bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimodality palliative treatment with transarterial chemoembolization and high-intensity focused ultrasound for gastric leiomyosarcoma multiple liver metastasis pain
Authors: Cheng Chien-shan , Chen Lianyu , Xie Jing , Chen Zhen
Published: September 2019

Introduction:

Gastric leiomyosarcoma (LMS) is a rare malignancy with minimal therapeutic options and has poor prognosis once metastasis develops.

Patient concerns:

A case of gastric LMS with multiple metastases, pain, and progressive anemia 13 months after the initial diagnosis in a 43-year-old woman.

Diagnosis:

Gastric LMS with liver metastases and multiple retroperitoneal lymphatic metastases.

Interventions:

Minimally invasive therapies of repeated tetrahydropalmatine and oxaliplatin-based transarterial chemoembolization and high-intensity focused ultrasound treatment were performed.

Outcomes:

The treatments resulted in significant pain relief (numerical rating scale from 8–2 points) after the initial treatment, improvement in performance status and quality of life, and a progression-free survival of 4 months after treatment.

Conclusion:

This combined modality palliative treatment approach was well tolerated with noticeable pain relief.
Isolated subacute combined degeneration in late-onset cobalamin C deficiency in children
Authors: Cui Junling , Wang Yuanyuan , Zhang Huifeng , Cui Xiaopu , Wang Lihui , Zheng Huacheng
Published: September 2019

Rationale:

Subacute combined degeneration (SCD) is a disease caused by decreased vitamin B12 intake or metabolic disorders. It is more common in the elderly and rarely seen in children. Here, we report 2 pediatric cases of SCD in late-onset cobalamin C (CblC) deficiency.

Patient concerns:

The patients complained of unsteady gait. Their physical examination showed sensory ataxia. Magnetic resonance imaging showed classic manifestations of SCD. The serum vitamin B12 level was normal, but urine methylmalonic acid and serum homocysteine levels were high.

Diagnosis:

The pathogenic gene was confirmed as MMACHC. The 2 patients each had 2 pathogenic mutations C.482 G>A and C.271dupA and C.365A>T and C.609G>A in this gene. They were diagnosed with combined methylmalonic acidemia and homocysteinemia-CblC subtype.

Interventions:

The patients were treated with methylcobalamin 500 μg intravenous injection daily after being admitted. After the diagnosis, levocarnitine, betaine, and vitamin B12 were added to the treatment.

Outcomes:

Twelve days after treatment, the boy could walk normally, and his tendon reflex and sense of position returned to normal. The abnormal gait seemed to have become permanent in the girl and she walked with her legs raised higher than normal.

Lessons:

To the best of our knowledge, this is the first report of 2 cases of isolated SCD in children with late-onset CblC disorder. Doctors should consider that SCD could be an isolated symptom of CblC disorder. The earlier the treatment, the lower the likelihood of sequelae.
Thromboelastometric evaluation of coagulation profiles of cold-stored autologous whole blood
Authors: Iwata Shihoko , Hirasaki Yuji , Nomura Minoru , Ozaki Makoto
Published: September 2019

Preoperative autologous blood donation is a well-established procedure to reduce the need for allogeneic blood transfusion. We hypothesized that coagulation activity is maintained in cold-stored whole blood, because the fundamental polymerization properties of fibrin are preserved.

Fifty adult patients who underwent elective cardiothoracic surgery were enrolled.

Autologous whole blood collected 2 to 4 times at almost 1-week intervals before surgery was stored at approximately 4°C until reinfusion at the time of surgery. Blood samples were drawn just before reinfusion, and rotational thromboelastometry variables and fibrinogen levels were measured.

A total of 158 samples were analyzed. The mean duration of cold storage was 16.7 ± 7.4 days (range: 6–33 days). Platelet counts were very low due to collection through a leukoreduction filter. The mean fibrinogen level was 2.3 ± 0.6 g/L. Amplitude at 10 minutes after CT (A10), amplitude at 20 minutes after CT (A20), and maximum clot firmness (MCF) values as determined by FIBTEM analysis were 10.8 ± 3.8, 12.2 ± 4.2, and 13.1 ± 4.7 mm, respectively. Fibrinogen levels were strongly correlated with A10, A20, and FIBTEM-MCF values (ρ = 0.83, P < .0001, ρ = 0.84, P < .0001, ρ = 0.85, P < .0001, respectively). Fibrinogen levels were not correlated with the duration of cold storage (ρ = 0.06, P = .43).

The results of the present study demonstrate that fibrin polymerization occurs in cold-stored autologous whole blood, and that such activity is strongly correlated with fibrinogen levels. Furthermore, our data suggest that cold-stored leukoreduced autologous whole blood retains fibrin polymerization properties throughout 33 days.
Coexistence of lung adenocarcinoma and pulmonary tuberculosis within a single lesion
Authors: Byun Hong Gwon , Yoo Jin Young , Kim Sung Jin , Lee Ok Jun , Yoo Min Young
Published: September 2019

Rationale:

Pulmonary tuberculosis and lung adenocarcinoma are highly prevalent pulmonary diseases associated with high mortality. However, the coexistence of lung cancer and pulmonary tuberculosis is rare. Further, the morphological features of lung cancer with coexisting pulmonary tuberculosis are similar to that of lung cancer without pulmonary tuberculosis, even though the lesion is predominantly cavity. For these reasons, the diagnosis in patients with coexisting lung cancer and pulmonary tuberculosis could be delayed until the advanced stage, and therefore, prognosis in these patients is worse compared with that of lung cancer patients without coexisting pulmonary tuberculosis. Therefore, early diagnosis of the condition is essential for initiating timely and suitable treatment.

Patient concerns:

A 67-year-old man was detected abnormal finding on chest CT performed outside the hospital during health screening without significant symptom.

Diagnoses:

Chest CT revealed a 3.2, irregular, enhancing cavitary mass in right lower lobe of lung and PET-CT revealed significant uptake of 18 FDG by the cavitary mass, which was suggestive of lung cancer. Pathology results confirmed a diagnosis of coexisting lung adenocarcinoma and tuberculosis.

Interventions and outcome:

The patient underwent a right lower lobectomy. No significant complications occurred in a 24 month post-surgery follow-up period

Lessons:

Although rare, the coexistence of lung adenocarcinoma and tuberculosis within a single lesion can occur. Therefore, early diagnosis of such a lesion is essential to improve the prognosis in affected patients.
The efficacy and safety of polydeoxyribonucleotide for the treatment of knee osteoarthritis
Authors: Kim Man Soo , Cho Ryu Kyoung , In Yong
Published: September 2019

Introduction:

The purpose of this study was to use meta-analysis techniques to evaluate the efficacy and safety of polydeoxyribonucleotide (PDRN) injections for knee osteoarthritis (OA) treatment.

Methods:

Multiple comprehensive databases, including MEDLINE, EMBASE, and the Cochrane Library, were searched in November 2018 for studies that compared the effectiveness and safety of intra-articular PDRN injection for the knee joint with hyaluronic acid (HA) injection. Two reviewers independently determined study inclusion and they extracted data using a standardized data extraction form. The predefined primary outcome was Visual Analogue Scale. Secondary outcomes included Knee Injury and Osteoarthritis Outcome Score (KOOS), Knee Society Score (KSS), and adverse events.

Results:

Five randomized controlled trials were included in the meta-analysis. After 1 and 2 months, patients in the PDRN group showed significantly better improvement in pain than the HA group (P = .04 and P = .02, respectively). There was no significant difference in pain after 4 months. The pooled analysis showed that no significant differences were seen in function (KOOS and KSS) scores between the PDRN and HA groups (all P > .05) at all time points. There was no significant difference in adverse events between 2 groups (relative risks = 2.15, 95% confidential interval: 0.17–26.67, P = .55).

Conclusion:

The intra-articular use of PDRN was similar in function to HA, and the pain-relief effect was superior to HA for 2 months post-injection. Therefore, it could be a favorable alternative to HA to treat persistent pain associated with knee OA while avoiding side effects.

Level of evidence I
Safety of a Triple‐chamber Bag Parenteral Nutrition in Children Ages up to 24 Months
Authors: Arnell Henrik , Valla Frederic V. , Malfilâtre Geneviève , Pladys Patrick , Senterre Thibault , Pontes‐Arruda Alessandro
Published: September 2019

Objectives:

Hypermagnesemia has been reported in preterm neonates treated with commercial pediatric triple‐chamber bag (3CB) parenteral nutrition (PN). This postmarketing study was requested by the European Medicines Agency to assess the safety of a 3CB PN product in full‐term neonates and children up to 24 months of age.

Methods:

This prospective, multicenter, observational study enrolled hospitalized, full‐term, newborn infants and children up to 24 months of age receiving >70% of nutrition as PN and requiring ≥50% of nutrition as PN for ≥5 days. All patients received 3CB PN during the study for ⩽15 days. The primary outcome was serum magnesium, summarized by age group (0–1, >1–12, and >12–24 months). Secondary outcomes were nutritional intake and adverse events (AEs), including clinically significant abnormal laboratory results and vital signs.

Results:

A total of 102 eligible patients were included. Median (interquartile range) parenteral magnesium intake was 0.23 (0.18–0.30) mmol · kg−1 · day−1. Mean serum magnesium showed no consistent changes during treatment in any age group. One moderate and 3 mild AEs of hypermagnesemia were reported in 4 patients (3.9%), all ages 0 to 1 month. Other AEs in >2 patients were hypertriglyceridemia (6.9%), laryngitis (3.9%), hyperkalemia, hypokalemia, hyponatremia, hypophosphatemia, and neonatal hypotension (each 2.9%). Other serum electrolytes were stable, and revealed no safety concerns.

Conclusions:

Mean serum magnesium levels were not affected by 3CB PN in full‐term neonates and children up to 24 months of age. The risk of hypermagnesemia AEs was low when providing median parenteral magnesium of 0.2 to 0.3 mmol · kg−1 · day−1 in this population.
Necrotic Loxoscelism of the Scalp
Authors: Horta Ricardo , Barreiro Diogo
Published: September 2019

A 15 month old boy was referred to our department after he and his mother moved to our country. He had been bitten by a brown recluse spider (Loxosceles reclusa) at the age of 7 months, in Brazil. Initially, he presented to the emergency department of his local hospital with rash in the scalp, near the bite. After a few days, he developed systemic disease with multiorgan failure and was admitted on intensive care unit, where he has been treated for 2 months. During this hospital stay he developed skin necrosis of the scalp, right preauricular, mandibular, and neck regions. He also developed right foot ischemia, which resulted in amputation. At the discharge time, he was under topical treatment with silver sulfadiazine, which was maintained until our observation, 8 months after being bitten. The child was successfully treated, and is now stable and awaiting lower limb prosthetic replacement.

Loxoscelism (bites by spiders of the genus Loxosceles) is the only proven arachnological cause of dermonecrosis. The brown recluse spider, Loxosceles reclusa, is the best known and can cause necrotic dermatologic injury throw an enzyme, sphingomyelinase D, that has been shown to be cytotoxic to endothelial and red blood cells. Although the majority of persons bitten by a brown recluse spider probably will not seek medical attention, some patients may develop systemic loxoscelism, especially children.
Myelomeningocele: Medical Considerations and Stomatologic Aspects in the Dental Treatment
Authors: Amaral Cristhiane Olívia Ferreira do , Nardeli Caroline Soares , Saito Isabela Caroline , Valério Juliana Suguimoto , Filho Marcelo Sávio Paiva Amaral , Straioto Fabiana Gouveia
Published: September 2019

The aim was to analyze systemic and oral aspects of patients with myelomeningocele (MMC), relevant for their dental treatment. Dental treatment of these individuals requires the dentist's extensive knowledge and careful information to determine the dental treatment plan. Thirty participants aged 3 to 16 years were divided into 2 groups: study group (15 MMC individuals) and control group (15 healthy subjects). All patients were evaluated for: systemic conditions, use of medications, sequela of the underlying pathology, oral hygiene, diseases, convulsion, cerebrospinal fluid (CSF), allergy, behavior, learning, and mouth physical examination to assess the oral conditions. The study group presented: higher percentage using drugs (P < 0.05), 40% had convulsions (P < 0.05), 86.67% using CSF shunt, 53.33% presented latex allergies (P < 0.05), 53.33% were classified as anxious and with cognitive deficit (P < 0.05), showed more gingivitis (P < 0.05). The MMC individuals, in the majority, have shown cognitive impairment and anxious behavior, use of controlled drugs, convulsion, CSF shunt use, and latex allergy. The presence of periodontal tissue damage was higher in patients with MMC.
Evaluation of Reproducible and Transparent Research Practices in Sports Medicine Research: A Cross-sectional study
Authors: Evans Sheridan , Fladie Ian A. , Anderson J. Michael , Tritz Daniel , Vassar Matt
Published: September 2019

Background

In recent years, urgency has been placed on the “reproducibility crisis” facing biomedical research. Despite efforts toward improvement, certain elements needed to reproduce a study are often lacking from publications. The current state of reproducibility within the sports medicine research community remains unknown.

Purpose

Our study sought to evaluate the presence of eight indicators of reproducibility and transparency to determine the current state of research reporting in sports medicine research.

Study Design

Cross-sectional review

Methods

Using the National Library of Medicine catalog, we identified 41 MEDLINE-indexed, English language sports medicine journals. From the 41 journals, we randomly sampled 300 publications that were recorded on PubMed as being published between January 1, 2014, and December 31, 2018. Two investigators extracted data in duplicate and blinded fashion.

Results

Of the 300 publications sampled, 280 were accessible and were screened for empirical data. Studies that lack empirical data were excluded from our analysis. Of the remaining 195 with empirical data, 10 (5.13%) publications provided data availability statements, 1 (0.51%) provided a protocol, 0 (0.0%) provided an analysis script, and 9 (4.62%) were pre registered.

Conclusion

Reproducibility and transparency indicators are lacking in sports medicine publications. The majority of publications lack the necessary resources for reproducibility such as material, data, analysis scripts, or protocol availability. While the current state of reproducibility cannot be fixed overnight, we feel combined efforts of data sharing, open access, and verifying disclosure statements can help to improve overall reporting.
Induction of hierarchy and time through one-dimensional probability space with certain topologies
Authors: Adachi Shun
Published: September 2019

In a previous study, the authors utilized a single dimensional operationalization of species density that at least partially demonstrated dynamic system behavior. For completeness, a theory needs to be developed related to homology/cohomology, induction of the time dimension, and system hierarchies. The topological nature of the system is carefully examined and for testing purposes, species density data for a wild Dictyostelia community data are used in conjunction with data derived from liquid-chromatography mass spectrometry of proteins. Utilizing a Clifford algebra, a congruent zeta function, and a Weierstraß ℘ function in conjunction with a type VI Painlevé equation, we confirmed the induction of hierarchy and time through one-dimensional probability space with certain topologies. This process also served to provide information concerning interactions in the model. The previously developed “small s” metric can characterize dynamical system hierarchy and interactions, using only abundance data along time development.
Acute cerebellar knockdown ofSgcereproduces salient features of Myoclonus-dystonia (DYT11) in mice
Authors: Washburn Samantha G. , Fremont Rachel , Moreno M. Camila , Angueyra Chantal , Khodakhah Kamran
Published: September 2019

Myoclonus dystonia (DYT11) is a movement disorder caused by loss-of-function mutations inSGCEand characterized by involuntary jerking and dystonia that frequently improve after drinking alcohol. Existing transgenic mouse models of DYT11 exhibit only mild motor symptoms, possibly due to rodent-specific developmental compensation mechanisms, which have limited the study of neural mechanisms underlying DYT11. To circumvent potential compensation, we used short hairpin RNA (shRNA) to acutely knock down Sgcein the adult mouse and found that this approach produced dystonia and repetitive, myoclonic-like movements in mice that improved after administration of ethanol. Acute knockdown ofSgcein the cerebellum, but not the basal ganglia, produced motor symptoms, likely due to aberrant cerebellar activity. The acute knockdown model described here reproduces the salient features of DYT11 and provides a platform to study the mechanisms underlying symptoms of the disorder, and to explore potential therapeutic options.
Genetic drug target validation using Mendelian randomization
Authors: Schmidt A F , Finan C , Gordillo-Marañón M , Asselbergs F W , Freitag D F , Patel R S , Tyl B , Chopade S , Faraway R , Zwierzyna M , Hingorani A D
Published: September 2019

Mendelian randomisation analysis has emerged as an important tool to elucidate the causal relevance of a range of environmental and biological risk factors for human disease. However, inference on cause is undermined if the genetic variants used to instrument a risk factor of interest also associate with other traits that open alternative pathways to the disease (horizontal pleiotropy). We show how the ‘no horizontal pleiotropy assumption’ in MR analysis is strengthened when proteins are the risk factors of interest. Proteins are the proximal effectors of biological processes encoded in the genome, and are becoming assayable on an-omics scale. Moreover, proteins are the targets of most medicines, so Mendelian randomization (MR) studies of drug targets are becoming a fundamental tool in drug development. To enable such studies we introduce a formal mathematical framework that contrasts MR analysis of proteins with that of risk factors located more distally in the causal chain from gene to disease. Finally, we illustrate key model decisions and introduce an analytical framework for maximizing power and elucidating the robustness of drug target MR analyses.
The Object Space Task reveals a dissociation between semantic-like and episodic-like memory in a mouse model of Kleefstra Syndrome
Authors: Schut Evelien H.S. , Alonso Alejandra , Smits Steven , Khamassi Mehdi , Samanta Anumita , Negwer Moritz , Kasri Nael Nadif , Lobato Irene Navarro , Genzel Lisa
Published: September 2019

Kleefstra syndrome is a disorder caused by a mutation in theEHMT1gene characterized in humans by general developmental delay, mild to severe intellectual disability and autism. Here, we characterized semantic- and episodic-like memory in theEhmt1+/-mouse model using the Object Space Task. We combined conventional behavioral analysis with automated analysis by deep-learning networks, a session-based computational learning model and a trial-based classifier.Ehmt1+/-mice showed more anxiety-like features and generally explored objects less, but the difference decreased over time. Interestingly, when analyzing memory-specific exploration,Ehmt1+/-show increased expression of semantic-like memory, but a deficit in episodic-like memory. A similar dissociation of semantic and episodic memory performance has been previously reported in humans with autism. Using our automatic classifier to differentiate between genotypes, we found that semantic-like memory features are better suited for classification than general exploration differences. Thus, detailed behavioral classification with the Object Space Task produced a more detailed behavioral phenotype of theEhmt1+/-mouse model.

One Sentence Summary

Ehmt1+/-mice show decreased exploration and episodic-like memory but increased semantic-like memory In the Object Space Task. (143 of 150)
Genetic underpinnings of sociability in the UK Biobank
Authors: Bralten J , Klemann CJHM , Mota NR , De Witte W , Arango C , Fabbri C , Kas MJ , van der Wee N , Penninx BWJH , Serretti A , Franke B , Poelmans G
Published: September 2019

Difficulties with sociability include a tendency to avoid social contacts and activities, and to prefer being alone rather than being with others. While sociability is a continuously distributed trait in the population, decreased sociability represent a common early manifestation of multiple neuropsychiatric disorders such as Schizophrenia (SCZ), Bipolar Disorder (BP), Major Depressive Disorder (MDD), Autism Spectrum Disorders (ASDs), and Alzheimer’s disease (AD). We aimed to investigate the genetic underpinnings of sociability as a continuous trait in the general population. In this respect, we performed a genome-wide association study (GWAS) using a sociability score based on 4 social functioning-related self-report questions in the UK Biobank sample (n=342,461) to test the effect of individual genetic variants. This was followed by LD score analyses to investigate the genetic correlation with psychiatric disorders (SCZ, BP, MDD, ASDs) and a neurological disorder (AD) as well as related phenotypes (Loneliness and Social Anxiety). The phenotypic data indeed showed that the sociability score was decreased in individuals with ASD, (probable) MDD, BP and SCZ, but not in individuals with AD. Our GWAS showed 604 genome-wide significant SNPs, coming from 18 independent loci (SNP-based h2=0.06). Genetic correlation analyses showed significant correlations with SCZ (rg=0.15, p=9.8e-23), MDD (rg=0.68, p=6.6e-248) and ASDs (rg=0.27, p=4.5e-28), but no correlation with BP (rg=0.01, p=0.45) or AD (rg=0.04, p=0.55). Our sociability trait was also genetically correlated with Loneliness (rg=0.45, p=2.4e-8) and Social Anxiety (rg=0.48, p=0.002). Our study shows that there is a significant genetic component to variation in population levels of sociability, which is relevant to some psychiatric disorders (SCZ, MDD, ASDs), but not to BP and AD.
Network propagation of rare mutations in Alzheimer’s disease reveals tissue-specific hub genes and communities
Authors: Scelsi Marzia A. , Napolioni Valerio , Greicius Michael D. , Altmann Andre ,   for the Alzheimer’s Disease Neuroimaging Initiative (ADNI),   the Alzheimer’s Disease Sequencing Project (ADSP)
Published: September 2019

Background

State-of-the-art rare variant association testing methods aggregate the contribution of rare variants in biologically relevant genomic regions to boost statistical power. However, testing single genes separately does not consider the complex interaction landscape of genes, nor the downstream effects of non-synonymous variants on protein structure and function. Here we present the NETwork Propagation-based Assessment of Genetic Events (NETPAGE), an integrative approach aimed at investigating the biological pathways through which rare variation results in complex disease phenotypes.

Results

We applied NETPAGE to sporadic, late-onset Alzheimer’s disease (AD), using whole-genome sequencing from the AD Neuroimaging Initiative (ADNI) cohort, as well as whole-exome sequencing from the AD Sequencing Project (ADSP). NETPAGE is based on network propagation, a framework that models information flow on a graph and simulates the percolation of genetic variation through gene networks. The result of network propagation is a set of smoothed gene scores used to predict disease status through sparse regression. The application of NETPAGE to AD enabled the identification of a set of connected genes whose smoothed mutation profile acted as a robust predictor of case-control status, based on gene interactions in the hippocampus. Additionally, smoothed scores significantly correlated with risk of conversion to AD in Mild Cognitive Impairment (MCI) subjects. Lastly, we showed tissue-specific transcriptional dysregulation of the core genes in two independent RNA-seq datasets, as well as significant enrichments in terms and gene sets with known connections to AD.

Conclusions

The presented framework enables enhanced genetic association testing for a wide range of traits, diseases, and sample sizes.
Pangenome Analysis of Enterobacteria Reveals Richness of Secondary Metabolite Gene Clusters and their Associated Gene Sets
Authors: Mohite Omkar S. , Lloyd Colton J. , Monk Jonathan M. , Weber Tilmann , Palsson Bernhard O.
Published: September 2019

The growing number of sequenced genomes enables the study of secondary metabolite biosynthetic gene clusters (BGC) in phyla beyond well-studied soil bacteria. We mined 2627 enterobacterial genomes to detect 8604 BGCs, including nonribosomal peptide synthetases, siderophores, polyketide-nonribosomal peptide hybrids, and 60 other BGC types, with an average of around 3.3 BGCs per genome. These BGCs represented 212 distinct BGC families, of which only 20 have associated products in the MIBiG standard database with functions such as siderophores, antibiotics, and genotoxins. Pangenome analysis identified genes associated with a specific BGC encoding for colon cancer-related colibactin. In one example, we associated genes involved in the type VI secretion system with the presence of a colibactin BGC inEscherichia. This richness of BGCs in enterobacteria opens up the possibility to discover novel secondary metabolites, their physiological roles and provides a guide to identify and understand PKS associated gene sets.
Adipokines set neural tone by regulating synapse number
Authors: Brent Ava E. , Rajan Akhila
Published: September 2019

Energy sensing neural circuits decide to expend or conserve resources by integrating tonic steady-state energy store information with phasic signals for hunger and food intake. Tonic signals, in the form of adipose tissue-derived adipokines, set the baseline level of energy-sensing neuron activity, providing context for interpretation of phasic messages. However, the mechanism by which tonic adipokine information establishes baseline neuronal function is unclear. Here we show that Upd2, a Drosophila Leptin ortholog, regulates actin-based synapse reorganization by reducing inhibitory synaptic contacts, thereby providing a permissive neural tone for insulin release under conditions of nutrient surplus. Unexpectedly, Insulin acts on the same upstream inhibitory neurons to conversely increase synapse number, hence re-instating negative tone. Our results suggest that two surplus-sensing hormonal systems, Leptin/Upd2 and Insulin, converge on a neuronal circuit with opposing outcomes that establish tonic, energy-store-dependent neuron activity.

Highlights

The adipokine Upd2 regulates number of inhibitory synaptic contacts on Insulin neurons.

Upd2 activates an actin-regulating complex of Arouser, Basigin, and Gelsolin in target neurons.

Arouser, Basigin, and Gelsolin reduce the extent of inhibitory contact on Insulin neurons.

Insulin resets negative tone by increasing the number of synaptic contacts made by its own upstream inhibitory neurons.
PARPi synthetic lethality derives from replication-associated single-stranded DNA gaps
Authors: Cong Ke , Kousholt Arne Nedergaard , Peng Min , Panzarino Nicholas J. , Lee Wei Ting Chelsea , Nayak Sumeet , Krais John , Calvo Jennifer , Bere Matt , Rothenberg Eli , Johnson Neil , Jonkers Jos , Cantor Sharon B.
Published: September 2019

BRCA1 or BRCA2 (BRCA)-deficient tumor cells have defects in DNA double strand break repair by homologous recombination (HR) and fork protection (FP) that are thought to underlie the sensitivity to poly(ADP-ribose) polymerase inhibitor (PARPi). Given the recent finding that PARPi accelerates DNA replication, it was proposed that high speed DNA replication leads to DNA double strand breaks (DSBs). Here, we tested the alternative hypothesis that PARPi sensitivity in BRCA deficient cells results from combined replication dysfunction that causes a lethal accumulation of replication-associated single-stranded DNA (ssDNA) gaps. In support of a gap toxicity threshold, PARPi-induced ssDNA gaps accumulate more excessively in BRCA deficient cells and are suppressed inde novoand genetic models of PARPi resistance while defects in HR or FP often lack this correlation. We also uncouple replication speed from lethality. The clear link between PARPi sensitivity and ssDNA gaps provides a new paradigm for understanding synthetic lethal interactions.
Replication gaps are a cancer vulnerability counteracted by translesion synthesis
Authors: Nayak Sumeet , Calvo Jennifer A. , Cong Ke , Berthiaume Emily , Jackson Jessica , Dash Radha Charon , Vindigni Alessandro , Hadden Kyle M. , Cantor Sharon B.
Published: September 2019

The replication stress response which serves as an anti-cancer barrier is activated not only by DNA damage and replication obstacles, but also oncogenes, mystifying how cancer evolves. Here, we identify that oncogene expression, similar to cancer therapies, induces single stranded DNA (ssDNA) gaps that reduce cell fitness, unless suppressed by translesion synthesis (TLS). DNA fiber analysis and electron microscopy reveal that TLS restricts replication fork slowing, reversal, and fork degradation without inducing replication fork gaps. Evidence that TLS gap suppression is fundamental to cancer, a small molecule inhibitor targeting the TLS factor, REV1, not only disrupts DNA replication and cancer cell fitness, but also synergizes with gap-inducing therapies. This work illuminates that gap suppression during replication is critical for cancer cell fitness and therefore a targetable vulnerability.
Applying knowledge-driven mechanistic inference to toxicogenomics
Authors: Tripodi Ignacio J. , Callahan Tiffany J. , Westfall Jessica T. , Meitzer Nayland S. , Dowell Robin D. , Hunter Lawrence E.
Published: September 2019

Government regulators and others concerned about toxic chemicals in the environment hold that a mechanistic, causal explanation of toxicity is strongly preferred over a statistical or machine learning-based prediction by itself. Elucidating a mechanism of toxicity is, however, a costly and time-consuming process that requires the participation of specialists from a variety of fields, often relying on animal models. We present an innovative mechanistic inference framework (MechSpy), which can be used as a hypothesis generation aid to narrow the scope of mechanistic toxicology analysis. MechSpy generates hypotheses of the most likely mechanisms of toxicity, by combining a semantically-interconnected knowledge representation of human biology, toxicology and biochemistry with gene expression time series on human tissue. Using vector representations of biological entities, MechSpy seeks enrichment in a manually-curated list of high-level mechanisms of toxicity, represented as biochemically- and causally-linked ontology concepts. Besides predicting the canonical mechanism of toxicity for many well-studied compounds, we experimentally validated some of our predictions for other chemicals without an established mechanism of toxicity. This framework can be modified to include additional mechanisms of toxicity, and is generalizable to other types of mechanisms of human biology.

Author summary

Several recent computational methods have displayed excellent performance in predicting toxicity outcomes [1–3] of chemicals. Yet, to our knowledge, there is to date no computational approach to generate mechanistic hypotheses to answer why these chemicals elicit a toxic response. There is great value in understanding the mechanism of toxicity for a chemical that appears to elicit an adverse response. Novel small molecule development is one example, where a chemical that failed initial toxicological screenings could be assessed to evaluate the actual mechanism of toxicity, greatly reducing research time and expenses on subsequent ones. The value of a mechanistic awareness of toxicity also applies to pharmacovigilance, when researching rare adverse effects of a drug in subsets of the population. The development of oncological chemotherapeutics is another example, where certain mechanisms of cytotoxicity can actually be desirable to eliminate different types of tumor cells. More importantly, the costs, time expenditure, and ethical concerns of toxicity animal models, make in vitro and in silico approaches an enticing alternative. We present a solution that uses a combination of gene expression assays and biomedical knowledge to address the gap of answering the why question.
Differential urine proteome analysis of a bovine IRBP induced uveitis rat model by discovery and parallel reaction monitoring proteomics
Authors: Qin Weiwei , Li Lujun , Wang Ting , Gao Youhe
Published: September 2019

Uveitis, a group of intraocular inflammatory diseases, is one of the major causes of severe visual impairment among working age population. Urine is a promising resource for biomarker research, which could sensitively reflect the changes of the body. This study was designed to explore urinary protein biomarkers for diagnosis and/or monitoring of uveitis. Experimental autoimmune uveitis (EAU) rat model induced by bovine interphotoreceptor retinoid-binding protein (IRBP) was used to mimic the uveitis. In the discovery phase, urine samples from EAU and control rats were analyzed by data independent acquisition (DIA) approach combined with high-resolution mass spectrometry. Overall, 704 high confidential proteins were identified, of which 100 were differentially expressed (37, 33, 37, and 44 on day 5, 8, 12, and 16, respectively, after bovine IRBP immunization) (1.5-fold change, P<0.05). Gene Ontology analysis of the dysregulated proteins showed that chronic inflammatory response, neutrophil aggregation and immune system processes were significantly enriched. Finally, parallel reaction monitoring (PRM) approach was used for further validation. A total of 12 urinary proteins (MMP8, NGAL, HPT, UROM, RISC, A1AG, TTHY, KNT1, C9, PTER, CBG, and FUCA1) changed significantly, even when there is no clinical manifestations and histopathological ocular damages in the EAU rats. Our findings represent the first step towards urinary protein diagnostic biomarkers for uveitis.

Biological Significance

This is the first study investigating urinary protein candidate biomarkers for uveitis using data independent acquisition (DIA) combined with parallel reaction monitoring (PRM) in experimental autoimmune uveitis (EAU) rats. The results revealed that urine is a promising resource for early diagnostics of uveitis. Further research including clinical urine samples is needed to determine the sensitivity and specificity of these candidate biomarkers for uveitis.
Chromatin accessibility variations across pancreatic islet maturation
Authors: Sobel Jonathan , Guay Claudiane , Rodriguez-Trejo Adriana , Stoll Lisa , Menoud Véronique , Regazzi Romano
Published: September 2019

Glucose-induced insulin secretion, a peculiar property of fully matureβ-cells, is only achieved after birth and is preceded by a phase of intense proliferation. These events occurring in the neonatal period are decisive for the establishment of an appropriate functionalβ-cell mass that provides the required insulin throughout life. However, key regulators of gene expression involved in cellular reprogramming along pancreatic islet maturation remain to be elucidated. The present study addressed this issue by mapping open chromatin regions in newborn versus adult rat islets using the ATAC-seq assay. Accessible regions were then correlated with the expression profiles of mRNAs to unveil the regulatory networks governing functional islet maturation. This led to the identification of Scrt1, a novel transcriptional repressor controllingβ-cell proliferation.
Physiological Differences Between Advanced Crossfit Athletes, Recreational Crossfit Participants, and Physically-Active Adults
Authors: Mangine Gerald T. , Stratton Matthew T. , Almeda Christian G. , Roberts Michael D. , Esmat Tiffany A. , VanDusseldorp Trisha A. , Feito Yuri
Published: September 2019

This investigation examined anthropometric, hormonal, and physiological differences between advanced (ADV; n = 8, 27.8 ± 4.2 years, 170 ± 11 cm, 79.8 ± 13.3 kg) and recreational (REC; n = 8, 33.5 ± 8.1 years, 172 ± 14 cm, 76.3 ± 19.5 kg) CrossFit (CF) trained participants in comparison to physically-active controls (CON; n = 7, 27.5 ± 6.7 years, 171 ± 14 cm, 74.5 ± 14.3 kg). ADV and REC were distinguished by their past competitive success. REC and CON were resistance-trained (>2 years) and exercised on 3-5 days·wk-1for the past year, but CON utilized traditional resistance and cardiovascular exercise. All participants provided a fasted, resting blood sample and completed assessments of resting metabolic rate, body composition, muscle morphology, isometric mid-thigh pull strength, peak aerobic capacity, and a 3-minute maximal cycle ergometer sprint across two separate occasions (separated by 3-7 days). Blood samples were analyzed for testosterone, cortisol, and insulin-like growth factor-1. One-way analysis of variance revealed ADV to possess lower body fat percentage (6.7-8.3%,p= 0.007), greater bone and non-bone lean mass (12.5-26.8%,p≤ 0.028), muscle morphology characteristics (14.2-59.9%,p< 0.05), isometric strength characteristics (15.4-41.8%,p< 0.05), peak aerobic capacity (18.8-19.1%,p= 0.002), and anaerobic performance (15.4-51.1%,p≤ 0.023) compared to both REC and CON. No differences were seen between REC and CON, or between all groups for resting metabolic rate or hormone concentrations. These data suggest ADV possess several physiological advantages over REC and CON, whereas similar physiological characteristics were present in individuals who have been regularly participating in either CF or resistance and cardiovascular training for the past year.
Rab11A regulates the constitutive secretory pathway duringToxoplasma gondiiinvasion of host cells and parasite replication
Authors: Kannan Venugopal , Sylia Chehade , Elisabeth Werkmeister , Nicolas Barois , Javier Periz , Frank Lafont , Isabelle Tardieux , Jamal Khalife , Langsley Gordon , Markus Meissner , Sabrina Marion
Published: September 2019

Toxoplasma gondiipossesses an armada of secreted virulent factors that enable parasite invasion and survival into host cells. These factors are contained in specific secretory organelles, the rhoptries, micronemes and dense granules that release their content upon host cell recognition. Dense granules are secreted in a constitutive manner during parasite replication and play a crucial role in modulating host metabolic and immune responses. While the molecular mechanisms triggering rhoptry and microneme release upon host cell adhesion have been well studied, constitutive secretion remains a poorly explored aspect ofT. gondiivesicular trafficking. Here, we investigated the role of the small GTPase Rab11A, a known regulator of exocytosis in eukaryotic cells. Our data revealed an essential role of Rab11A in promoting the cytoskeleton driven transport of DG and the release of their content into the vacuolar space. Rab11A also regulates transmembrane protein trafficking and localization during parasite replication, indicating a broader role of Rab11A in cargo exocytosis at the plasma membrane. Moreover, we found that Rab11A also regulates extracellular parasite motility and adhesion to host cells. In line with these findings, MIC2 secretion was altered in Rab11A-defective parasites, which also exhibited severe morphological defects. Strikingly, by live imaging we observed a polarized accumulation of Rab11A-positive vesicles and dense granules at the apical pole of extracellular motile parasites suggesting that a Rab11A-dependent apically polarized transport of cargo regulates parasite motility.
A nucleus-forming jumbophage evades CRISPR-Cas DNA targeting but is vulnerable to type III RNA-based immunity
Authors: Malone Lucia M. , Warring Suzanne L. , Jackson Simon A. , Warnecke Carolin , Gardner Paul P. , Gumy Laura F. , Fineran Peter C.
Published: September 2019

CRISPR-Cas systems provide bacteria with adaptive immunity against bacteriophages1. However, DNA modification2,3, the production of anti-CRISPR proteins4,5 and potentially other strategies enable phages to evade CRISPR-Cas. Here we discovered a Serratia jumbophage that evaded type I CRISPR-Cas systems, but was sensitive to type III immunity. Jumbophage infection resulted in a nucleus-like structure enclosed by a proteinaceous phage shell – a phenomenon only reported recently for distantly related Pseudomonas phages6,7. All three native CRISPR-Cas complexes in Serratia – type I-E, I-F and III-A – were spatially excluded from the phage nucleus and phage DNA was not targeted. However, the type III-A system still arrested jumbophage infection by targeting phage RNA in the cytoplasm in a process requiring Cas7, Cas10 and an accessory nuclease. Type III, but not type I, systems frequently targeted nucleus-forming jumbophages that were identified in global viral sequence datasets. These findings explain why many bacteria harbour both RNA- and DNA-targeting CRISPR-Cas systems1,8. Together, our results indicate that jumbophage nucleus-like compartments serve as a barrier to DNA-targeting, but not RNA-targeting defences, and that this phenomenon is widespread amongst jumbophages.
Gene-Gene interactions and pleiotropy in the brain nicotinic pathway associated with the heaviness and precocity of tobacco smoking among outpatients with multiple substance use disorders
Authors: Icick Romain , Besson Morgane , Zerdazi El-Hadi , Prince Nathalie , Bloch Vanessa , Laplanche Jean-Louis , Faure Philippe , Bellivier Frank , Maskos Uwe , Vorspan Florence
Published: September 2019

Introduction

Tobacco smoking is a major health burden worldwide, especially in populations suffering from other substance use disorders (SUDs). Several smoking phenotypes have been associated with single nucleotide polymorphisms (SNPs) of nicotinic acetylcholine receptors (nAChRs). Yet, little is known about the genetics of tobacco smoking in populations with other SUDs, particularly regarding gene-gene interactions and pleiotropy, which are likely involved in the polygenic architecture of SUDs. Thus, we undertook a candidate pathway association study of nAChR-related genes and smoking phenotypes in a sample of SUD patients.

Methods

493 patients with genetically-verified Caucasian ancestry were characterized extensively regarding patterns of tobacco smoking, other SUDs, and 83 SNPs from the nicotinic pathway, encompassing all brain nAChR subunits and metabolic/chaperone/trafficking proteins. Single-SNP, gene-based and SNP × SNP interactions analyses were performed to investigate associations with relevant tobacco smoking phenotypes. This included Bayesian analyses to detect pleiotropy, and adjustment on clinical and sociodemographic confounders.

Results

After multiple adjustment, we found independent associations between CHRNA3 rs8040868 and a higher number of cigarettes per day (CPD), and between RIC3 rs11826236 and a lower age at smoking initiation. Two SNP × SNP interactions were associated with age at onset (AAO) of daily smoking. There was pleiotropy regarding three SNPs in CHRNA3 (CPD, AAO daily smoking), ACHE (CPD, HSI) and CHRNB4 (CPD, both AAOs).

Discussion

Despite limitations, the present study shows that the genetics of tobacco smoking in SUD patients are both distinct and partially shared across smoking phenotypes, and involve metabolic and chaperone effectors of the nicotinic pathway.
Dynamic perceptual feature selectivity in primary somatosensory cortex upon reversal learning
Authors: Chéreau Ronan , Bawa Tanika , Fodoulian Leon , Carleton Alan , Pagès Stéphane , Holtmaat Anthony
Published: September 2019

Neurons in primary sensory cortex encode a variety of stimulus features upon perceptual learning. However, it is unclear whether the acquired stimulus selectivity remains stable when the same input is perceived in a different context. Here, we monitored the activity of individual neurons in the mouse primary somatosensory cortex in a reward-based texture discrimination task. We tracked their stimulus selectivity before and after changing reward contingencies, which allowed us to identify various classes of neurons. We found neurons that stably represented a texture or the upcoming behavioral choice, but the majority was dynamic. Among those, a subpopulation of neurons regained selectivity contingent on stimulus-value. These value-sensitive neurons forecasted the onset of learning by displaying a distinct and transient increase in activity, depending on past behavioral experience. Thus, stimulus selectivity of excitatory neurons during perceptual learning is dynamic and largely relies on behavioral contingencies, even in primary sensory cortex.
Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions
Authors: Baloni Priyanka , Funk Cory C. , Yan Jingwen , Yurkovich James T. , Kueider-Paisley Alexandra , Nho Kwangsik , Heinken Almut , Jia Wei , Mahmoudiandehkordi Siamak , Louie Gregory , Saykin Andrew J. , Arnold Matthias , Kastenmüller Gabi , Griffiths William J , Thiele Ines ,   AMP-AD consortium,   The Alzheimer’s Disease Metabolomics Consortium, Kaddurah-Daouk Rima , Price Nathan D.
Published: September 2019

Alzheimer’s disease (AD) is the leading cause of dementia, with metabolic dysfunction seen years before the emergence of clinical symptoms. Increasing evidence suggests a role for primary and secondary bile acids, the end-product of cholesterol metabolism, influencing pathophysiology in AD. In this study, we analyzed transcriptomes from 2114 post-mortem brain samples from three independent cohorts and identified that the genes involved in alternative bile acid synthesis pathway was expressed in brain compared to the classical pathway. These results were supported by targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals. We reconstructed brain region-specific metabolic networks using data from three independent cohorts to assess the role of bile acid metabolism in AD pathophysiology. Our metabolic network analysis suggested that taurine transport, bile acid synthesis and cholesterol metabolism differed in AD and cognitively normal individuals. Using the brain transcriptional regulatory network, we identified putative transcription factors regulating these metabolic genes and influencing altered metabolism in AD. Intriguingly, we find bile acids from the brain metabolomics whose synthesis cannot be explained by enzymes we find in the brain, suggesting they may originate from an external source such as the gut microbiome. These findings motivate further research into bile acid metabolism and transport in AD to elucidate their possible connection to cognitive decline.