bluuebunny/crossref_metadata_2025 huggingface dataset:
Continuous irrigation and suction with a triple-cavity drainage tube in combination with sequential somatostatin–somatotropin administration for the management of postoperative high-output enterocutaneous fistulas
Authors: Kong Xiangheng , Cao Yuning , Yang Daogui , Zhang Xiangyang
Published: November 2019

Introduction:

Enterocutaneous fistula is considered one of the most serious complications in general surgery and is associated with high morbidity and mortality. Although various treatments are reported to have varying success, high-output enterocutaneous fistulas (output over 500 ml/day) continue to be associated with high mortality, and few papers on this topic exist in the literature. The aim of this study is to describe an effective multidisciplinary treatment method for postoperative high-output enterocutaneous fistula and discuss the clinical development of the therapeutic strategy.

Patient concerns:

Three patients suffered high-output enterocutaneous fistulas, in which case 1 presented with duodenal fistula, case 2 with ileal fistula, and case 3 with small bowel fistula.

Diagnosis

: All 3 cases were diagnosed with high-output enterocutaneous fistulas by drainage of intestinal contents.

Interventions:

With the exception of routine treatment including fluid resuscitation, correction of the electrolyte balance, control of infection, and optimal nutrition, all the cases accepted continuous irrigation and suction with triple-cavity drainage tubes in combination with sequential somatostatin–somatotropin administration were given. With regard to establishing effective drainage, the triple-cavity tube placement was performed by insertion through the initial drainage channel in case 1, percutaneous puncture with dilation by graduated dilators in case 2, and tract reconstruction in case 3. The technical details of the approach are described and clinical characteristics including fistula location, defect size, output volume, approach of triple-cavity tube placement, length of fistula tract, somatostatin and somatotropin administration time, and fistula healing time were recorded and compared. In addition, other various techniques reported in the literature are reviewed and discussed.

Outcomes:

All the patients were cured by the multidisciplinary treatments and were followed up without fistula recurrence and other relevant complications at 1 week, 1 month, and 3 months after the treatments.

Conclusion:

The strategy involving continuous irrigation and suction with a triple-cavity drainage tube in combination with sequential somatostatin–somatotropin administration may be a safe and effective alternative treatment for postoperative high-output enterocutaneous fistula and a more practical method that is easy to execute to manage this problem. Long-term studies, involving more patients, are still necessary to confirm this suggestion.
Immediate and short-term radiological changes after combining static stretching and transcutaneous electrical stimulation in adults with cavus foot
Authors: Fernández-Seguín Lourdes María , Heredia-Rizo Alberto Marcos , Díaz-Mancha Juan Antonio , González-García Paula , Ramos-Ortega Javier , Munuera-Martínez Pedro V.
Published: November 2019

Background:

Cavus foot is a deformity represented by an increased and rigid medial longitudinal arch, and it is often associated with persistent pain and gait disturbances. None of the conservative conventional treatments for cavus foot have shown conclusive evidence of effectiveness, and so further is research needed to understand how to manage this condition better. This study aimed to assess the immediate and short-term radiological changes after combining static stretching and transcutaneous electrical stimulation of the plantar fascia in adults with idiopathic cavus foot.

Methods:

A randomized, single-blinded clinical trial was conducted. Sixty-eight participants with idiopathic cavus foot, as determined by an internal Moreau–Costa–Bertani angle (MCBA) less than 125° in a lateral weight-bearing foot radiograph, were equally distributed into a neuromuscular stretching group (NSG) or a control group (no intervention). The NSG underwent a single session, combining transcutaneous electrical nerve stimulation with static stretching of the plantar fascia. Primary measurements of 3 angles were taken using a lateral weight-bearing foot radiograph: the internal MCBA; the calcaneal pitch angle (CPA); and the first metatarsal declination angle (FMDA). Outcomes were collected at baseline, immediately postintervention, and 1 week after intervention.

Results:

Analysis of variance revealed a significant group effect for all angles (all,P < .05). NSG participants showed a significant increase in the internal MCBA (P = .03), and a significant decrease in the CPA (P = .01) and FMDA (P = .04) from baseline to immediately postintervention. These changes remained statistically significant 1 week after the intervention (all,P < .05).

Conclusion:

The combination of static stretching and transcutaneous electrical stimulation of the plantar fascia, compared with no treatment, achieved immediate and short-term changes in the internal MCBA, the CPA, and the FMDA, which resulted in flattening the medial longitudinal plantar arch in adults with idiopathic cavus foot.
Difference in gait recovery rate of hemiparetic stroke patients according to paralyzed side
Authors: Kim Cheol-Hyun , Chu Hongmin , Kang Geon-Hui , Sung Kang-Keyng , Kang Dae Gill , Lee Ho Sub , Lee Sangkwan
Published: November 2019

In Donguibogam, a representative encyclopedic source of knowledge on traditional Korean medicine, left-sided hemiparesis due to stroke is called “Tan” as a sort of “Heyol-Byeong,” while right-sided hemiparesis due to stroke is called “Tan” as a sort of “Gi-Byeong.” According to the theory of Donguibogam, diseases on the left or right side of the human body must be treated differently. Clinically, the symptoms caused by left and right hemisphere lesions in stroke patients differ, as the functions of the left and right hemispheres differ. Considering these facts, when treating patients in clinical practice, it may be useful to distinguish between diseases on the left or right side according to Donguibogam. This study set out to confirm whether side-dependent gait rehabilitation could be used to treat hemiparetic stroke patients. Gait was selected for analysis, as it is the most important factor in returning stroke patients to daily life.

This study conducted a retrospective chart review of stroke patients who satisfied the following criteria: outpatient or inpatient at the Wonkwang University Korean Medicine Hospital in Gwangju (WKUGH) with hemiparesis due to stroke; aged between 19 and 85 years old; with a stroke onset within the past 6 months; having undergone gait analysis (GAITRite) more than twice between September 1, 2017 and June 30, 2018 at the WKUGH, with a minimum 2-week interval between the first and next gait analysis; right-handed stroke patient; able to walk unaided. The spatio-temporal parameters for analysis included the FAP, walking velocity, step length, stance time, and swing time as obtained with GAITRite.

In the initial gait analysis, there was no significant difference between the 2 groups in all spatio-temporal parameters. However, in the follow-up gait analysis, the left hemiparesis group showed a significantly higher FAP and faster walking velocity than the right hemiparesis group.

This study found a difference in the recovery rate between the left and right hemiparesis groups. Based on this, we suggest that a different treatment strategy for gait rehabilitation can be used according to the paralyzed side.

This study was approved by the Institutional Review Board (IRB) of the Wonkwang University Korean Medicine Hospital in Gwangju (WKUGH), Republic of Korea (WKIRB 2018 – 25, November 28, 2018). This trial was registered with the Clinical Research Information Service (CRIS) of the Korea National Institute of Health (NIH), Republic of Korea (KCT0002984).
Neutrophil to lymphocyte ratio (NLR) as a prognostic marker for in-hospital mortality of patients with sepsis
Authors: Ni Jie , Wang Hongye , Li Yue , Shu Yimei , Liu Yihai
Published: November 2019

Neutrophil-to-lymphocyte ratio (NLR) has been reported to serve as a prognostic marker in inflammatory diseases. The purpose of this study was to evaluate the association of NLR at admission with in-hospital mortality in patients with sepsis presenting to emergency department.

This was a secondary analysis based on a single-center, retrospective, cohort study. Patients with sepsis admitted to an academic emergency department between January 2010 and January 2015 were enrolled. NLR of patients was analyzed from the hospital's electronic health record (EHR) system. A total of 174 adult patients, of which 80 (46.0%) died in hospital. The primary outcome was in-hospital mortality. Secondary outcome was 28-day mortality.

Contrary to previous studies, a larger NLR was found to have less odds of in-hospital mortality, as well as the presence of bacteremia. Patients who has severe/shock or had a history of chronic heart failure (CHF) had larger odds of death during hospital. Multivariate logistic regression analysis indicated that low NLR was an independent predictor of in-hospital mortality (OR = –0.98; 95% CI –0.96 to –0.99; P = .022). However, no correlation was found between the NLR and 28-day hospital mortality in patients with sepsis (P = .988). As a predictor of in-hospital survival, the area under curve (AUC) of the NLR was 0.622 (95%CI 0.54–0.71; P = .006) and the cut-off value was 9.11 with 0.551 sensitivity and 0.707 specificity.

NLR at admission was an independent predictor of in-hospital mortality of sepsis patients.
Identification of breast cancer-related circRNAs by analysis of microarray and RNA-sequencing data
Authors: Zhao Chun-Hua , Qu Le , Zhang Hui , Qu Rui
Published: November 2019

Background:

An increasing number of studies indicate that circular RNAs (circRNAs) participate in tumorigenesis. The aim of this study was to elucidate the regulatory mechanisms of circRNAs in breast cancer based on the construction of the circRNA-related ceRNA network.

Methods:

The expression profiles of circRNAs, miRNAs, and mRNAs were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. A ceRNA network was constructed by Cytoscape. The interactions among proteins were analyzed using the STRING database, and hub genes were extracted using the cytoHubba application. The functions of the differentially expressed mRNAs (DEmRNAs) were analyzed by the Kyoto Encyclopedia of Gene and Genomes (KEGG) and the Gene Ontology (GO) database.

Results:

In total, 7 differentially expressed circRNAs (DEcircRNAs), 27 differentially expressed miRNAs (DEmiRNAs), and 102 DEmRNAs were selected for the construction of the ceRNA network of breast cancer. We established a protein–protein interaction network and identified 6 hub genes. Then, a circRNA-miRNA-hub gene regulatory module was established based on 2 DEcircRNAs, 2 DEmiRNAs, and 2 DEmRNAs. GO and KEGG pathway analyses indicated the possible association of DEmRNAs with breast cancer onset and progression.

Conclusions:

The circRNA hsa_circ_0000519 is likely critical in the pathogenesis of breast cancer and may serve as a future therapeutic biomarker.
Sexual Dimorphism in Children and Adolescents With Acute Lymphoblastic Leukemia: Influence on Incidence and Survival
Authors: Jaime-Pérez José C. , Hernández-De los Santos José A. , Fernández Lucía T. , Padilla-Medina José R. , Gómez-Almaguer David
Published: November 2019

Acute lymphoblastic leukemia (ALL) incidence and poor prognosis are higher in male individuals. There is a lack of studies assessing the influence of sex in ALL. We documented this influence in a homogenous cohort. Three hundred three ALL Hispanic patients 1 to 20 years of age diagnosed over 10 years at a university hospital were evaluated. Patients were divided by sex and stratified by age. Survival rates were assessed by the Kaplan-Meier method, and the Cox model was used for univariate and multivariate analysis. The median age for female individuals was 6 years versus 9 years for male individuals (P=0.002). In the whole cohort, there was a male preponderance (P=0.025), with a 1.3 male-to-female ratio. For male individuals, the 5-year relapse-free survival was 46%; for female individuals, it reached 58.7%, (P=0.009). Male individuals 1-9 years of age had a lower 5-year relapse-free survival than female individuals, 51.5% versus 66.7% (95% confidence interval, 65.35-68.01; P=0.020); this was not the case for overall survival (P=0.660). The male-to-female ratio in the 10 to 15 years’ group was 1.59, and 2.35 in the 16 to 20 years’ group. Incidence and relapse of ALL were higher in male individuals. A skewed distribution in the 10 to 20 years’ age group disproportionately affected male individuals, suggesting a hormonal influence.
Designing a Multistakeholder Collaboration to Improve Preventive Care for Children With Sickle Cell Anemia
Authors: Bates Katherine E. , Davis Corinne S. , Reeves Sarah L. , Freed Gary L.
Published: November 2019

Newly developed measures of health care quality for children with sickle cell anemia (SCA) have revealed significant performance gaps in recommended care. Historically, health systems, Medicaid health plans, and state Medicaid programs have not partnered with patients and families to improve SCA care delivery. We organized 2 novel multistakeholder design meetings to identify potential interventions to deliver high-quality preventive care for children with SCA. Invitees included patients with SCA, families, and representatives from pediatric hematology clinics, Medicaid health plans, community organizations, and a state Medicaid program. Participants identified some barriers to care through presentations and facilitated discussions. Over 35 potential interventions and 6 drivers of high-quality SCA preventive care delivery were organized into a key driver diagram. Many barriers to SCA care delivery could be addressed by Medicaid health plan resources to support members with chronic disease; however, these resources are infrequently used in the pediatric SCA population. Bridging gaps between stakeholder groups identified many potential interventions to improve SCA preventive care delivery at all levels of the health care system. Similar multistakeholder discussions may be useful for other communities interested in improving preventive care for children with SCA or other chronic pediatric diseases.
Pediatric Metastatic Cardiac Angiosarcoma Successfully Treated With Multimodal Therapy: Case Report and Review of Literature
Authors: Koo Jane , Knight-Perry Jessica , Galambos Csaba , Browne Lorna P. , Cost Carrye R.
Published: November 2019

Cardiac angiosarcoma (AS) is an extremely rare, malignant vascular tumor with <10 cases reported in the pediatric literature. Prognosis is dismal with overall survival often <1 year from initial diagnosis. In this report, we present the case of a 10-year-old boy with metastatic cardiac AS who is currently alive and is the longest pediatric survivor of metastatic cardiac AS reported in the literature. This is the only published pediatric case to successfully use a combination of surgical resection, conventional chemotherapy, radiation and targeted therapies including bevacizumab and pazopanib for metastatic cardiac AS.
Non-neoplastic Polyps of the Gallbladder
Authors: Taskin Orhun C. , Bellolio Enrique , Dursun Nevra , Seven Ipek Erbarut , Roa Juan C. , Araya Juan C. , Villaseca Miguel , Tapia Oscar , Vance Courtney , Saka Burcu , Balci Serdar , Bagci Pelin , Losada Hector , Sarmiento Juan , Memis Bahar , Pehlivanoğlu Burcin , Basturk Olca , Reid Michelle D. , Koshiol Jill , Cheng Jeanette D. , Kapran Yersu , Adsay Volkan
Published: November 2019

There is no systematic histopathologic analysis of non-neoplastic polyps in the gallbladder. In this study, in addition to a computer search for cases designated as “polyp,” a systematic review of 2533 consecutive routinely sampled archival and 203 totally submitted prospective cholecystectomies were analyzed for >2 mm polyps (cut-off was based on radiologic sensitivity). A total of 447 non-neoplastic polyps were identified. The frequency was 3% in archival cases and 5% in totally submitted cases. Only 21 (5%) were ≥1 cm. The average age was 52 years, and the female to male ratio was 3.1. Two distinct categories were delineated: (1) injury-related polyps (n=273): (a) Fibro(myo)glandular polyps (n=214) were small (mean=0.4 cm), broad-based, often multiple (45%), almost always (98%) gallstone-associated, and were composed of a mixture of (myo)fibroblastic tissue/lobular glandular units with chronic cholecystitis. Dysplasia seen in 9% seemed to be secondary involvement. (b) Metaplastic pyloric glands forming polypoid collections (n=42). (c) Inflammatory-type polyps associated with acute/subacute injury (11 granulation tissue, 3 xanthogranulomatous, 3 lymphoid). (2) Cholesterol polyps (n=174) occurred in uninjured gallbladders, revealing a very thin stalk, edematous cores devoid of glands but with cholesterol-laden macrophages in 85%, and cholesterolosis in the uninvolved mucosa in 60%. Focal low-grade dysplasia was seen in 3%, always confined to the polyp, unaccompanied by carcinoma. In conclusion, non-neoplastic polyps are seen in 3% of cholecystectomies and are often small. Injury-related fibromyoglandular polyps are the most common. Cholesterol polyps have distinctive cauliflower architecture, often in a background of uninjured gallbladders with cholesterolosis and may lack the cholesterol-laden macrophages in the polyp itself. Although dysplastic changes can involve non-neoplastic polyps, they do not seem to be the cause of invasive carcinoma by themselves.
Biallelic PTCH1 Inactivation Is a Dominant Genomic Change in Sporadic Keratocystic Odontogenic Tumors
Authors: Stojanov Ivan J. , Schaefer Inga-Marie , Menon Reshma S. , Wasman Jay , Gokozan Hamza N. , Garcia Elizabeth P. , Baur Dale A. , Woo Sook-Bin , Sholl Lynette M.
Published: November 2019

Keratocystic odontogenic tumors (KCOTs) are locally aggressive odontogenic neoplasms with recurrence rates of up to 60%. Approximately 5% of KCOTs are associated with nevoid basal cell carcinoma (Gorlin) syndrome and 90% of these show genomic inactivation of the PTCH1 gene encoding Patched 1. Sporadic KCOTs reportedly have PTCH1 mutations in 30% of cases, but previous genomic analyses have been limited by low tumor DNA yield. The aim of this study was to identify recurrent genomic aberrations in sporadic KCOTs using a next-generation sequencing panel with complete exonic coverage of sonic hedgehog (SHH) pathway members PTCH1, SMO, SUFU, GLI1, and GLI2. Included were 44 sporadic KCOTs from 23 female and 21 male patients with a median age of 50 years (range, 10 to 82 y) and located in the mandible (N=33) or maxilla (N=11). Sequencing identified PTCH1 inactivating mutations in 41/44 (93%) cases, with biallelic inactivation in 35 (80%) cases; 9q copy neutral loss of heterozygosity targeting the PTCH1 locus was identified in 15 (34%) cases. No genomic aberrations were identified in other sequenced SHH pathway members. In summary, we demonstrate PTCH1 inactivating mutations in 93% of sporadic KCOTs, indicating that SHH pathway alterations are a near-universal event in these benign but locally aggressive neoplasms. The high frequency of complete PTCH1 loss of function may provide a rational target for SHH pathway inhibitors to be explored in future studies.
Moral Distress of Clinicians in Canadian Pediatric and Neonatal ICUs*
Authors: Dryden-Palmer Karen , Moore Gregory , McNeil Clare , Larson Charles Philip , Tomlinson George , Roumeliotis Nadia , Janvier Annie , Parshuram Christopher S. ,   on behalf of the Program of Wellbeing, Ethical practice and Resilience (POWER) Investigators
Published: November 2019

Objective:

To quantify moral distress in neonatal ICU and PICU clinicians and to identify associated factors.

Design:

A national cross-sectional survey of clinicians working in an neonatal ICU or PICU. Moral distress was assessed with the Moral Distress Scale-Revised and by self-rating. Depersonalization was assessed on the subscale of the Maslach Burnout Inventory. Respondents reported their attendance at each of six hospital supports that may serve to mitigate moral distress in frontline staff. Analyses compared outcomes across respondent characteristics and hierarchical linear regression evaluated individual, ICU, hospital, and regional effects.

Setting:

Eligible ICUs were PICUs and level-3 neonatal ICUs in Canada.

Subjects:

Eligible participants had worked in the participating ICU for more than 3 months.

Interventions:

None.

Measurements and Main Results:

We identified 54 eligible ICUs from 31 hospitals. Forty-nine Canadian neonatal ICUs and PICUs (91%) contributed 2,852 complete responses for a 45.2% response rate. Most respondents were nurses (64.9%) or from a neonatal ICU (66.5%). The median and interquartile range Moral Distress Scale-Revised were 79 (52–113); 997 respondents (34.2%) had Moral Distress Scale-Revised scores greater than or equal to 100, and 234 respondents (8.3%) strongly agreed that work caused them significant moral distress. Nurses had a median (interquartile range) Moral Distress Scale-Revised score of 85 (57–121), 19 points higher than physicians and 8 points higher than respiratory therapists (p < 0.0001). Moral Distress Scale-Revised scores increased from 53 (35–79) for those working in ICU less than 1 year to 83 (54–120) in those working in ICU more than 30 years (p < 0.0001); 22.5% reported high degrees of depersonalization, which was associated with moral distress (p < 0.0001). Variability in Moral Distress Scale-Revised scores was explained by individual-level (92%), hospital-level (5%), and ICU-level effects (1%). Frequency of participation in potentially mitigating hospital supports had small effects (< 10 points) on mean Moral Distress Scale-Revised scores.

Conclusions:

Moral distress is common in clinicians working in ICUs for children. Addressing moral distress will require interventions tailored to individuals in higher-risk groups.
The Comparison of Pierre Robin Sequence and Non-Syndromic Cleft Palate
Authors: Kocaaslan Fatma Nihal Durmus , Sendur Samet , Koçak Ismail , Çelebiler Özhan
Published: November 2019

Introduction:

The aim of this study was to evaluate pre-operative nutritional status, associated syndromes and abnormalities, and post-operative outcomes of patients with Pierre Robin Sequence (PRS) versus those with non-syndromic isolated cleft palate (CIP).

Methods:

Between January 1995 and December 2013, patients with a cleft palate Veau I-II according to the Veau classification with and without PRS who underwent primary repair were retrospectively analyzed. The nutrition status, age at the time of palatoplasty, additional anomalies, gestational complications, and post-operative speech abnormalities and outcomes were evaluated.

Results:

A total of 59 patients with PRS (PRS group) and 132 patients without PRS (non-PRS group) were included in the study. Of all patients, 92 were males and 99 were females with a mean age of 14 ± 4.18 (range, 6 to 26) years. The rate of gestational complications, enteral nutrition, complete cleft, additional anomalies, and velopharyngeal insufficiency was significantly higher in the PRS group (P < 0.05). However, the incidence of fistulas and age at the time of palatoplasty did not significantly differ between the groups.

Conclusion:

Based on our study results, enteral nutrition, respiratory problems, pregnancy complications, velopharyngeal insufficiency, and additional anomalies, but not post-operative palatal fistulas, are more frequently seen in patients with PRS. Although pre-operative care and treatment and rehabilitation in patients with PRS are more complicated than those with the CIP, our experience demonstrates that meticulous repair and follow-up can minimize complications, such as fistulas.
Automated Lesion Segmentation and Quantitative Analysis of Nevus in Whole-Face Images
Authors: Chen Wei , Chai Yuanhao , Chai Gang , Hu Yong , Chen Mingang , Xu Haisong , Zhang Yan
Published: November 2019

Background:

Nevus is very common; however, melanoma is slightly related to the deterioration of nevus because of its vulnerability to solarization, friction, aging, heredity, and other factors. Early diagnosis is essential for melanoma treatment, since patients have a high survival rate with early detection and treatment. Computer-aided diagnosis has been applied in the differential diagnosis of melanoma and benign nevi and achieved high accuracy, but it does not suit the screening of nevi because most studies are based on dermoscopy with a narrow field of vision and performed by professional doctors. Therefore, this study aimed to present the accuracy and effectiveness of our algorithm.

Methods:

Based on whole-face images of patients, the authors used logistic regression and the Newton method to detect the nevus region. Then, Python and OpenCV were employed to detect the lesion edge and compute the area of the regions. A multicenter clinical trial with a sample size of 600 was then conducted to evaluate the effectiveness of the algorithm.

Results:

The algorithm detected 2672 nevi from 600 patients, in which there were 195 patients of missed diagnosis and 310 patients of misdiagnosis. The Kappa value between 2 groups was 0.860 (>0.8). Paired t-test showed no significant difference between 2 groups’ area results (P = 0.265, P > 0.05).

Conclusion:

Within the limitations of this study, the authors demonstrated a high agreement between algorithm's detection and doctor's diagnosis. Our new algorithm has great effectiveness in nevus detection, edge segmentation, and area measurement.
Mindfulness-based programs and practices for people with intellectual and developmental disability
Authors: Singh Nirbhay N. , Hwang Yoon-Suk
Published: November 2019

Purpose of review

People with intellectual and developmental disability (IDD) commonly exhibit behaviors that present challenges to their parents, caregivers, and teachers. Mindfulness-based practices and programs have emerged as a viable alternative to current interventions for such behaviors and the stress faced by their caregivers. This review addresses publications between 2018 and 2019 that examined the effectiveness of mindfulness-based practices and programs for people living with IDD.

Recent findings

Individuals with IDD can learn mindfulness practices to self-manage their aggressive and destructive behaviors. Individual practices and group-based programs continue to show that mindfulness approaches are effective for this population. Randomized controlled trials indicate that comprehensive mindfulness-based programs (e.g., mindfulness-based stress reduction, MYmind, and mindfulness-based positive behavior support) are effective for enhancing the quality of life of people living with IDD.

Research supports the use of informal mindfulness practices for challenging behaviors of people with IDD. Formal mindfulness-based programs continue to be evaluated for their effectiveness across different populations, cultures, levels of IDD, components of the program, and length of training. The research literature on mindfulness is still in the early stages of development and much work remains.
Revealing acquired resistance mechanisms of kinase-targeted drugs using an on-the-fly, function-site interaction fingerprint approach
Authors: Zhao Zheng , Bourne Philip E.
Published: November 2019

Although kinase-targeted drugs have achieved significant clinical success, they are frequently subject to the limitations of drug resistance, which has become a primary vulnerability to targeted drug therapy. Therefore, deciphering resistance mechanisms is an important step in designing more efficacious, anti-resistant, drugs. Here we studied two FDA-approved kinase drugs: Crizotinib and Ceritinib, which are first- and second-generation anaplastic lymphoma kinase (ALK) targeted inhibitors, to unravel drug-resistance mechanisms. We used an on-the-fly, function-site interaction fingerprint (on-the-fly Fs-IFP) approach by combining binding free energy surface calculations with the Fs-IFPs. Establishing the potentials of mean force and monitoring the atomic-scale protein-ligand interactions, before and after the L1196M-induced drug resistance, revealed insights into drug-resistance/anti-resistant mechanisms. Crizotinib prefers to bind the wild type ALK kinase domain, whereas Ceritinib binds more favorably to the mutated ALK kinase domain, in agreement with experimental results. We determined that ALK kinase-drug interactions in the region of the front pocket are associated with drug resistance. Additionally, we find that the L1196M mutation does not simply alter the binding modes of inhibitors, but also affects the flexibility of the entire ALK kinase domain. Our work provides an understanding of the mechanisms of ALK drug resistance, confirms the usefulness of the on-the-fly Fs-IFP approach and provides a practical paradigm to study drug-resistance mechanisms in prospective drug discovery.
Chimpanzee fibroblasts exhibit greater adherence and migratory phenotypes than human fibroblasts
Authors: Zintel Trisha M. , Ducey Delaney , Babbitt Courtney C.
Published: November 2019

Background and objectives

Previous work has identified that gene expression differences in cell adhesion pathways exist between humans and chimpanzees. Here, we used a comparative cell biology approach to assay interspecies differences in cell adhesion phenotypes in order to better understand the basic biological differences between species’ epithelial cells that may underly the organism-level differences we see in wound healing and cancer.

Methodology

We used skin fibroblast cell lines from humans and chimpanzees to assay cell adhesion and migration. We then utilized published RNA-Seq data from the same cell lines exposed to a cancer / wound-healing mimic to determine what gene expression changes may be corresponding to altered cellular adhesion dynamics between species.

Results

The functional adhesion and migration assays revealed that chimpanzee fibroblasts adhered sooner and remained adherent for significantly longer and move into a “wound” at faster rate than human fibroblasts. The gene expression data suggest that the enhanced adhesive properties of chimpanzee fibroblasts may be due to chimpanzee fibroblasts exhibiting significantly higher expression of cell and focal adhesion molecule genes than human cells, both during a wound healing assay and at rest.

Conclusions and implications

Chimpanzee fibroblasts exhibit stronger adhesion and greater cell migration than human fibroblasts. This may be due to divergent gene expression of focal adhesion and cell adhesion molecules, such as integrins, laminins, and cadherins, as well as ECM proteins like collagens. This is one of few studies demonstrating that these divergences in gene expression between closely related species can manifest in fundamental differences in cell biology. Our results provide better insight into species-specific cell biology phenotypes and how they may influence more complex traits, such as cancer metastasis and wound healing.
GPCRmd uncovers the dynamics of the 3D-GPCRome
Authors: Rodríguez-Espigares Ismael , Torrens-Fontanals Mariona , Tiemann Johanna K.S. , Aranda-García David , Ramírez-Anguita Juan Manuel , Stepniewski Tomasz Maciej , Worp Nathalie , Varela-Rial Alejandro , Morales-Pastor Adrián , Lacruz Brian Medel , Pándy-Szekeres Gáspár , Mayol Eduardo , Giorgino Toni , Carlsson Jens , Deupi Xavier , Filipek Slawomir , Filizola Marta , Gómez-Tamayo José Carlos , Gonzalez Angel , Gutierrez-de-Teran Hugo , Jimenez Mireia , Jespers Willem , Kapla Jon , Khelashvili George , Kolb Peter , Latek Dorota , Marti-Solano Maria , Matricon Pierre , Matsoukas Minos-Timotheos , Miszta Przemyslaw , Olivella Mireia , Perez-Benito Laura , Provasi Davide , Ríos Santiago , Rodríguez-Torrecillas Iván , Sallander Jessica , Sztyler Agnieszka , Vaidehi Nagarajan , Vasile Silvana , Weinstein Harel , Zachariae Ulrich , Hildebrand Peter W. , Fabritiis Gianni De , Sanz Ferran , Gloriam David E. , Cordomi Arnau , Guixà-González Ramon , Selent Jana
Published: November 2019

G protein-coupled receptors (GPCRs) are involved in numerous physiological processes and are the most frequent targets of approved drugs. The explosion in the number of new 3D molecular structures of GPCRs (3D-GPCRome) during the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this protein family. While experimentally-resolved structures undoubtedly provide valuable snapshots of specific GPCR conformational states, they give only limited information on their flexibility and dynamics associated with function. Molecular dynamics (MD) simulations have become a widely established technique to explore the conformational landscape of proteins at an atomic level. However, the analysis and visualization of MD simulations requires efficient storage resources and specialized software, hence limiting the dissemination of these data to specialists in the field. Here we present the GPCRmd (http://gpcrmd.org/), an online platform that incorporates web-based visualization capabilities as well as a comprehensive and user-friendly analysis toolbox that allows scientists from different disciplines to visualize, analyse and share GPCR MD data. GPCRmd originates from a community-driven effort to create the first open, interactive, and standardized database of GPCR MD simulations. We demonstrate the power of this resource by performing comparative analyses of multiple GPCR simulations on two mechanisms critical to receptor function: internal water networks and sodium ion interaction.
When polymorphism and monomorphism meet: discordant genomic and phenotypic clines across a lizard contact zone
Authors: Dong Caroline M. , McLean Claire A. , Elliott Adam , Moussalli Adnan , Stuart-Fox Devi
Published: November 2019

Colour polymorphism can promote rapid evolution and speciation, particularly when populations differ in the number or composition of morphs. The contact zone betweenCtenophorus modestus(swift dragon) andC. decresii(tawny dragon) is a compelling study system in which to examine evolutionary processes and outcomes when polymorphic and monomorphic populations meet.Ctenophorus modestusis polymorphic for male throat coloration and lacks ultraviolet (UV) reflectance whileC. decresiiis monomorphic with UV-blue throats. We characterised genomic and phenotypic clines across the contact zone based on single nucleotide polymorphisms, the mitochondrial ND4 gene, and male colour traits, and concurrently assessed the phenotype of captive-bred F1 hybrids. Our results indicate that genomic introgression is asymmetric, with high frequencies of backcrossing toC. modestusbut notC. decresii, accompanied by the prevalence of theC. modestusmtDNA haplotype in hybrids. The clines for throat phenotype are abrupt and displaced towards the range ofC. decresii, relative to the genetic and dorsolateral phenotype clines. By contrast, both throat and dorsolateral phenotypes in captive-bred F1 hybrids are intermediate. Our results are consistent with the hypothesis that throat coloration, a polymorphic sexual signal inC. modestus, is the target of selection during incipient speciation and provide insight into the microevolutionary processes that may link polymorphism and speciation.
CRISPR screening of porcine sgRNA library identified host factors essential for Japanese encephalitis virus replication
Authors: Zhao Changzhi , Liu Hailong , Xiao Tianhe , Wang Zichang , Nie Xiongwei , Li Xinyun , Qian Ping , Qin Liuxing , Han Xiaosong , Zhang Jinfu , Ruan Jinxue , Zhu Mengjin , Miao Yiliang , Zuo Bo , Yang Kui , Xie Shengsong , Zhao Shuhong
Published: November 2019

Japanese encephalitis virus (JEV) is a mosquito-borne zoonotic flavivirus that causes encephalitis and reproductive disorders in mammalian species. However, key host genes involved in the JEV life cycle and cell death are poorly understood. Here, we designed 85,674 single guide RNAs (sgRNAs) targeting 17,743 protein-coding genes, 11,053 long ncRNAs (lncRNAs), and 551 microRNAs (miRNAs) in the porcine genome, and subsequently developed a porcine sgRNA library and genome-scale CRISPR/Cas9 knockout (PigGeCKO) system. These sgRNAs were delivered into porcine kidney-15 (PK-15) cells that constitutively express Cas9, positive selection screening of the resulting PigGeCKO cell collection for resistance to JEV-induced cell death led to the identification of several previously unreported genes required for JEV infection. We conducted follow-up studies to verify the dependency of JEV on these genes, and identified functional contributions for six of the many candidate JEV-related host genes, including an endoplasmic reticulum membrane protein complex subunit 3 (EMC3) and calreticulin (CALR). Additionally, we identified that four genes associated with heparan sulfate proteoglycans (HSPGs) metabolism, specifically those responsible for HSPG sulfurylation, facilitated JEV entry into PK-15 cells. Thus, beyond our development of the largest CRISPR-based functional genomic screening platform for pig research to date, this work deepens our basic understanding of flavivirus infection and identifies multiple potentially vulnerable targets for the development of medical and breeding technologies to prevent and treat diseases caused by Japanese encephalitis virus.
Deep profiling reveals substantial heterogeneity of integration outcomes in CRISPR knock-in experiments
Authors: Canaj Hera , Hussmann Jeffrey A. , Li Han , Beckman Kyle A. , Goodrich Leeanne , Cho Nathan H. , Li Yucheng J. , Santos Daniel A. , McGeever Aaron , Stewart Edna M. , Pessino Veronica , Mandegar Mohammad A. , Huang Cindy , Gan Li , Panning Barbara , Huang Bo , Weissman Jonathan S. , Leonetti Manuel D.
Published: November 2019

CRISPR/Cas technologies have transformed our ability to add functionality to the genome by knock-in of payload via homology-directed repair (HDR). However, a systematic and quantitative profiling of the knock-in integration landscape is still lacking. Here, we present a framework based on long-read sequencing and an integrated computational pipeline (knock-knock) to analyze knock-in repair outcomes across a wide range of experimental parameters. Our data uncover complex repair profiles, with perfect HDR often accounting for a minority of payload integration events, and reveal markedly distinct mis-integration patterns between cell-types or forms of HDR templates used. Our analysis demonstrates that the two sides of a given double-strand break can be repaired by separate pathways and identifies a major role for sequence micro-homology in driving donor mis-integration. Altogether, our comprehensive framework paves the way for investigating repair mechanisms, monitoring accuracy, and optimizing the precision of genome engineering.
Seed mass and plant origin interact to determine species germination patterns
Authors: Veselá Andrea , Dostálek Tomáš , Rokaya Maan , Münzbergová Zuzana
Published: November 2019

Ongoing changes in temperature and precipitation regime may have strong impact on vulnerable life-history stages such as germination. Differences in germination patterns among species and populations may reflect their adaptation to conditions of their origin or may be determined by the phylogenetic constrains. These two effects are, however, rarely separated. All the germination patterns may also be modified by seed mass.

We studied 40 populations of 14 species ofImpatienscoming from Himalayas. Germination of seeds of different origin was tested in four target temperatures, three simulating original conditions plus a warmer climate change scenario. We also studied effect of shorter stratification and warmer temperature in combination as another possible effect of climate change.

Original and target climate interacted and had strong impact on total germination, but not on germination speed and seed dormancy. Interaction between seed mass and original climate indicated different germination strategies in light and heavy seeds. Only seed mass was affected by phylogenetic relationships among the species, while germination response (with exception of T50) was driven primarily by climate of origin.

This study is the first to show that the effect of seed mass interacts with original climate in determining species germination patterns under changing climate. The differences in seed mass are thus likely crucial for species ability to adapt to novel conditions as seed mass, unlike seed germination patterns, is strongly phylogenetically constrained. Further studies exploring how seed mass modifies species germination under changing climate are needed to confirm generality of these findings.
Extremely widespread parthenogenesis and a trade-off between alternative forms of reproduction in mayflies (Ephemeroptera)
Authors: Liegeois Maud , Sartori Michel , Schwander Tanja
Published: November 2019

Studying alternative forms of reproduction in natural populations is of fundamental importance for understanding the costs and benefits of sex. Mayflies are one of the few animal groups where sexual reproduction co-occurs with different types of parthenogenesis, providing ideal conditions for identifying benefits of sex in natural populations. Here, we establish a catalogue of all known mayfly species capable of reproducing by parthenogenesis, as well as mayfly species unable to do so. Overall, 1.8% of the described species reproduce parthenogenetically, which is an order of magnitude higher than reported in other animal groups. This frequency even reaches 47.8% if estimates are based on the number of studied rather than described mayfly species. In terms of egg-hatching success, sex is a more successful strategy than parthenogenesis, and we found a trade-off between the efficiency of sexual and parthenogenetic reproduction across species. This means that improving the capacity for parthenogenesis may come at the cost of being less able to reproduce sexually, even in facultative parthenogens. Such a trade-off can help explain why facultative parthenogenesis is extremely rare among animals despite its potential to combine the benefits of sexual and parthenogenetic reproduction. We argue that parthenogenesis is frequently selected in mayflies in spite of this probable trade-off because their typically low dispersal ability and short and fragile adult life may frequently generate situations of mate limitation in females. Mayflies are currently clearly underappreciated for understanding the benefits of sex under natural conditions.
Systems biology approach identifies functional modules and regulatory hubs related to secondary metabolites accumulation after the transition from autotrophic to heterotrophic growth condition in the microalga
Authors: Panahi B , Farhadian Mohammad , Hejazi Mohammad amin
Published: November 2019

Heterotrophic cultures are among the most promising strategies put forth to overcome the low biomass and secondary metabolites productivity challenge. To shedding light on the underlying molecular mechanisms, weighted gene co-expression network analysis (WGCNA) was integrated with transcriptome meta-analysis, connectivity analysis, functional enrichment, and hub genes identification. Meta-analysis and Functional enrichment analysis demonstrated that with the progress to developmental phases at heterotrophic growth condition, most of the biological processes are up-regulated, which leads to the change of genetic architectures and phenotypic outcomes. WGNCA analysis of meta-genes also created four significant functional modules across logarithmic (LG), transition (TR), and production peak (PR) phases. The expression pattern and connectivity characteristics of the brown module as a non-preserved module vary across LG, TR, and PR phases. Functionally analysis identified “Carotenoid biosynthesis”, “Fatty acid metabolism”, and “Methane metabolism” as enriched pathways in the non-preserved module. Moreover, the integrated approach was applied here, identified some hub genes, such as serine hydroxymethyltransferase (SHMT1) for development of metabolites accumulating strains in microalgae. Our study provided a new insight into underlying mechanisms of metabolite accumulation and opens new avenue for the future applied studies in the microalgae field.
The left angular gyrus is causally involved in information buffering and context formation: evidence from a narrative reading task
Authors: Branzi Francesca M. , Pobric Gorana , Jung JeYoung , Lambon Ralph Matthew A.
Published: November 2019

The role of the left angular gyrus (Ag) in semantic processing remains unclear. In this study, we used transcranial magnetic stimulation (TMS) to test the hypothesis that the left Ag supports the information buffering processes necessary for context-dependent semantic integration (narrative reading task). We applied online TMS to the left Ag to disrupt the buffering processes while female and male human participants integrated information between two paragraphs of text presented sequentially (i.e., context and target conditions). We assessed the effect of TMS on the left Ag by recording reading times for target conditions during the reading task and by asking participants to retrieve contextual information given the target condition as cue in a successive memory task. TMS applied over the left Ag during the reading task impaired the retrieval of contextual information in the memory task without affecting reading times. These results suggest that the Ag supports information buffering and context formation. This study provides the first evidence of a causal role of the left Ag in language tasks that require context-dependent semantic integration.

Significance statement

The present study offers novel insights into the processes that are associated with the left angular gyrus (Ag) activation during context-dependent naturalistic language processing. We used TMS while human participants read written narratives to interfere with online language integration. We measured how TMS over the left Ag was affecting reading times and retrieval of integrated narrative representations. We were able to show that the left Ag is causally involved in information buffering and context formation.
Complex spikes encode reward expectation signals during visuomotor association learning
Authors: Sendhilnathan Naveen , Ipata Anna , Goldberg Michael E.
Published: November 2019

Climbing fiber input to Purkinje cells has been thought to instruct learning related changes in simple spikes and cause behavioral changes through an error-based learning mechanism. Although, this framework explains simple motor learning, it cannot be extended to learning higher-order skills. Recently the cerebellum has been implicated in a variety of cognitive tasks and reward-based learning. Here we show that when a monkey learns a new visuomotor association, complex spikes predict the time of the beginning of the trial in a learning independent manner as well as encode a learning contingent reward expectation signal after the stimulus onset and reward delivery. These complex spike signals are unrelated to and were unlikely to instruct the reward based signal found in the simple spikes. Our results provide a more general role of complex spikes in learning and higher-order processing while gathering evidence for their participation in reward based learning.