splicing
Authors: Ge Qiang , Tang Yongyan , Luo Wei , Zhang Jingyu , Chong Kang , Xu Yunyuan
Published: September 2020

Background

Grain size is one of the key agronomic traits that impact grain yield. Several regulatory pathways had been reported to participate in grain size determination via cell expansion or proliferation in rice. However, little is known about cyclophilin and spliceosome participation in grain shape regulation.

Results

Here, we identified OsCYP20–2, a cyclophilin that influences spliceosome assembly to determine grain length. oscyp20–2 t1, a knock out mutant of OsCYP20–2 caused by T-DNA insertion, produced shorter grains with deficient cell elongation. Through yeast two-hybrid screening and pull-down assays, OsSYF2, a pre-mRNA splicing factor, was identified as an interacting protein of OsCYP20–2. The phenotypes of transgenic lines indicated that OsSYF2 positively regulates grain length via its influence on cell expansion. Transcriptomic analysis showed that OsSYF2 controls the expression and pre-mRNA alternative splicing of genes involved in sugar metabolism. In addition, these two genes have similar effects on panicle architecture.

Conclusions

Taken together, OsSYF2, an interacting protein of OsCYP20–2, controls grain length and panicle architecture by regulating the alternative splicing of pre-mRNA involved in cell elongation and sugar metabolism.
Grain Size Selection Using Novel Functional Markers Targeting 14 Genes in Rice
Authors: Zhang Lin , Ma Bin , Bian Zhong , Li Xiaoyuan , Zhang Changquan , Liu Jiyun , Li Qun , Liu Qiaoquan , He Zuhua
Published: September 2020

Background

Grain size is an extremely important aspect of rice breeding, affecting both grain yield and quality traits. It is controlled by multiple genes and tracking these genes in breeding schemes should expedite selection of lines with superior grain yield and quality, thus it is essential to develop robust, efficient markers.

Result

In this study, 14 genes related to grain size (GW2, GS2, qLGY3, GS3, GL3.1, TGW3, GS5, GW5, GS6, TGW6, GW6a, GLW7, GL7 and GW8) were selected for functional marker development. Twenty-one PCR-gel-based markers were developed to genotype the candidate functional nucleotide polymorphisms (FNPs) of these genes, and all markers can effectively recognize the corresponding allele types. To test the allele effects of different FNPs, a global collection of rice cultivars including 257 accessions from the Rice Diversity Panel 1 was used for allele mining, and four grain-size-related traits were investigated at two planting locations. Three FNPs for GW2, GS2 and GL3.1 were genotyped as rare alleles only found in cultivars with notably large grains, and the allele contributions of the remaining FNPs were clarified in both the indica and japonica subspecies. Significant trait contributions were found for most of the FNPs, especially GS3, GW5 and GL7. Of note, GW5 could function as a key regulator to coordinate the performance of other grain size genes. The allele effects of several FNPs were also tested by QTL analysis using an F2 population, and GW5 was further identified as the major locus with the largest contribution to grain width and length to width ratio.

Conclusions

The functional markers are robust for genotyping different cultivars and may facilitate the rational design of grain size to achieve a balance between grain yield and quality in future rice breeding efforts.
Breathing life into consumer rights: smartphone tools facilitating the “right to know” on substances of very high concern in REACH articles
Authors: Schenten Julian , Brenig Mattheus , Führ Martin , Bizer Kilian
Published: September 2020

Background

The EU chemicals regulation “Registration, Evaluation, Authorisation and Restriction of Chemicals” (REACH) aims to reduce the usage of substances of very high concern (SVHCs) by firms. Therefore, a consumer right-to-know about SVHCs in articles is intended to create market-based incentives. However, awareness of the right-to-know among EU citizens is low. Moreover, the response window of 45 days afforded to suppliers impedes immediate, informed decisions by consumers. Consequently, despite being in effect for more than 10 years, only few consumer send requests. Civil society actors have developed smartphone applications reducing information search costs, allowing users to send right-to-know requests upon scanning an article’s barcode. Answers are stored in a database and made available to the public immediately. This paper assesses to which extent smartphone tools contribute to an increased use of the right-to-know by undertaking a case study of the application “ToxFox” by the German non-profit organisation Bund für Umwelt und Naturschutz Deutschland (BUND).

Results

An analysis of the data from the BUND database for the period 2016 to 2018 reveals that about 20 thousand users have sent almost 49 thousand requests. This has led to more than 9 thousand database entries, including 189 articles which contain SVHCs above the legal threshold. The data also indicate that receiving information on requested articles encourages further use of the application. Many suppliers accept the application and pro-actively provide information on articles without SVHCs above the threshold. However, most consumers use the application only for a short time, and suppliers are struggling to reply to right-to-know requests.

Conclusion

Evaluating the results, the study identifies options to enhance the application’s design in terms of user motivation and legal certainty, and to enhance the framework governing "barcode" assignments to articles with a view to better contributing to transparency. As for policy implications, a lack of consumer requests can in part be traced back to design flaws of the right-to-know and a lack of implementation and enforcement of REACH. In addition, suppliers have to increase their supply chain communication efforts to make sure they are in a position to properly answer consumer requests. We recommend several policy options addressing these and additional aspects, thus contributing to the legislative review of Art. 33 REACH.
IonCRAM: a reference-based compression tool for ion torrent sequence files
Authors: Shokrof Moustafa , Abouelhoda Mohamed
Published: September 2020

Background

Ion Torrent is one of the major next generation sequencing (NGS) technologies and it is frequently used in medical research and diagnosis. The built-in software for the Ion Torrent sequencing machines delivers the sequencing results in the BAM format. In addition to the usual SAM/BAM fields, the Ion Torrent BAM file includes technology-specific flow signal data. The flow signals occupy a big portion of the BAM file (about 75% for the human genome). Compressing SAM/BAM into CRAM format significantly reduces the space needed to store the NGS results. However, the tools for generating the CRAM formats are not designed to handle the flow signals. This missing feature has motivated us to develop a new program to improve the compression of the Ion Torrent files for long term archiving.

Results

In this paper, we present IonCRAM, the first reference-based compression tool to compress Ion Torrent BAM files for long term archiving. For the BAM files, IonCRAM could achieve a space saving of about 43%. This space saving is superior to what achieved with the CRAM format by about 8–9%.

Conclusions

Reducing the space consumption of NGS data reduces the cost of storage and data transfer. Therefore, developing efficient compression software for clinical NGS data goes beyond the computational interest; as it ultimately contributes to the overall cost reduction of the clinical test. The space saving achieved by our tool is a practical step in this direction. The tool is open source and available at Code Ocean, github, and http://ioncram.saudigenomeproject.com.
Allelic diversity and patterns of selection at the major histocompatibility complex class I and II loci in a threatened shorebird, the Snowy Plover (Charadrius nivosus)
Authors: Cruz-López Medardo , Fernández Guillermo , Hipperson Helen , Palacios Eduardo , Cavitt John , Galindo-Espinosa Daniel , Gómez del Angel Salvador , Pruner Raya , Gonzalez Oscar , Burke Terry , Küpper Clemens
Published: September 2020

Background

Understanding the structure and variability of adaptive loci such as the major histocompatibility complex (MHC) genes is a primary research goal for evolutionary and conservation genetics. Typically, classical MHC genes show high polymorphism and are under strong balancing selection, as their products trigger the adaptive immune response in vertebrates. Here, we assess the allelic diversity and patterns of selection for MHC class I and class II loci in a threatened shorebird with highly flexible mating and parental care behaviour, the Snowy Plover (Charadrius nivosus) across its broad geographic range.

Results

We determined the allelic and nucleotide diversity for MHC class I and class II genes using samples of 250 individuals from eight breeding population of Snowy Plovers. We found 40 alleles at MHC class I and six alleles at MHC class II, with individuals carrying two to seven different alleles (mean 3.70) at MHC class I and up to two alleles (mean 1.45) at MHC class II. Diversity was higher in the peptide-binding region, which suggests balancing selection. The MHC class I locus showed stronger signatures of both positive and negative selection than the MHC class II locus. Most alleles were present in more than one population. If present, private alleles generally occurred at very low frequencies in each population, except for the private alleles of MHC class I in one island population (Puerto Rico, lineage tenuirostris).

Conclusion

Snowy Plovers exhibited an intermediate level of diversity at the MHC, similar to that reported in other Charadriiformes. The differences found in the patterns of selection between the class I and II loci are consistent with the hypothesis that different mechanisms shape the sequence evolution of MHC class I and class II genes. The rarity of private alleles across populations is consistent with high natal and breeding dispersal and the low genetic structure previously observed at neutral genetic markers in this species.