bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic responses of rice cultivars with different tolerance to combined drought and heat stress under field conditions
Authors: Lawas Lovely Mae F , Li Xia , Erban Alexander , Kopka Joachim , Jagadish S V Krishna , Zuther Ellen , Hincha Dirk K
Published: May 2019

Background

Rice is susceptible to both drought and heat stress, in particular during flowering and grain filling, when both grain yield and quality may be severely compromised. However, under field conditions, these 2 stresses rarely occur separately. Under well-watered conditions, plants avoid heat stress by transpirational cooling, while this is not possible under drought conditions. Although investigating combined drought and heat stress is clearly more agronomically relevant than analyzing the effects of the single stresses, only a few studies of this stress combination, in particular under field conditions, have been published.

Results

Three rice cultivars differing in drought and heat tolerance were grown in the field under control and drought conditions in 3 consecutive years. Drought was applied either during flowering or during early grain filling and resulted in simultaneous heat stress, leading to reduced grain yield and quality. Analysis by gas chromatography−mass spectrometry showed distinct metabolic profiles for the 3 investigated organs (flag leaves, flowering spikelets, developing seeds). The metabolic stress responses of the plants also strongly differed between cultivars and organs. Correlation analysis identified potential metabolic markers for grain yield and quality under combined drought and heat stress from both stress-regulated metabolites and from metabolites with constitutive differences between the cultivars.

Conclusions

Gas chromatography−mass spectrometry resolved metabolic responses to combined drought and heat stress in different organs of field-grown rice. The metabolite profiles can be used to identify potential marker metabolites for yield stability and grain quality that are expected to improve breeding efforts towards developing rice cultivars that are resilient to climate change.
Gigwa v2—Extended and improved genotype investigator
Authors: Sempéré Guilhem , Pétel Adrien , Rouard Mathieu , Frouin Julien , Hueber Yann , De Bellis Fabien , Larmande Pierre
Published: May 2019

Background

The study of genetic variations is the basis of many research domains in biology. From genome structure to population dynamics, many applications involve the use of genetic variants. The advent of next-generation sequencing technologies led to such a flood of data that the daily work of scientists is often more focused on data management than data analysis. This mass of genotyping data poses several computational challenges in terms of storage, search, sharing, analysis, and visualization. While existing tools try to solve these challenges, few of them offer a comprehensive and scalable solution.

Results

Gigwa v2 is an easy-to-use, species-agnostic web application for managing and exploring high-density genotyping data. It can handle multiple databases and may be installed on a local computer or deployed as an online data portal. It supports various standard import and export formats, provides advanced filtering options, and offers means to visualize density charts or push selected data into various stand-alone or online tools. It implements 2 standard RESTful application programming interfaces, GA4GH, which is health-oriented, and BrAPI, which is breeding-oriented, thus offering wide possibilities of interaction with third-party applications. The project home page provides a list of live instances allowing users to test the system on public data (or reasonably sized user-provided data).

Conclusions

This new version of Gigwa provides a more intuitive and more powerful way to explore large amounts of genotyping data by offering a scalable solution to search for genotype patterns, functional annotations, or more complex filtering. Furthermore, its user-friendliness and interoperability make it widely accessible to the life science community.
Hormonal regulation of vascular endothelial growth factor A (VEGFA) gene expression in granulosa and theca cells of cattle1
Authors: Nichols Jacqueline A , Perego Maria Chiara , Schütz Luis F , Hemple Amber M , Spicer Leon J
Published: May 2019

Vascular endothelial growth factor A (VEGFA) stimulates angiogenesis and is associated with increased vascularity in ovarian follicles of cattle. The objectives of this study were to investigate the developmental and hormonal regulation of VEGFA expression in ovarian granulosa and theca cells (TC) of cattle. Bovine ovaries were collected from a local slaughterhouse and granulosa cells (GC) and TC were collected from small (SM; 1 to 5 mm) and large (LG; 8 to 20 mm) follicles. Cells were collected fresh or cultured in serum-free medium and treated with various factors that regulate angiogenesis and follicular development. RNA was collected for analysis of VEGFA mRNA abundance via quantitative PCR. In SM-follicle GC (SMGC), prostaglandin E2 (PGE2) and FSH decreased (P < 0.05) VEGFA mRNA abundance by 30 to 46%, whereas in LG-follicle GC (LGGC), PGE2 and FSH were without effect (P > 0.10). In SMGC, dihydrotestosterone (DHT), sonic hedgehog (SHH), and growth differentiation factor-9 (GDF9) decreased (P < 0.05) VEGFA expression by 30 to 40%. Fibroblast growth factor-9 (FGF9) and estradiol (E2) were without effect (P > 0.10) on VEGFA mRNA in both SMGC and LGGC, whereas progesterone increased (P < 0.05) VEGFA mRNA in LGGC but had no effect in LGTC. Bone morphogenetic protein-4 (BMP4), LH, and FGF9 increased (P < 0.05) abundance of VEGFA mRNA by 1.5- to 1.9-fold in LGTC. Insulin-like growth factor-1 (IGF1) was without effect (P > 0.10) on VEGFA mRNA in both TC and GC. An E2F transcription factor inhibitor, HLM0064741 (E2Fi), dramatically (i.e., 8- to 13-fold) stimulated (P < 0.01) the expression of VEGFA mRNA expression in both SMGC and LGTC. Abundance of VEGFA mRNA was greater (P < 0.05) in LGGC and SMGC than in LGTC. Also, SMTC had greater (P < 0.05) abundance of VEGFA mRNA than LGTC. In conclusion, VEGFA mRNA abundance was greater in GC than TC, and VEGFA expression decreased in TC during follicle development. Some treatments either suppressed, stimulated, or had no effect on VEGFA expression depending on the cell type. The inhibition of E2F transcription factors had the greatest stimulatory effect of all treatments evaluated, and thus, E2Fs may play an important role in regulating angiogenesis during follicle growth in cattle.
Digital Breast Tomosynthesis: Clinical Operations
Authors: Friedewald Sarah M , Bhole Sonya , Wang Lilian , Gupta Dipti
Published: May 2019

Digital breast tomosynthesis (DBT) is rapidly becoming the standard of care for breast cancer screening. Implementing DBT into practice is relatively straightforward. However, there are important elements of the transition that one must consider to facilitate this process. Understanding the Digital Imaging and Communications in Medicine (DICOM) standard for DBT, as well as how images are displayed, is critical to a successful transition. Standardization of these processes will allow easier transmission of images from facility to facility, and limit the potential for errors in interpretation. Additionally, recent changes in federal regulations will require compliance with mandated training for the radiologist, technologist, and physicist, as well as accreditation for each DBT unit. These regulations aim to ensure high-quality imaging across the country as has been previously seen with standard digital mammography. Synthesized imaging is the most recent improvement for DBT, potentially obviating the need for a simultaneous traditional digital mammogram exposure. Studies have demonstrated near equivalent performance when comparing the combination imaging of DBT and digital mammography versus DBT combined with synthetic imaging. As the quality of the synthetic images continues to improve, it is increasingly likely that it will replace the traditional mammogram. Adherence to DBT-specific parameters will enhance the physician experience and ultimately translate to increased cancer detection and fewer false positive examinations, benefiting all women who are screened for breast cancer.
A Cluster of Bunyavirus-Associated Severe Fever With Thrombocytopenia Syndrome Cases in a Coastal Plain Area in China, 2015: Identification of a Previously Unidentified Endemic Region for Severe Fever With Thrombocytopenia Bunyavirus
Authors: Hu Jianli , Li Zhifeng , Cai Jiaping , Liu Donglin , Zhang Xuefeng , Jiang Renjie , Guo Xilin , Liu Dapeng , Zhang Yufu , Cui Lunbiao , Shen Jinjin , Zhu Fengcai , Bao Changjun
Published: May 2019

Background

Severe fever with thrombocytopenia syndrome (SFTS) is a typical tick-borne, natural focal disease. The natural foci of SFTS were considered to exist in hilly and mountainous areas before 2015. A cluster of 3 patients exposed to a patient with a fulminant disease consistent with SFTS occurred from July to August 2015 in Dongtai County, which is characterized by alluvial plains; this prompted investigation.

Methods

The epidemiological, clinical, and laboratory features of 4 patients in the cluster were analyzed. Serum samples from the indigenous healthy population and native domesticated animals were collected to conduct laboratory tests, along with small wild animals and ticks.

Results

In 3 secondary case patients, high fever, thrombocytopenia and leukopenia developed within 8–13 days after contact with blood or bloody secretions from the index patient; SFTS was then diagnosed by means of reverse-transcription polymerase chain reaction. Genomic sequencing and analysis of S and L segments of 2 viral strains isolated from 2 secondary case patients showed that they shared 99.8%–99.9% homology in nucleotide sequence. The seroprevalences among indigenous healthy population, native livestock, native poultry, and small wild animals was 0.74%, 17.54%, 6.67%, and 1.12%, respectively. Three questing ticks, 61 feeding ticks, and 178 small wild animals were collected in August 2015. Survey on tick density and seasonal fluctuation in 2016 showed that ticks were active from March to October. All ticks were identified as Haemaphysalis longicornis. Severe fever with thrombocytopenia bunyavirus (SFTSV)–specific RNA was detected in the ticks collected in 2016, and the minimum SFTSV infection rate in these ticks was 0.54% (1 of 185).Wild mammals and ticks collected in August 2015 tested negative for SFTSV-specific RNA.

Conclusions

Aside from hilly or mountainous area, a coastal plain was identified as the natural foci of SFTSV in Dongtai County, China. The involvement of migration in the evolution of SFTSV might lead to a transregional transmission event of SFTSV.
Jodh Singh, The Ghadar Movement and the Anti-Colonial Deviant in the Anglo-American Imagination*
Authors: Singh Gajendra
Published: May 2019

This article is a study of an early Indian anti-colonial revolutionary movement (the Ghadar Movement) through the life and testimonies of Jodh Singh. Jodh Singh straddled the worlds of official imaginaries and revolutionary realities. He was a Punjabi Sikh and had been a migrant labourer, revolutionary, turncoat and approver before being imprisoned for refusing to give evidence in a courtroom in San Francisco in 1917 and suffering a psychotic breakdown in the early weeks of 1918. The detailed interviews and analyses of Jodh Singh’s madness offer some measure of intimacy with the rank and file of the Ghadar Movement about whom very little was ever recorded or preserved. It also becomes a prism through which an understanding can be reached of the neuroses that plagued both the United Kingdom and the United States. The desire to prosecute a trans-national and trans-Pacific conspiracy about which they knew very little, resulted in Ghadar assuming a fictive, nightmarish quality in the Anglo-American imagination. And Jodh Singh, diagnosed as possessing all the degenerative qualities of the ‘homosexual type’was one such victim.
Energy spectra in $p$-shell $\Lambda$ hypernuclei and $^{19}_{\Lambda}\textrm{F}$ and spin-dependent $\Lambda N$ interactions
Authors: Kanada-En’yo Yoshiko , Isaka Masahiro , Motoba Toshio
Published: May 2019

Energy spectra of $0s$-orbit $\Lambda$ states in $p$-shell $\Lambda$ hypernuclei ($^{A}_\Lambda Z$) and those in $^{19}_{\Lambda}\textrm{F}$ are studied with the microscopic cluster model and antisymmetrized molecular dynamics using the $G$-matrix effective $\Lambda N$ ($\Lambda NG$) interactions. Spin-dependent terms of the ESC08a version of the $\Lambda NG$ interactions are tested and phenomenologically tuned to reproduce observed energy spectra in $p$-shell $^{A}_\Lambda Z$. Spin-dependent contributions of the $\Lambda N$ interactions to spin-doublet splitting and excitation energies are discussed. Energy spectra for unobserved excited states in $p$-shell $^{A}_\Lambda Z$ and $^{19}_{\Lambda}\textrm{F}$ are predicted with the modified $\Lambda NG$ interactions.
The State of American Federalism 2018–2019: Litigation, Partisan Polarization, and the Administrative Presidency
Authors: Goelzhauser Greg , Konisky David M
Published: May 2019

Several themes characterize the state of American federalism. Increasing political polarization shapes preferences with respect to locating the vertical balance of power. To implement these preferences, the federal government is primarily relying on regulatory rollback and unilateral action. With Congress largely unable or unwilling to check the executive branch, states have pushed back on use of the tools of the administrative presidency through litigation. We address these themes through an analysis of voting and elections along with important policy developments from the previous year in the areas of immigration, health care, environmental policy, education, gun control, and criminal justice. We also review important federalism developments from the Supreme Court’s 2017 term.
Elite without Elitism? Boundary Work and the Israeli Elite Philanthropy in a Changing Field of Power
Authors: Krauz-Lahav Noa , Kemp Adriana
Published: May 2019

The crisis of neoliberalism and the upsurge of populist politics have renewed interest in how contemporary economic elites justify their privileged position, trying to be “moral” and “rich” in an era of increasing inequality and an anti-elite climate. We addressed this question through an ethnographic analysis of the socio-cultural life of the heirs of the Israeli economic elite and of the boundary-making processes that philanthropy allows them as they face internal and external challenges. Adopting analytical tools from a cultural process approach to inequality and a contextual approach to elite distinction, we suggest that the heirs generate distinct social and symbolic position within a changing field of power by presenting themselves as an “elite without elitism.” This is accomplished through a mutually reinforcing interplay between intra-elite distinctions and “inter-class inconspicuous distinction.” We contribute to the current analysis of elite reproduction “beyond Bourdieu” first by pointing at the (re)production of power and difference within the elite, and second by showing that where distinctions are drawn, matters.
A novel screw view model of 3D navigation for upper cervical pedicle screw placement
Authors: Zhao Jianwu , Yang Lili , Zheng Shuang , Qu Yang , Zhang Xiwen , Kang Mingyang , Dong Rongpeng , Zhao Xin , Yu Tong
Published: May 2019

Rationale:

The purpose of this study is to introduce the technique of screw view model of navigation (SVMN) for upper cervical pedicle screw (UCPS) insertion. With the assistance of SVMN technology, the difficulty of screw placement manipulation can be diminished and the accuracy of placement can be improved.

Patient concerns:

A 49-year-old man presented with numbness of extremities and limited activity for 2 years.

Diagnoses:

He was diagnosed with old fracture of C1 vertebra and atlantoaxial subluxation.

Interventions:

We used SVMN to assist UCPS insertion and lateral mass screw insertion in this patient.

Outcomes:

A total of 2 pedicle screws and 2 lateral mass screws were inserted, all screws were defined as excellent position according to postoperative computer tomography (CT). The neurological function was intact postoperatively. The operation time was 293 minutes, the total fluoroscopic time was 4.1 minutes and the bleeding volume was 302 ml. There were no complications during the 48 months follow-up period.

Conclusions:

The application of SVMN in UCPS insertion could achieve satisfactory effect of internal fixation for upper cervical spine and avoid neurovascular damage. The utilization of SVMN for UCPS insertion is a safe and efficacious method. Besides, it also increased the patients’ hospital cost, and the surgeon must be quite familiar with the functional state of computer navigation.
The relation of serum nesfatin-1 level with anthropometric and metabolic parameters in children and adolescents
Authors: Kim Shin-Hee , Ahn Moon Bae , Cho Won Kyoung , Cho Kyoung Soon , Jung Min Ho , Suh Byung-Kyu
Published: May 2019

Nesfatin-1, a recently discovered anorexigenic neuropeptide, seems to play an important role in hypothalamic pathways regulating food intake and energy homeostasis. The aim of this study was to evaluate the relation of serum nesfatin-1 level with metabolic and anthropometric parameters in children and adolescents.

This study prospectively included 78 Korean children and adolescents (42 obese/overweight group and 36 healthy control group). Fasting serum nesfatin-1 was quantitatively assayed by ELISA. Lipid profile, fasting blood glucose, fasting insulin, and the homeostasis model assessment of insulin resistance (HOMA-IR) were measured as metabolic parameters.

Serum nesfatin-1 levels were significantly lower in obese/overweight group than in control group (median 1.4 vs 2.0 ng/mL;P = .003). Pubertal subjects have the lower serum nesfatin-1 level than pre-pubertal subjects (median 1.5 vs 2.6 ng/mL;P = .02). Nesfatin-1 levels negatively correlated with chronological age (r = −0.37;P = .001), BMI (r = −0.33;P = .003), and BMI SDS (r = −0.26;P = .02).

In conclusion, our results suggest that serum nesfatin-1 negatively correlated with BMI in children and adolescents. It suggests that nesfatin-1 might have an important role in regulation of food intake in obese children and adolescents.
An atypical case of serotonin syndrome with normal dose of selective serotonin inhibitors
Authors: Liu Yun , Yang Hailong , He Fei , Xu Peng , Tong Hanwen , Liu Yao , Ni Jie , Zhang Qiulin , Wang Jun
Published: May 2019

Rationale:

As increasing frequency of serotonergic drug use, SS (serotonin syndrome) occurred more than ever. But clinicians have not enough knowledge and experience about SS as a potentially life-threatening condition. SS is usually caused by the increased serotonin activity in the central nervous system which may due to a serotonergic agent overdose or the concomitant use of 2 or more serotonergic antidepressants. We report a case of SS due to a normal dose of selective serotonin inhibitors (SSRIs) thus to remind clinicians to pay attention to such patients and make an early diagnosis and initiation of therapy in the clinical practice.

Patient concerns:

We report here a 49-year-old man presented with lethargic, less communicative, and insomnia for 20 days while a diagnosis of depression was considered and he was treated with SSRIs.

Diagnosis:

The patient in our case fulfilled the 3 criteria existed now for diagnosing SS, including the Sternbach criteria, Radomski revised diagnostic criteria, and the Hunter serotonin toxicity criteria.

Interventions:

All the antidepressants were stopped and cyproheptadine with an initial dose of 12 mg a day was started along with supportive care. The patient was also admitted to emergency intensive care unit for further treatment. He was sedated and paralyzed by intravenous Midazolam and Clonazepam along with physical cooling and supportive care.

Outcomes:

All of the patient's symptoms abated gradually and he soon could get off the bed and be communicative. Finally, the patient made a full recovery and he was discharged from the hospital.

Lessons:

Our case suggests an atypical clinical course while the medicine the patient takes was not in so much dose. We assumed that there may have been some variation in metabolism of these agents, resulting in increased possibility that led to the subsequent syndrome. Thus, it is essential for clinicians to keep in mind when patients taking serotonergic agents who demonstrate acute change in their mental status. Besides, clinicians should be aware of such patients who seem to be sensitive to SSRIs, who may require a genetic testing before the initiation of SSRI therapy.
A study on the relationship between sexual morality education and mental health level of Chinese female college students
Authors: Wang Yu-Hang , Luo Qian-Ying , Shi Zhou-Ting
Published: May 2019

The aim of this study was to explore the relationship between different models of sexual morality education and the mental health level of female college students, to provide a scientific basis for college conduct an effective sexual morality education program that can improve the psychologic health level of female college students.

The experimental and control groups were comprised of female college students who received different models of sexual morality education. Total and factor scores derived from the Symptom Checklist 90 (SCL90) were compared between these groups.

The total mental health SCL90 score for female college students in the control group was 1.48 ± 0.39, and the scores of 3 factors including SCL90-3 (interpersonal sensitivity, P < .01), SCL90-4 (depression, P < .05), and SCL90-5 (anxiety, P < .05) were all significantly higher than the national norm. The total mental health scores for female students in the purely theoretical experimental group and the integrated practical training experimental group were 1.40 ± 0.42 and 1.33 ± 0.39, respectively, both of which were significantly different from the control group (P < .05), while the difference between the 2 groups was near the threshold of significance (P = .052). There were significant differences between the integrated practical training experimental group and the control group for scores of 5 factors including SCL90-2 (obsessive-compulsive symptoms), SCL90-3 (interpersonal sensitivity), SCL90-4 (depression), SCL90-5 (anxiety), and SCL90-6 (hostility) (Ps < .01). There were also significant differences between the purely theoretical experimental group and the control group for scores of 3 factors including SCL90-2 (obsessive-compulsive symptoms), SCL90-3 (interpersonal sensitivity), and SCL90-6 (hostility) (Ps < .05). And, there were also significant differences between the 2 experimental groups for scores for 3 factors including SCL90-3 (interpersonal sensitivity), SCL90-4 (depression), and SCL90-5 (anxiety) (Ps < .05).

Different models of sexual morality education have significantly different impacts on the mental health level of female college students. The integrated practical education model can significantly and effectively improve the mental health of female college students, and as such colleges and universities should adopt this integrated model to better improve these students’ mental health.
Threshold Isocontouring on High b-Value Diffusion-Weighted Images in Magnetic Resonance Mammography
Authors: Zong Fangrong , Bickelhaupt Sebastian , Kuder Tristan Anselm , Lederer Wolfgang , Daniel Heidi , Stieber Anne , Schlemmer Heinz-Peter , Galvosas Petrik , Laun Frederik Bernd
Published: May 2019

Objectives

Motivated by the similar appearance of malignant breast lesions in high b-value diffusion-weighted imaging (DWI) and positron emission tomography, the purpose of this work was to evaluate the applicability of a threshold isocontouring approach commonly used in positron emission tomography to analyze DWI data acquired from female human breasts with minimal interobserver variability.

Methods

Twenty-three female participants (59.4 ± 10.0 years) with 23 lesions initially classified as suggestive of cancers in x-ray mammography screening were subsequently imaged on a 1.5-T magnetic resonance imaging scanner. Diffusion-weighted imaging was performed prior to biopsy with b values of 0, 100, 750, and 1500 s/mm2. Isocontouring with different threshold levels was performed on the highest b-value image to determine the voxels used for subsequent evaluation of diffusion metrics. The coefficient of variation was computed by specifying 4 different regions of interest drawn around the lesion. Additionally, a receiver operating statistical analysis was performed.

Results

Using a relative threshold level greater than or equal to 0.85 almost completely suppresses the intra-individual and inter-individual variability. Among 4 studied diffusion metrics, the diffusion coefficients from the intravoxel incoherent motion model returned the highest area under curve value of 0.9. The optimal cut-off diffusivity was found to be 0.85 μm2/ms with a sensitivity of 87.5% and specificity of 90.9%.

Conclusion

Threshold isocontouring on high b-value maps is a viable approach to reliably evaluate DWI data of suspicious focal lesions in magnetic resonance mammography.
Treating advanced penile cancer: where do we stand in 2019?
Authors: Aydin Ahmet Murat , Cheriyan Salim , Spiess Philippe E.
Published: May 2019

Purpose of review

Penile squamous cell carcinoma (PSCC) remains a challenging malignancy to treat and there is an urgent need of significant improvements at all levels of medical care. In the current review, we summarized the significant obstacles encountered during management of PSCC and discussed the clinical relevance of novel findings and their potential to address these obstacles.

Recent findings

The recent genetic and immunological advances suggest that patients with PSCC can benefit from available targeted therapy and immunotherapy options. Moreover, evidence has accumulated over time suggesting that majority of the patients diagnosed with PSCC suffer from psychosocial problems and impaired rehabilitation.

Effective prevention strategies against PSCC are urgently needed especially in developing countries given the limited therapeutic options. About a quarter of patients with metastatic PSCC appear to benefit from available targeted therapies and about half of the patients can be a suitable candidate for immune checkpoint blockade as half of the PSCC cases exhibit PD-L1 expression. Moreover, increased public awareness, healthcare provider education and social support programs may help patients suffering from PSCC coping with the psychosocial burdens of the disease.
Differentiating Deep Tissue Pressure Injury (DTPI) From Other Causes of Purpura in the Sacrococcygeal Area
Authors: Solmos Susan , Radkevich-Brown Olga , LaFond Cynthia
Published: May 2019

BACKGROUND:

Recent revisions to the pressure injury staging system include guidance on differential diagnoses for deep tissue pressure injury (DTPI). Accurately identifying DTPI is critical; however, purpura in the setting of vascular disorders and systemic infectious processes can share similar features confounding diagnosis.

CASES:

In this three-case series, we describe suspected DTPI with an uncharacteristic shape or occurring in the presence of additional lesions distributed outside of typical pressure areas prompted further evaluation.

CONCLUSIONS:

The interdisciplinary approach we adapted was useful in determining the cause of purpura when the DTPI was ruled out by the certified wound care nurse.
Skeletal muscle stem cell self-renewal and differentiation kinetics revealed by EdU lineage tracing during regeneration
Authors: Pawlikowski Bradley , Betta Nicole Dalla , Antwine Tiffany , Olwin Bradley B.
Published: May 2019

Skeletal muscle maintenance and repair is dependent on the resident adult muscle stem cell (MuSC). During injury, and in diseased muscle, stem cells are engaged to replace or repair damaged muscle, which requires the stem cells to exit quiescence and expand, followed by differentiation to regenerate myofibers and self-renewal to replenish the stem cell population. Following an injury, little is known regarding the timing of MuSC (skeletal muscle stem cell) self-renewal, myoblast expansion or myoblast differentiation. To determine the timing and kinetics of these cell fate decisions, we employed DNA-based lineage tracing to label newly replicated cells and followed cell fates during skeletal muscle regeneration. MuSCs activate and expand as myoblasts rapidly following injury, where the majority differentiate into myonuclei, establishing the centrally located myonuclear pool. Re-establishing the majority MuSC pool by self-renewal occurs after 5 days post-muscle injury, accompanied by low levels of myonuclear accretion that generate only peripheral myonuclei. In aged mice, possessing ∼1/2 the number of MuSCs present in young adult mice, the timing of post injury MuSC self-renewal is delayed, and although MuSCs expansion as myoblasts in aged muscle is impaired, the number of MuSC unexpectedly recovers to young adult levels during regeneration. Following an induced muscle injury, we found that myonuclei are generated within the first four days post injury derived from myoblasts expanding from activated MuSCs. Only later during regeneration, from 5 d to 14 d post injury, is the MuSC pool replenished by self-renewal, accompanied by generation of peripheral myonuclei.
Sequencing and comparative analysis of threeChlorellagenomes provide insights into strain-specific adaptation to wastewater
Authors: Wu Tian , Li Linzhou , Jiang Xiaosen , Yang Yong , Song Yanzi , Chen Liang , Xu Xun , Shen Yue , Gu Ying
Published: May 2019

MicroalgalChlorellahas been demonstrated to process wastewater efficiently from piggery industry, yet optimization through genetic engineering of such a bio-treatment is currently challenging, largely due to the limited data and knowledge in genomics. In this study, we first investigated the differential growth rates among three wastewater-processingChlorellastrains:Chlorella sorokinianaBD09,Chlorella sorokinianaBD08 andChlorella sp.Dachan, and the previously publishedChlorella sorokinianaUTEX 1602, showing us that BD09 maintains the best tolerance in synthetic wastewater. We then performed genome sequencing and analysis, resulting in a high-quality assembly for each genome with scaffold N50 >2 Mb and genomic completeness ≥ 91%, as well as genome annotation with 9,668, 10,240, 9,821 high-confidence gene models predicted for BD09, BD08, and Dachan, respectively. Comparative genomics study unravels that metabolic pathways, which are involved in nitrogen and phosphorus assimilation, were enriched in the faster-growing strains. We found that gene structural variation and genomic rearrangement might contribute to differential capabilities in wastewater tolerance among the strains, as indicated by gene copy number variation, domain reshuffling of orthologs involved, as well as a ∼1 Mb-length chromosomal inversion we observed in BD08 and Dachan. In addition, we speculated that an associated bacterium,Microbacterium chocolatum, which was identified within Dachan, play a possible role in synergizing nutrient removal. Our three newly sequencedChlorellagenomes provide a fundamental foundation to understand the molecular basis of abiotic stress tolerance in wastewater treatment, which is essential for future genetic engineering and strain improvement.
Proteome-by-phenome Mendelian Randomisation detects 38 proteins with causal roles in human diseases and traits
Authors: Bretherick Andrew D. , Canela-Xandri Oriol , Joshi Peter K. , Clark David W. , Rawlik Konrad , Boutin Thibaud S. , Zeng Yanni , Amador Carmen , Navarro Pau , Rudan Igor , Wright Alan F. , Campbell Harry , Vitart Veronique , Hayward Caroline , Wilson James F. , Tenesa Albert , Ponting Chris P. , Kenneth Baillie J. , Haley Chris
Published: May 2019

Target identification remains a crucial challenge in drug development. To enable unbiased detection of proteins and pathways that have a causal role in disease pathogenesis or progression, we propose proteome-by-phenome Mendelian Randomisation (P2MR). We first detected genetic variants associated with plasma concentration of 249 proteins. We then used 64 replicated variants in two-sample Mendelian Randomisation to quantify evidence of a causal role for each protein across 846 phenotypes: this yielded 509 robust protein-outcome links. P2MR provides substantial promise for drug target prioritisation. We provide confirmatory evidence for a causal role for the proteins encoded at multiple cardiovascular disease risk loci (FGF5, IL6R, LPL, LTA), and discovered that intestinal fatty acid binding protein (FABP2) contributes to disease pathogenesis. Additionally, we find and replicate evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia. Our results provide specific prediction of the effects of changes of plasma protein concentration on complex phenotypes in humans.
A new clinical tool to predict outcome in early-stage melanoma patients
Authors: Mancuso Filippo , Lage Sergio , Rasero Javier , Díaz-Ramón José Luis , Apraiz Aintzane , Pérez-Yarza Gorka , Ezkurra Pilar A. , Penas Cristina , Sánchez-Diez Ana , García-Vazquez María Dolores , Gardeazabal Jesús , Izu Rosa , Mujika Karmele , Cortés Jesús , Asumendi Aintzane , Boyano María Dolores
Published: May 2019

Around 25% of early-stage melanoma patients eventually develop metastasis. Thus, we set out to define serological biomarkers that could be used along with clinical and histopathological features of the disease to predict these events. We previously demonstrated that in stage II melanoma patients, serum levels of dermcidin (DCD) were associated with metastatic progression. Based on the relevance of the immune response on the cancer progression and the recent association of DCD with local and systemic immune response against cancer cells, serum DCD was analyzed in a new cohort of patients along with IL-4, IL-6, IL-10, IL-17A, IFNγ TGFβ and GM-CSF. We included 448 melanoma patients, 323 of whom were diagnosed as stages I-II according to AJCC. Levels of selected cytokines were determined by ELISA and Luminex and obtained data were analyzed employing Machine Learning and Kaplan-Meier techniques to define an algorithm capable of accurately classifying early-stage melanoma patients with a high and low risk of developing metastasis. The results show that in early-stage melanoma patients, serum levels of the cytokines IL-4, GM-CSF and DCD together with the Breslow thickness are those that best predict melanoma metastasis. Moreover, resulting algorithm represents a new tool to discriminate subjects with good prognosis from those with high risk for a future metastasis.

Novelty and Impact

We have developed a prognostic equation that considers the serum IL-4, GM-CSF and DCD levels, along with the Breslow thickness to accurately classify melanoma outcome in patients. In this sense, a rigorous follow-up is recommended for early-stage melanoma patients with a high Breslow thickness, high serum IL-4 levels and low GM-CSF and DCD levels at the time of diagnosis, given the elevated risk for these patients to develop metastasis during follow-up.
Quantitative Models of Phage-Antibiotics Combination Therapy
Authors: Rodriguez-Gonzalez Rogelio A. , Leung Chung-Yin , Chan Benjamin K. , Turner Paul E. , Weitz Joshua S.
Published: May 2019

The spread of multi-drug resistant (MDR) bacteria is a global public health crisis. Bacteriophage therapy (or “phage therapy”) constitutes a potential alternative approach to treat MDR infections. However, the effective use of phage therapy may be limited when phage-resistant bacterial mutants evolve and proliferate during treatment. Here, we develop a nonlinear population dynamics model of combination therapy that accounts for the system-level interactions between bacteria, phage and antibiotics for in-vivo application given an immune response against bacteria. We simulate the combination therapy model for two strains of Pseudomonas aeruginosa, one which is phage-sensitive (and antibiotic resistant) and one which is antibiotic-sensitive (and phage-resistant). We find that combination therapy outperforms either phage or antibiotic alone, and that therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at sub-inhibitory concentrations of antibiotics, e.g., ciprofloxacin. These in-silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of innate immunity in shaping therapeutic outcomes.
TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease
Authors: Herhaus Lina , Bhaskara Ramachandra M. , Håkon Lystad Alf , Simonsen Anne , Hummer Gerhard , Dikic Ivan
Published: May 2019

Autophagy is a highly conserved catabolic process through which defective or otherwise harmful cellular components are targeted for degradation via the lysosomal route. Regulatory pathways, involving post-translational modifications such as phosphorylation, play a critical role in controlling this tightly orchestrated process. Here, we demonstrate that TBK1 regulates autophagy by phosphorylating autophagy modifiers LC3C and GABARAP-L2 on surface-exposed serine residues (LC3C S93 and S96; GABARAP-L2 S87 and S88). This phosphorylation event impedes their binding to the processing enzyme ATG4 by destabilizing the complex. Phosphorylated LC3C/GABARAP-L2 cannot be removed from liposomes by ATG4 and are thus protected from ATG4-mediated premature removal from nascent autoph-agosomes. This ensures a steady coat of lipidated LC3C/GABARAP-L2 throughout the early steps in autophagosome formation and aids in maintaining a unidirectional flow of the autophagosome to the lysosome. Taken together, we present a new regulatory mechanism of autophagy, which influences the conjugation and de-conjugation of LC3C and GABARAP-L2 to autophagosomes by TBK1-mediated phosphorylation.
Chromosome-levelde novoassembly of the pig-tailed macaque genome using linked-read sequencing and HiC proximity scaffolding
Authors: Roodgar Morteza , Babveyh Afshin , Huong Lan , Zhou Wenyu , Sinha Rahul , Lee Hayan , Hanks John B. , Avula Mohan , Jiang Lihua , Lee Hoyong , Song Giltae , Chaib Hassan , Weissman Irv L. , Batzoglou Serafim , Holmes Susan , Smith David G. , Mankowski Joseph L. , Prost Stefan , Snyder Michael P.
Published: May 2019

Old world monkey species share over 93% genome homology with humans and develop many disease phenotypes similar to those of humans, making them highly valuable animal models for the study of numerous human diseases. However, the quality of genome assembly and annotation for old world monkeys including macaque species lags behind the human genome effort. To close this gap and enhance functional genomics approaches, we employed a combination ofde novolinked-read assembly and scaffolding using proximity ligation assay (HiC) to assemble the pig-tailed macaque (Macaca nemestrina) genome. This combinatorial method yielded large scaffolds at chromosome-level with a scaffold N50 of 127.5 Mb; the 23 largest scaffolds covered 90% of the entire genome. This assembly revealed large-scale rearrangements between pig-tailed macaque chromosomes 7,12, and13 and human chromosomes 2, 14, and 15.
Global ecotypes in the ubiquitous marine clade SAR86
Authors: Hoarfrost Adrienne , Nayfach Stephen , Ladau Joshua , Yooseph Shibu , Arnosti Carol , Dupont Chris L , Pollard Katherine S.
Published: May 2019

SAR86 is an abundant and ubiquitous heterotroph in the surface ocean that plays a central role in the function of marine ecosystems. We hypothesized that despite its ubiquity, different SAR86 subgroups may be endemic to specific ocean regions and functionally specialized for unique marine environments. However, the global biogeographical distributions of SAR86 genes, and the manner in which these distributions correlate with marine environments, have not been investigated. We quantified SAR86 gene content across globally-distributed metagenomic samples and modeled these gene distributions as a function of 51 environmental variables. We identified five distinct clusters of genes within the SAR86 pangenome, each with a unique geographic distribution associated with specific environmental characteristics. Gene clusters are characterized by strong taxonomic enrichment of distinct SAR86 genomes and partial assemblies, as well as differential enrichment of certain functional groups, suggesting differing functional and ecological roles of SAR86 ecotypes. We then leveraged our models and high-resolution, remote sensing-derived environmental data to predict the distributions of SAR86 gene clusters across the world’s oceans, creating global maps of SAR86 ecotype distributions. Our results reveal that SAR86 exhibits previously unknown, complex biogeography, and provide a framework for exploring geographic distributions of genetic diversity from other microbial clades.
Sepsis-associated Pathways Segregate Cancer Groups
Authors: Tripathi Himanshu , Mukhopadhyay Samanwoy , Mohapatra Saroj Kant
Published: May 2019

Background

Sepsis and cancer are both leading causes of death, and occurrence of any one, increases the likelihood of the other. While cancer patients are susceptible to sepsis, survivors of sepsis are also susceptible to develop certain cancers. This mutual dependence for susceptibility suggests shared biology between the two disease categories. Earlier analysis had revealed cancer-related pathway to be up-regulated in Septic Shock (SS), an advanced stage of sepsis. This has motivated a more comprehensive comparison of the transcriptomes of SS and cancer.

Methods

Gene Set Enrichment Analysis was performed to detect the pathways enriched in SS and cancer. Thereafter, hierarchical clustering was applied to identify relative segregation of 17 cancer types in to two groupsvis-a-visSS. Biological significance of the selected pathways was explored by network analysis. Clinical significance of the pathways was tested by survival analysis. A robust classifier of cancer groups was developed based on machine learning.

Results

A total of 66 pathways were observed to be enriched in both SS and cancer. However, clustering segregated cancer types into two categories based on the direction of transcriptomic change. In general, there was up-regulation in SS and one group of cancer (termed Sepsis-Like Cancers, or SLC), but not in other cancers. SLC group mainly consisted of malignancies of the gastrointestinal tract (head and neck, oesophagus, stomach, liver and biliary system) often associated with infection. Machine learning classifier successfully segregated the two cancer groups with high accuracy (> 98%). Additionally, pathway up-regulation was observed to be associated with survival in the SLC group of cancers.

Conclusion

Transcriptome-based systems biology approach segregates cancer into two groups (SLC and CA) based on similarity with SS. Host response to infection plays a key role in pathogenesis of SS and SLC. However, we hypothesize that some component of the host response is protective in both SS and SLC.
Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility
Authors: Kachuri Linda , Johansson Mattias , Rashkin Sara R. , Graff Rebecca E. , Bossé Yohan , Manem Venkata , Caporaso Neil E. , Landi Maria Teresa , Christiani David C. , Vineis Paolo , Liu Geoffrey , Scelo Ghislaine , Zaridze David , Shete Sanjay S. , Albanes Demetrius , Aldrich Melinda C. , Tardón Adonina , Rennert Gad , Chen Chu , Goodman Gary E. , Doherty Jennifer A. , Bickeböller Heike , Field John K. , Davies Michael P. , Dawn Teare M. , Kiemeney Lambertus A. , Bojesen Stig E. , Haugen Aage , Zienolddiny Shanbeh , Lam Stephen , Marchand Loïc Le , Cheng Iona , Schabath Matthew B. , Duell Eric J. , Andrew Angeline S. , Manjer Jonas , Lazarus Philip , Arnold Susanne , McKay James D. , Emami Nima C. , Warkentin Matthew T. , Brhane Yonathan , Obeidat Ma’en , Martin Richard M. , Relton Caroline , Smith George Davey , Haycock Philip C. , Amos Christopher I. , Brennan Paul , Witte John S. , Hung Rayjean J.
Published: May 2019

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1:rg=0.098, p=2.3×10−8) and the ratio of FEV1to forced vital capacity (FEV1/FVC:rg=0.137, p=2.0×10−12). Mendelian randomization analyses demonstrate that reduced FEV1increases squamous cell carcinoma risk (odds ratio (OR)=1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR=1.17, 1.01-1.35) and lung cancer in never smokers (OR=1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.