bluuebunny/crossref_metadata_2025 huggingface dataset:
Current Volumetric Models Overestimate Vestibular Schwannoma Size Following Stereotactic Radiosurgery
Authors: Sherry Alexander D. , Khattab Mohamed H. , Totten Douglas J. , Wharton David M. , Luo Guozhen , Manzoor Nauman F. , Rivas Alejandro , Chambless Lola B. , Davis Larry T. , Attia Albert , Cmelak Anthony J.
Published: November 2019

Objective:

Accurate volume assessment is essential for the management of vestibular schwannoma after stereotactic radiosurgery (SRS). A cuboidal approximation for volume is the standard surveillance method; however, this may overestimate tumor volume. We sought to evaluate several volumetric models and their suitability for post-SRS surveillance.

Study Design:

Retrospective cohort study.

Setting:

Tertiary referral center.

Patients:

We evaluated 54 patients with vestibular schwannoma before and after SRS.

Intervention(s):

Gold-standard volumes were obtained by a radiation oncologist using contouring software. Volume was also calculated by cuboidal, ellipsoidal, and spherical formulae using tumor diameters obtained by a neuroradiologist.

Main Outcome Measure(s):

Percent error (PE) and absolute percent error (APE) were calculated. Paired t test evaluated bias, and the Bland–Altman method evaluated reproducibility. Linear regression evaluated predictors of model error.

Results:

All models overestimated volume compared with the gold standard. The cuboidal model was not reproducible before SRS (p < 0.001), and no model was reproducible after SRS (cuboidal p < 0.001; ellipsoidal p = 0.02; spherical p = 0.02). Significant bias was present before SRS for the cuboidal model (p < 0.001), and post-SRS for all models [cuboidal (p < 0.001), ellipsoidal (p < 0.02), and spherical (p = 0.005)]. Model error was negatively associated with pretreatment volume for the cuboidal (PE p = 0.03; APE p = 0.03), ellipsoidal (PE p = 0.03; APE p = 0.04), and spherical (PE p = 0.02; APE p = 0.03) methods and lost linearity post-SRS.

Conclusions:

The standard cuboidal practice for following vestibular schwannoma tumor volume after SRS overestimates size. Ellipsoidal and spherical estimations have improved performance but also overestimate volume and lack reliability post-SRS. The development of other volumetric models or application of contouring software should be investigated.
A novel mutation in the GP1BA gene in Bernard–Soulier syndrome
Authors: Özdemir Zeynep C. , Düzenli Kar Yeter , Ceylaner Serdar , Bör Özcan
Published: November 2019

The Bernard–Soulier syndrome (BSS) is a rare disease with a prevalence of 1/1000 000; it is characterized by macrothrombocytopenia. BSS develops as a result of a defect in the glycoprotein GPIb-IX-V complex on the platelet surface. In this article, we present a pediatric patient with the novel mutation that has been identified for the first time in BSS. A 13-month-old male patient was admitted with severe thrombocytopenia unresponsive to intravenous immunoglobulin in the neonatal period and recurrent mucocutaneous bleeding which initiated at 5 months of age. glycoprotein (GP) IX (CD42a) expression was normal as per flow cytometry results. Genetic analysis revealed a homozygous c.243C>A (p.Cys81∗) (p.C81∗) mutation. This novel mutation identified by us presents with severe thrombocytopenia and normal GPIX (CD42a) expression and is mistaken for immune thrombocytopenia in the neonatal period. This mutation creates an early stop codon and possibly leads to loss of function of the receptor.
A novel homozygous mutation (Gly1715Ser) causing hereditary factor V deficiency in a Chinese patient
Authors: Liu Siqi , Luo Shasha , Yang Lihong , Jin Yanhui , Xie Haixiao , Xie Yaosheng , Li Xiaolong , Wang Mingshan
Published: November 2019

To explore the phenotype and genotype of a Chinese family with hereditary factor V deficiency. Routine blood coagulation indexes were detected by one-stage clotting method, whereas factor V antigen was detected by ELISA. All exons and intron–exon boundaries of F5 gene were amplified by PCR and sequenced directly. The suspected mutation was confirmed by reverse sequencing. Bioinformatics softwares were used to analyze the possible impact of this mutation. Phenotypic analysis showed that the proband had significantly prolonged prothrombin time and activated partial thromboplastin time, and his factor V clotting activity was decreased to 3%. Genetic analysis revealed a homozygous missense mutation c.5227G>A (p.Gly1715Ser) in exon 16 of F5 gene. Bioinformatics and structural analysis demonstrated this mutation was deleterious and could affect the integrity of local intermolecular structures. The missense mutation (Gly1715Ser) was responsible for the decrease of factor V clotting activity and factor V antigen in this family, and caused type I hereditary factor V deficiency.
Isolated tumour microparticles induce endothelial microparticle release in vitro
Authors: Faulkner Lucy G. , Alqarni Saeed , Maraveyas Anthony , Madden Leigh A.
Published: November 2019

Cancer induces a hypercoagulable state, resulting in an increased risk of venous thromboembolism. One of the mechanisms driving this is tissue factor (TF) production by the tumour, released in small lipid bound microparticles. We have previously demonstrated that tumour cell line media-induced procoagulant changes in HUVEC. The aim of this study was to investigate the effect of tumour microparticles and recombinant human TF (rhTF) on the endothelium. Procoagulant microparticles from the PANC-1 cell line were harvested by ultrafiltration. HUVEC were then incubated with these procoagulant microparticles or rhTF. Flow cytometry was used to investigate the effect of endothelial cell surface protein expression and microparticle release. Microparticles but not soluble TF was responsible for the procoagulant activity of cell-free tumour media. We also demonstrated an increase in endothelial microparticle release with exposure to tumour microparticles, with a positive linear relationship observed (R
2 = 0.6630 P ≤ 0.0001). rhTF did not induce any of the changes observed with microparticles. Here we demonstrate that procoagulant activity of tumour cell line media is dependent on microparticles, and that exposure of endothelial cells to these microparticles results in an increase in microparticle release from HUVEC. This suggests a mechanism of transfer of procoagulant potential from the cancer to the remote endothelium.
HBeAg Negativity Is Associated With More Advanced Liver Fibrosis in Patients With Chronic Hepatitis B
Authors: Wang Jian , Wu Weihua , Yan Xiaomin , Wei Jie , Yao Kefang , Yang Yue , Xiong Yali , Xia Juan , Liu Yong , Chen Yuxin , Jia Bei , Zhang Zhaoping , Ding Weimao , Huang Rui , Wu Chao
Published: November 2019

Background:

Serum hepatitis B e antigen (HBeAg) status is associated with the progression of chronic hepatitis B (CHB). The authors aimed to investigate the relationship between HBeAg status and liver pathology in CHB patients.

Methods:

A total of 683 treatment-naive CHB patients who had undergone liver biopsy were retrospectively enrolled from 2 medical centers. Propensity score-matching (PSM) method was performed to adjust the imbalance of baseline confounders between HBeAg-positive and HBeAg-negative CHB patients.

Results:

HBeAg-negative CHB patients (n=338) exhibited more advanced liver fibrosis than HBeAg-positive CHB patients (n=345) before PSM (P<0.001). However, there were no significant differences in the distribution of inflammation grades between HBeAg-positive and HBeAg-negative CHB patients (P=0.051). Of these 683 CHB patients, 123 patients were included in each group after PSM. HBeAg-negative CHB patients still showed significantly advanced liver fibrosis as compared with HBeAg-positive CHB patients (P=0.03) after PSM. Furthermore, the distribution of liver inflammation grades in the HBeAg-negative CHB patients was also more severe than patients with HBeAg-positive (P=0.037). HBeAg-negative status was identified as an independent risk factor of significant liver fibrosis (P=0.011) by multivariate analysis.

Conclusions:

HBeAg negativity is associated with more advanced liver fibrosis in CHB patients.
Molecular imaging and radionuclide therapy of neuroendocrine tumors
Authors: Haider Mintallah , Al-Toubah Taymeyah , El-Haddad Ghassan , Strosberg Jonathan
Published: November 2019

Purpose of review

Neuroendocrine tumors are heterogeneous neoplasms with variable prognoses and clinical behaviors. The majority of well differentiated NETs express somatostatin receptors. Identification of these receptors has contributed to advancements in molecular and targeted radiotherapies.

Recent findings

Molecular scans provide important diagnostic, staging, and prognostic data. Somatostatin-receptor imaging aids in selection of patients who are eligible for somatostatin-receptor-targeting therapies. Peptide receptor radionuclide therapy has recently demonstrated robust efficacy in a phase III study of progressive midgut NETs. Current studies are investigating novel receptor agonists and antagonists, new classes of radioactive isotopes, and radiosensitizing combination treatments.

The sophistication of molecular imaging is improving and its importance is increasing as a diagnostic, predictive, and prognostic tool. Theranostics, the coupling of molecular imaging with receptor-targeted therapy, represents a novel approach to cancer treatment.
Infliximab-induced Depression and Suicidal Behavior in Adolescent with Crohn’s Disease: Case Report and Review of Literature
Authors: Shayowitz Michelle , Bressler Moshe , Ricardo Alison P. , Grudnikoff Eugene
Published: November 2019

Introduction:

Infliximab, an anti-inflammatory agent, is used to treat various autoimmune disorders. There are at least 3 reports of severe psychiatric adverse effects of the drug, including suicidal behaviors in adults and psychosis in adult and adolescent patients. We report a case of an adolescent who developed depression and suicidal behaviors shortly after beginning infliximab. Although there have been reports of adolescents developing acute psychosis shortly after starting infliximab, this is, to our knowledge, the first report of adolescent suicidal behavior in the setting of infliximab treatment.

Methods:

We describe a patient’s presentation and clinical course, as well as existing reports of adverse psychiatric effects of infliximab.

Results:

A 16-year-old male with a 2-year history of disabling symptoms and complications of Crohn’s disease was initiated on a trial of infliximab. Within days of the first infliximab infusion, he experienced symptoms of depression, which intensified over weeks and resulted in a serious suicide attempt. The patient was treated with fluoxetine, melatonin, and psychotherapy, which effectively managed his infliximab-induced depressive disorder with suicidal thoughts and behaviors. Posttreatment, he tolerated additional infliximab infusions without the recurrence of psychiatric symptoms.

Conclusions:

Treatment with infliximab may rarely and suddenly cause severe and potentially life-threatening psychiatric symptoms. Therefore, youth with chronic illnesses considered for infliximab treatment should be screened for preexisting, as well as for a family history of, psychiatric disorders and suicidal behavior.
Putting Together the Pieces: Development and Validation of a Risk-Assessment Model for Nipple-Sparing Mastectomy
Authors: Frey Jordan D. , Salibian Ara A. , Choi Mihye , Karp Nolan S.
Published: November 2019

Background:

Optimizing outcomes and assessing appropriate candidates for breast reconstruction after nipple-sparing mastectomy is an ongoing goal for plastic surgeons.

Methods:

All patients undergoing nipple-sparing mastectomy from 2006 to June of 2018 were reviewed and randomly divided into test and validation groups. A logistic regression model calculating the odds ratio for any complication from 12 risk factors was derived from the test group, whereas the validation group was used to validate this model.

Results:

The test group was composed of 537 nipple-sparing mastectomies (50.2 percent), with an overall complication rate of 27.2 percent (146 nipple-sparing mastectomies). The validation group was composed of 533 nipple-sparing mastectomies (49.8 percent), with an overall complication rate of 22.9 percent (122 nipple-sparing mastectomies). A logistic regression model predicting overall complications was derived from the test group. Nipple-sparing mastectomies in the test group were divided into deciles based on predicted risk in the model. Risk increased with probability decile; decile 1 was significantly protective, whereas deciles 9 and 10 were significantly predictive for complications (p < 0.0001). The relative risk in decile 1 was significantly decreased (0.39; p = 0.006); the relative risk in deciles 9 and 10 was significantly increased (2.71; p < 0.0001). In the validation group, the relative risk of any complication in decile 1 was decreased at 0.55 (p = 0.057); the relative risk in deciles 9 and 10 was significantly increased (1.89; p < 0.0001). In a receiver operating characteristic curve analysis, the area under the curve was 0.668 (p < 0.0001), demonstrating diagnostic meaningfulness of the model.

Conclusion:

The authors establish and validate a predictive risk model and calculator for nipple-sparing mastectomy with far-reaching impact for surgeons and patients alike.
Follow-Up Study: One-Step Salvage of Infected Prosthetic Breast Reconstructions Using Antibiotic-Impregnated Polymethylmethacrylate Plates and Concurrent Tissue Expander Exchange
Authors: Xue Amy S. , Volk Angela S. , DeGregorio Valerie L. , Jubbal Kevin T. , Bullocks Jamal M. , Izaddoost Shayan A.
Published: November 2019

Background:

Periprosthetic infections represent major complications in breast reconstruction, frequently leading to expander-implant loss. No consensus regarding a management algorithm for attempted salvage currently exists. This study assessed outcomes of the authors’ salvage protocol using an antibiotic-impregnated polymethylmethacrylate implant with expander device exchange.

Methods:

A retrospective chart review identified infected implant-based breast reconstruction cases treated between 2009 and 2017. Of 626 cases initially identified, a total of 62 cases had severe prosthetic infections, and underwent either prosthetic salvage (n = 45) or immediate explantation (n = 17). All the prosthetic salvage patients received intravenous antibiotics followed by surgical débridement, insertion of polymethylmethacrylate plates, device exchange, and postoperative antibiotics. After clinical resolution of infection, tissue expansion was performed, with the polymethylmethacrylate plates remaining in situ until exchanged for permanent implants.

Results:

The authors’ study demonstrated a primary infection clearance rate of 82.2 percent (n = 37). Compared to the traditional explantation group, a significantly higher percentage of the salvage patients completed final reconstruction (84.4 percent versus 35.3 percent; p < 0.001). Fewer patients abandoned reconstruction efforts after infection clearance (2.2 percent versus 58.8 percent; p < 0.001). The majority of cases (78.8 percent) that succeeded the salvage protocol ultimately received implant-based reconstruction; 62.5 percent that failed the salvage protocol still went on to receive autologous tissue reconstruction.

Conclusions:

Sustained local antibiotic delivery using polymethylmethacrylate implants and expander device exchange can successfully salvage an infected breast expander/implant. Compared with the traditional explantation approach, more patients complete final reconstruction. Other benefits include preserved skin envelope integrity and possibly improved long-term aesthetic outcomes.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Updates in trichomonas treatment including persistent infection and 5-nitroimidazole hypersensitivity
Authors: Muzny Christina A. , Van Gerwen Olivia T. , Kissinger Patricia
Published: November 2019

Purpose of review

The purpose of this review is to update information on treatment of Trichomonas vaginalis. T. vaginalis is estimated to be the most common treatable sexually transmitted infection. In the world and is associated with poor birth outcomes, cervical cancer, sperm motility and morphology issues, and HIV acquisition and transmission.

Recent findings

The efficacy of the recommended 2-g oral single-dose metronidazole (MTZ) for the treatment of T. vaginalis in women has recently been challenged. Two recent multicentered randomized trials and a meta-analysis have demonstrated that the 7-day dose of MTZ 500 mg twice daily was nearly two times more efficacious at clearing infection compared with the 2-g dose. Partner treatment is also essential, since up to 70% of male sexual partners can be infected and rescreening of treated women at 3 months is also recommended given the high repeat infection rates. Future studies should examine the importance of treating asymptomatic T. vaginalis, best treatment for men, the influence of the microbiome on treatment efficacy and different formulations of intravaginal treatments for hypersensitivity.

7-day 500 mg twice daily MTZ should be used as the first line treatment for T. vaginalis-infected women.
Muscle Recurrence of a Primarily Nodal Follicular Lymphoma Studied by Contrast-Enhanced 18F-FDG PET/CT
Authors: Belmonte Gianfranco , Caldarella Carmelo , Hohaus Stefan , Manfredi Riccardo , Minordi Laura Maria
Published: November 2019

We report the case of a 52-year-old woman with follicular lymphoma localized in the left inguinal region without any extranodal involvement and achieving a complete response after radiotherapy. After a 3-year disease-free interval, muscular recurrence at the left arm was shown by contrast-enhanced 18F-FDG PET/CT. Contrast-enhanced 18F-FDG PET/CT performed after immunochemotherapy documented complete disease remission. Lymphoid tissue is usually not present in the skeletal muscle, making muscular lymphomatous involvement quite unusual; muscular relapse of a primarily nodal lymphoma is even rarer.
Unraveling the Enigma of Nonarteritic Anterior Ischemic Optic Neuropathy
Authors: Rizzo Joseph F.
Published: November 2019

Non-arteritic anterior ischemic optic neuropathy (NAON) is the second most common optic neuropathy in adults. Despite extensive study, the etiology of NAION is not definitively known. The best evidence suggests that NAION is caused by an infarction in the region of the optic nerve head (ONH), which is perfused by paraoptic short posterior ciliary arteries (sPCAs) and their branches. To examine the gaps in knowledge that defies our understanding of NAION, a historical review was performed both of anatomical investigations of the ONH and its relevant blood vessels and the evolution of clinical understanding of NAION. Notably, almost all of the in vitro vascular research was performed prior our current understanding of NAION, which has largely precluded a hypothesis-based laboratory approach to study the etiological conundrum of NAION. More recent investigative techniques, like fluorescein angiography, have provided valuable insight into vascular physiology, but such light-based techniques have not been able to image blood vessels located within or behind the dense connective tissue of the sclera and laminar cribrosa, sites that are likely culpable in NAION. The lingering gaps in knowledge clarify investigative paths that might be taken to uncover the pathogenesis of NAION and possibly glaucoma, the most common optic neuropathy for which evidence of a vascular pathology also exists.
Sphingomonas populi sp. nov., isolated from bark of Populus × euramericana
Authors: Li Yong , Bian Dan-ran , Chang Ju-pu , Guo Li-min , Yang Xu-qi
Published: November 2019

One Gram-stain-negative, aerobic, motile bacterial strain, 3-7T, was isolated from symptomatic canker bark tissue of Populus × euramericana. 16S rRNA gene sequence data revealed that the novel isolate shared highest similarity with

Sphingomonas panacis

DCY99T (98.8 %), and <96.5 % sequence similarity with all other species with validly published names. Growth occurred between 15 and 37 °C and at pH 6.0–9.0, and optimal growth occurred at 30 °C and pH 7.0–8.0. Nitrogen was produced from nitrates. The strain was positive for acetoin production and activity of catalase, oxidase, β-galactosidase, arginine dihydrolase and β-glucosidase. The major fatty acids were C16 : 0, C18 : 1ω7c and/or C18 : 1ω6c. The polar lipids of the novel isolate included diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, sphingoglycolipid, glycolipid, two uncharacterized phospholipids and two uncharacterized lipids. The respiratory quinones detected in isolate 3-7T were Q-10 (96.9 %) and Q-9 (3.1 %). The DNA G+C content was 65.1 mol%. Based on phenotypic and genotypic characteristics, the isolate represents a novel species within the genus

Sphingomonas

, for which the name Sphingomonas populi is proposed. The type strain is 3-7T (=CFCC 11561T=LMG 30138T).
Marinobacter fonticola sp. nov., isolated from deep sea cold seep sediment
Authors: Sun Qing-lei , Sun Yan-ling , Sun Yuan-yuan , Luan Zhen-dong , Lian Chao
Published: November 2019

In this study, we report a novel Gram-negative bacterium, designated as strain CS412T, isolated from deep-sea sediment collected in a cold seep area of the South China Sea. Growth of strain CS412T occurred at 4–40 °C (optimum, 28 °C), pH 5.0–11.0 (optimum, pH 6.0) and with 0–19 % (w/v) NaCl (optimum, 1–2 %). Phylogenetic analysis based on 16S rRNA gene sequence data indicated that strain CS412T belonged to the genus

Marinobacter

. The closest phylogenetic neighbours of strain CS412T were

Marinobacter pelagius

HS225T (96.9 %),

Marinobacter szutsaonensis

NTU-104T (96.8%),

Marinobacter santoriniensis

NKSG1T (96.4%) and

Marinobacter koreensis

dd-M3T (96.3 %). The genomic DNA G+C content of strain CS412T was 58.0 mol%. The principal respiratory quinone was ubiquinone-9 (Q-9). The polar lipids of CS412T contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, aminophospholipidand and four glycolipids. The major fatty acids of CS412T contained cyclo-C19 : 0ω8c, C16 : 0, C18 : 1ω7c and C18 : 1ω7c 11-methyl. The results of phylogenetic, physiological, biochemical and morphological analyses suggested that strain CS412T represents a novel species of the genus

Marinobacter

, and the name Marinobacter fonticola sp. nov. is proposed with the type species CS412T (=CCTCC AB 2019197T=KCTC 72475T).
Spatial enrichment of phosphoinositide metabolism is a molecular switch to promote metastasis
Authors: Nacke Marisa , Sandilands Emma , Nikolatou Konstantina , Román-Fernández Álvaro , Mason Susan , Patel Rachana , Lilla Sergio , Yelland Tamas , Galbraith Laura , McGarry Lynn , Morton Jennifer P. , Shanks Emma , Leung Hing , Zanivan Sara , Ismail Shehab , Markert Elke , Blyth Karen , Bryant David M.
Published: November 2019

The signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. We developed 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that alternate variants of IQSEC1, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by spatially enriching cortical phosphoinositide metabolism. All IQSEC1 variants activate ARF5- and ARF6-dependent PIP5-kinase to promote PI(3,4,5)P3-AKT signalling and growth. In contrast, select pro-invasive IQSEC1 variants restrict PI(3,4,5)P3 production to discrete cortical domains to form invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion in vitro and metastasis in vivo. Induction of pro-invasive IQSEC1 variants and elevated IQSEC1 expression occurs in a number of tumour types and is associated with higher-grade metastatic cancer, activation of PIP3-signalling, and predicts long-term poor outcome across multiple cancers. Spatial enrichment of phosphoinositide metabolism therefore is a switch to induce invasion over growth in response to the same external signal. Targeting IQSEC1 as the central regulator of this switch may represent a therapeutic vulnerability to stop metastasis.

Highlights

Spatial enrichment of PI(3,4,5)P3 is a molecular switch to promote invasion.

IQSEC1 is a GEF for ARF5/6, promoting PIP5K-dependent PI(3,4,5)P3 production downstream of the HGF receptor Met.

Pro-invasive IQSEC1 variants restrict cortical PI(3,4,5)P3 production to subdomains that convert into invasive protrusions.

IQSEC1 inhibition attenuates in vitro invasion and metastasis in vivo.

IQSEC1 module is associated with poor outcome across tumour types.
2’3’-cGAMP triggers a STING and NF-κB dependent broad antiviral response in Drosophila
Authors: Cai Hua , Holleufer Andreas , Simonsen Bine , Schneider Juliette , Lemoine Aurélie , Gad Hans-Henrik , Huang Jingxian , Huang Jieqing , Chen Di , Peng Tao , Marques João T. , Hartmann Rune , Martins Nelson , Imler Jean-Luc
Published: November 2019

We recently reported that an orthologue of STING regulates infection by picorna-like viruses in drosophila. In mammals, STING is activated by the cyclic dinucleotide 2’3’-cGAMP produced by cGAS, which acts as a receptor for cytosolic DNA. Here, we show that injection of flies with 2’3’-cGAMP can induce expression of dSTING-regulated genes. Co-injection of 2’3’-cGAMP with a panel of RNA or DNA viruses results in significant reduction of viral replication. This 2’3’-cGAMP-mediated protection is still observed in flies mutant for the genes Atg7 and AGO2, which encode key components of the autophagy and small interfering RNA pathways, respectively. By contrast, it is abrogated in flies mutant for the NF-κB transcription factor Relish. Analysis of the transcriptome of 2’3’-cGAMP injected flies reveals a complex pattern of response, with early and late induced genes. Our results reveal that dSTING regulates an NF-κB-dependent antiviral program, which predates the emergence of Interferon Regulatory Factors and interferons in vertebrates.
Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma
Authors: Weaver Davis T. , Pishas Kathleen I. , Williamson Drew , Scarborough Jessica , Lessnick Stephen L. , Dhawan Andrew , Scott Jacob G.
Published: November 2019

MicroRNA (miRNA)-based therapies are an emerging class of targeted therapeutics with many potential applications. Ewing Sarcoma patients could benefit dramatically from personalized miRNA therapy due to inter-patient heterogeneity and a lack of druggable (to this point) targets. However, because of the broad effects miRNAs may have on different cells and tissues, trials of miRNA therapies have struggled due to severe toxicity and unanticipated immune response. In order to overcome this hurdle, a network science-based approach is well-equipped to evaluate and identify miRNA candidates and combinations of candidates for the repression of key oncogenic targets while avoiding repression of essential housekeeping genes. We first characterized 6 Ewing sarcoma cell lines using mRNA sequencing. We then estimated a measure of tumor state, which we term network potential, based on both the mRNA gene expression and the underlying protein-protein interaction network in the tumor. Next, we ranked mRNA targets based on their contribution to network potential. We then identified miRNAs and combinations of miRNAs that preferentially act to repress mRNA targets with the greatest influence on network potential. Our analysis identified TRIM25, APP, ELAV1, RNF4, and HNRNPL as ideal mRNA targets for Ewing sarcoma therapy. Using predicted miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as candidate optimal miRNAs for preferential repression of these targets. Ultimately, our work, as exemplified in the case of Ewing sarcoma, describes a novel pipeline by which personalized miRNA cocktails can be designed to maximally perturb gene networks contributing to cancer progression.

Author Summary

Precision medicine in cancer aims to find the right treatment, for the right patient, at the right time. Substantial variation between patient tumors, even of the same disease site, has limited the application of precision medicine in the clinic. In this study, we present novel computational tools for the identification of targets for cancer therapy using widely available sequencing data. We used a network-science based approach that leveraged multiple types of ’omic data to identify functionally relevant disease targets. Further, we developed algorithms to identify potential miRNA-based therapies that inhibit these predicted disease targets. We applied this pipeline to a novel Ewing Sarcoma transcriptomics data-set as well as publicly available patient data from the St. Jude Cloud. We identified a number of promising therapeutic targets for this rare disease, including EWSR1, the proposed driver of Ewing Sarcoma development. These novel data and methods will provide researchers with new tools for the development of precision medicine treatments in a variety of cancer systems.
En bloc preparation of Drosophila brains enables high-throughput FIB-SEM connectomics
Authors: Lu Zhiyuan , Xu C. Shan , Hayworth Kenneth J. , Rivlin Patricia , Plaza Stephen M. , Scheffer Louis , Rubin Gerald M. , Hess Harald F. , Meinertzhagen Ian A.
Published: November 2019

Deriving the detailed synaptic connections of the entire nervous system has been a long term but unrealized goal of the nascent field of connectomics. For Drosophila, in particular, three sample preparation problems must be solved before the requisite imaging and analysis can even begin. The first is dissecting the brain, connectives, and ventral nerve cord (roughly comparable to the brain, neck, and spinal cord of vertebrates) as a single contiguous unit. Second is fixing and staining the resulting specimen, too large for previous techniques such as flash freezing, so as to permit the necessary automated segmentation of neuron membranes. Finally the contrast must be sufficient to support synapse detection at imaging speeds that enable the entire connectome to be collected. To address these issues, we report three major novel methods to dissect, fix, dehydrate and stain this tiny but complex nervous system in its entirety; together they enable us to uncover a Focused Ion-Beam Scanning Electron Microscopy (FIB-SEM) connectome of the entire Drosophila brain. They reliably recover fixed neurons as round profiles with darkly stained synapses, suitable for machine segmentation and automatic synapse detection, for which only minimal human intervention is required. Our advanced procedures use: a custom-made jig to microdissect both regions of the central nervous system, dorsal and ventral, with their connectives; fixation and Durcupan embedment, followed by a special hot-knife slicing protocol to reduce the brain to dimensions suited to FIB; contrast enhancement by heavy metals; together with a progressive lowering of temperature protocol for dehydration. Collectively these optimize the brain’s morphological preservation, imaging it at a usual resolution of 8nm per voxel while simultaneously speeding the formerly slow rate of FIB-SEM. With these methods we could recently obtain a FIB-SEM image stack of the Drosophila brain eight times faster than hitherto, at approximately the same rate as, but without the requirement to cut, nor imperfections in, EM serial sections.
A Decentralised Neural Model Explaining Optimal Integration of Navigational Strategies in Insects
Authors: Sun Xuelong , Yue Shigang , Mangan Michael
Published: November 2019

Insect navigation arises from the coordinated action of concurrent guidance systems but the neural mechanisms through which each functions, and are then coordinated, remains unknown. We propose that insects require distinct strategies to retrace familiar routes (route-following) and directly return from novel to familiar terrain (homing) using different aspects of frequency encoded views that are processed in different neural pathways. We also demonstrate how the Central Complex and Mushroom Bodies regions of the insect brain may work in tandem to coordinate the directional output of different guidance cues through a contextually switched ring-attractor inspired by neural recordings. The resultant unified model of insect navigation reproduces behavioural data from a series of cue conflict experiments in realistic animal environments and offers testable hypotheses of where and how insects process visual cues, utilise the different information that they provide and coordinate their outputs to achieve the adaptive behaviours observed in the wild.
Dopamine and stress signalling interplay patterns social organization in mice
Authors: Battivelli Dorian , Vernochet Cécile , Nguyen Claire , Zayed Abdallah , Meirsman Aura Carole , Messaoudene Sarah , Fieggen Alexandre , Dreux Gautier , Marti Fabio , Contesse Thomas , Barik Jacques , Tassin Jean-Pol , Faure Philippe , Parnaudeau Sébastien , Tronche François
Published: November 2019

The rules leading to the emergence of a social organization and the role of social hierarchy on normal and pathological behaviours remain elusive. Here we show that groups of four isogenic male mice rapidly form enduring social ranks in a dominance hierarchy. Highest ranked individuals display enhanced anxiety and working memory, are more social and more susceptible to stress-related maladaptive behaviours. Are these differences causes or consequences to social life? We show that anxiety emerges from life in colony whereas sociability is a pre-existing trait. Strikingly, highest ranked individuals exhibit lower bursting activity of VTA dopamine neurons. Both pharmacogenetic inhibition of this neuronal population and the genetic inactivation of glucocorticoid receptor signalling in dopamine-sensing brain areas promote the accession to higher social ranks. Altogether, these results indicate that the shaping of social fate relies upon the interplay of dopamine system and stress response, impacting individual behaviour and potentially mental health.
Self-other representation in the social brain reflects social connection
Authors: Courtney Andrea L. , Meyer Meghan L.
Published: November 2019

Social connection is critical to well-being, yet how the brain reflects our attachment to other people remains largely unknown. We combined univariate and multivariate brain imaging analyses to assess whether and how the brain organizes representations of others based on how connected they are to our own identity. During an fMRI scan, participants (N=43) completed a self- and other-reflection task for 16 targets: the self, five close others, five acquaintances, and five celebrities. In addition, they reported their subjective closeness to each target and their own trait loneliness. We examined neural responses to the self and others in a brain region that has been associated with self-representation (medial prefrontal cortex; MPFC) and across the whole brain. The structure of self-other representation in the MPFC and across the social brain appeared to cluster targets into three social categories: the self, social network members (including close others and acquaintances), and celebrities. Moreover, both univariate activation in MPFC and multivariate self-other similarity in MPFC and across the social brain increased with subjective self-other closeness ratings. Critically, participants who were less socially connected (i.e. lonelier) showed altered self-other mapping in social brain regions. Most notably, in MPFC, loneliness was associated with reduced representational similarity between the self and others. The social brain apparently maintains information about broad social categories as well as closeness to the self. Moreover, these results point to the possibility that feelings of chronic social disconnection may be mirrored by a ‘lonelier’ neural self-representation.

Significance Statement

Social connection is critical to well-being, yet how the brain reflects our attachment to people remains unclear. We found that the social brain stratifies neural representations of people based on our subjective connection to them, separately clustering people who are and are not in our social network. Moreover, the people we feel closest to are represented most closely to ourselves. Finally, lonelier individuals also appeared to have a ‘lonelier’ neural self-representation in the MPFC, as loneliness attenuated the closeness between self and other neural representations in this region. The social brain appears to map our interpersonal ties, and alterations in this map may help explain why lonely individuals endorse statements such as ‘people are around me but not with me’.
Ensemble Machine Learning Modeling for the Prediction of Artemisinin Resistance in Malaria
Authors: Ford Colby T. , Janies Daniel
Published: November 2019

Antiparasitic resistance in malaria is a growing concern affecting many areas of the eastern world. Since the emergence of artemisinin resistance in the late 2000s in Cambodia, research into the underlying mechanisms has been underway.

The 2019 Malaria Dream Challenge posited the task of developing computational models that address important problems in advancing the fight against malaria. The first goal was to accurately predict Artemisinin drug resistance levels of Plasmodium falciparum isolates, as quantified by the IC50. The second goal was to predict the parasite clearance rate of malaria parasite isolates based on in vitro transcriptional profiles.

In this work, we develop machine learning models using novel methods for transforming isolate data and handling the tens of thousands of variables that result from these data transformation exercises. This is demonstrated by using massively parallel processing of the data vectorization for use in scalable machine learning. In addition, we show the utility of ensemble machine learning modeling for highly effective predictions of both goals of this challenge. This is demonstrated by the use of multiple machine learning algorithms combined with various scaling and normalization preprocessing steps. Then, using a voting ensemble, multiple models are combined to generate a final model prediction.
Trophic cascade driven by behavioural fine-tuning as naïve prey rapidly adjust to a novel predator
Authors: Jolly Chris J. , Smart Adam S. , Moreen John , Webb Jonathan K. , Gillespie Graeme R. , Phillips Ben L.
Published: November 2019

Abstract

The arrival of novel predators can trigger trophic cascades driven by shifts in prey numbers. Predators also elicit behavioural change in prey populations, via phenotypic plasticity and/or rapid evolution, and such changes may also contribute to trophic cascades. Here we document rapid demographic and behavioural changes in populations of a prey species (grassland melomys Melomys burtoni, a granivorous rodent) following the introduction of a novel marsupial predator (northern quoll Dasyurus hallucatus). Within months of quolls appearing, populations of melomys exhibited reduced survival and population declines relative to control populations. Quoll-invaded populations (n = 4) were also significantly shyer than nearby, quoll-free populations (n = 3) of conspecifics. This rapid but generalised response to a novel threat was replaced over the following two years with more threat-specific antipredator behaviours (i.e. predator-scent aversion). Predator-exposed populations, however, remained more neophobic than predator-free populations throughout the study. These behavioural responses manifested rapidly in avoidance of seeds associated with quoll scent, with discrimination playing out over a spatial scale of tens of metres. Presumably the significant and novel predation pressure induced by quolls drove melomys populations to fine-tune behavioural responses to be more predator-specific through time. These behavioural shifts could reflect individual plasticity (phenotypic flexibility) in behaviour or may be adaptive shifts from natural selection imposed by quoll predation. Our study provides a rare insight into the rapid ecological and behavioural shifts enacted by prey to mitigate the impacts of a novel predator and shows that trophic cascades can be strongly influenced by behavioural changed rates of seed predation by melomys across treatments. Quoll-invaded melomys populations exhibited lower per-capita seed take rates, and rapidly developed an as well as numerical responses.
Trem-2 modulation of gut microbiota is blunted during hepatotoxic injury and uncoupled from liver repair responses
Authors: Coelho Inês , Duarte Nádia , Macedo Maria Paula , Penha-Gonçalves Carlos
Published: November 2019

The involvement of gut microbiota in liver disease has been addressed in the context of the “leaky gut hypothesis” postulating that dysbiosis allow microbial components to elicit liver inflammatory responses and hepatic tissue damage. Conversely, commensal gut microbiota acting on innate immune receptors protect against hepatotoxic insults. Given that mice deficient for the triggering receptor expressed on myeloid cells-2 (Trem-2) show increased vulnerability to experimental drug-induced hepatic damage we explored the possibility that Trem-2 is a modulator of gut microbiota composition.

We found that microbiota composition in untreated Trem-2 KO mice differs from the wild-type showing overall decrease in microbiota diversity and increased representation of Verrucomicrobia. Interestingly, induction of liver damage with hepatotoxic drugs blunted this microbiota diversity difference and altered phyla composition with increased representation of Verrucomicrobia during acute hepatic injury and Proteobacteria during chronic challenge. Furthermore, co-housing experiments that homogenized microbiota diversity showed that the increased liver tissue vulnerability to hepatotoxic insults in Trem-2 KO mice was not dependent on microbiota composition. This work uncouples Trem-2 dependent alterations in gut commensal microbiota from Trem-2 pro-recovery effects in the damaged liver tissue. These findings support the possibility that unlinked actions of innate immune receptors contribute to disease association with microbiota alterations, particularly with the Verrucomicrobia phylum.

Importance

Trem-2 is a mammalian innate immunity receptor involved in development and resolution of tissue damage, namely in the brain and in the liver. Nevertheless, it is not known whether gut microbiota is contributing to these Trem-2 mediated phenotypes. We found that Trem-2 KO mice spontaneously display different gut microbiota composition as compared to wild-type mice, namely with increased abundance of the phylum Verrucomicrobia. Notably these differences do not impact the control of Trem-2 on liver tissue vulnerability to hepatotoxic insults. This work uncouples Trem-2 modulation of gut microbiota and the role of Trem-2 on responses to liver damage. This work brings new insights on role of innate immune receptors on the association of organic and systemic diseases with gut microbiota.
Host community assembly modifies the relationship between host and parasite richness
Authors: Halliday Fletcher W. , Heckman Robert W. , Wilfahrt Peter A. , Mitchell Charles E.
Published: November 2019

Host and parasite richness are generally positively correlated, but the stability of this relationship during community assembly remains untested. The composition of host communities can alter parasite transmission, and the relationship between host and parasite richness is sensitive to parasite transmission. Thus, changes in composition during host community assembly could strengthen or weaken the relationship between host and parasite richness. Host community assembly, in turn, can be driven by many processes, including resource enrichment. To test the hypothesis that host community assembly can alter the relationship between host and parasite richness, we experimentally crossed host diversity and resource supply to hosts, then allowed communities to assemble. As previously shown, initial host diversity and resource supply determined the trajectory of host community assembly, altering post-assembly host species richness, richness-independent host phylogenetic diversity, and colonization by exotic host species. Throughout community assembly, host richness predicted parasite richness. As predicted, this effect was moderated by exotic abundance: communities dominated by exotic species exhibited a stronger positive relationship between post-assembly host and parasite richness. Ultimately, these results suggest that, by modulating parasite transmission, community assembly can modify the relationship between host and parasite richness, providing a novel mechanism to explain contingencies in this relationship.
A limited set of transcriptional programs define major cell types
Authors: Breschi Alessandra , Muñoz-Aguirre Manuel , Wucher Valentin , Davis Carrie A. , Garrido-Martín Diego , Djebali Sarah , Gillis Jesse , Pervouchine Dmitri D. , Vlasova Anna , Dobin Alexander , Zaleski Chris , Drenkow Jorg , Danyko Cassidy , Scavelli Alexandra , Reverter Ferran , Snyder Michael P. , Gingeras Thomas R. , Guigó Roderic
Published: November 2019

We have produced RNA sequencing data for a number of primary cells from different locations in the human body. The clustering of these primary cells reveals that most cells in the human body share a few broad transcriptional programs, which define five major cell types: epithelial, endothelial, mesenchymal, neural and blood cells. These act as basic components of many tissues and organs. Based on gene expression, these cell types redefine the basic histological types by which tissues have been traditionally classified. We identified genes whose expression is specific to these cell types, and from these genes, we estimated the contribution of the major cell types to the composition of human tissues. We found this cellular composition to be a characteristic signature of tissues, and to reflect tissue morphological heterogeneity and histology. We identified changes in cellular composition in different tissues associated with age and sex and found that departures from the normal cellular composition correlate with histological phenotypes associated to disease.

One Sentence Summary

A few broad transcriptional programs define the major cell types underlying the histology of human tissues and organs.
A commonly used photosynthetic inhibitor fails to block electron flow to photosystem I in intact systems
Authors: Fitzpatrick Duncan , Aro Eva-Mari , Tiwari Arjun
Published: November 2019

In plant science, 2,4-dinitrophenylether of iodonitrothymol (DNP-INT) is frequently used as an alternative to 2,5-dibromo-6-isopropyl-3-methyl-1,4-benzoquinone (DBMIB) to examine the capacity of plastoquinol and semiquinone to reduce O2. DNP-INT is considered an effective inhibitor of the photosynthetic electron transfer chain (PETC) through its binding at the Q0 site of Cyt-b6f. The binding and action of DNP-INT has been previously characterized spectroscopically in purified Cyt-b6f complex reconstituted with Plastocyanin, PSII membranes and plastoquinone, as well as in isolated thylakoids based on its property to block MV-mediated O2 consumption. Contrary to the conclusions made from these experiments, we observed clear reduction of P700+ in samples incubated with DNP-INT during our recent investigation into the sites of oxygen consumption in isolated thylakoids. Therefore, we carried out an extensive investigation of DNP-INT’s chemical efficacy in isolated thylakoids and intact leaves. This included examination of its capacity to block the PETC before PSI, and therefore its inhibition of CO2 fixation. P700 redox kinetics were measured using Dual-PAM whilst Membrane Inlet Mass Spectrometry (MIMS) was used for simultaneous determination of the rates of O2 evolution and O2 consumption in isolated thylakoids and CO2 fixation in intact leaves, using two stable isotopes of oxygen (16O2,18O2) and CO2 (12C,13C), respectively. Based on these investigations we confirmed that DNP-INT is unable to completely block the PETC and CO2 fixation, therefore its use may produce artefacts if applied to isolated thylakoids or intact cells, especially when determining the locations of reactive oxygen species formation in the photosynthetic apparatus.