bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterogeneous HIV-1 Reactivation Patterns of Disulfiram and Combined Disulfiram+Romidepsin Treatments
Authors: Kula Anna , Delacourt Nadège , Bouchat Sophie , Darcis Gilles , Avettand-Fenoel Veronique , Verdikt Roxane , Corazza Francis , Necsoi Coca , Vanhulle Caroline , Bendoumou Maryam , Burny Arsene , De Wit Stephane , Rouzioux Christine , Rohr Oliver , Van Lint Carine
Published: February 2019

Objectives:

Few single latency-reversing agents (LRAs) have been tested in vivo, and only some of them have demonstrated an effect, albeit weak, on the decrease of latent reservoir. Therefore, other LRAs and combinations of LRAs need to be assessed. Here, we evaluated the potential of combined treatments of therapeutically promising LRAs, disulfiram and romidepsin.

Setting and Methods:

We assessed the reactivation potential of individual disulfiram or simultaneous or sequential combined treatments with romidepsin in vitro in latently infected cell lines of T-lymphoid and myeloid origins and in ex vivo cultures of CD8+-depleted peripheral blood mononuclear cells isolated from 18 HIV-1+ combination antiretroviral therapy–treated individuals.

Results:

We demonstrated heterogeneous reactivation effects of disulfiram in vitro in various cell lines of myeloid origin and no latency reversal neither in vitro in T-lymphoid cells nor ex vivo, even if doses corresponding to maximal plasmatic concentration or higher were tested. Disulfiram+romidepsin combined treatments produced distinct reactivation patterns in vitro. Ex vivo, the combined treatments showed a modest reactivation effect when used simultaneously as opposed to no viral reactivation for the corresponding sequential treatment.

Conclusions:

Exclusive reactivation effects of disulfiram in myeloid latency cell lines suggest that disulfiram could be a potential LRA for this neglected reservoir. Moreover, distinct reactivation profiles pinpoint heterogeneity of the latent reservoir and confirm that the mechanisms that contribute to HIV latency are diverse. Importantly, disulfiram+romidepsin treatments are not potent ex vivo and most likely do not represent an effective drug combination to achieve high levels of latency reversal in vivo.
Brief Report: Changes in Behavior After PrEP Initiation Among Australian Gay and Bisexual Men
Authors: Prestage Garrett , Maher Lisa , Grulich Andrew , Bourne Adam , Hammoud Mohamed , Vaccher Stefanie , Bavinton Benjamin , Holt Martin , Jin Fengyi
Published: February 2019

Introduction:

HIV pre-exposure prophylaxis (PrEP) has been increasingly adopted by gay and bisexual men (GBM). Little is known about whether individual GBM change their sexual behavior after PrEP initiation.

Methods:

Following Lives Undergoing Change (Flux) is a national, online, prospective observational study among Australian GBM. Using McNemar statistics, we compare rates of sexual behaviors before and coincident with PrEP initiation among 1518 non–HIV-positive men recruited between August 2014 and July 2017 who had not commenced PrEP at baseline and who completed at least one 6-monthly follow-up surveys by July 2018.

Results:

The proportion of men using PrEP rose to 24.2% over time. In total, 348 men initiated PrEP during follow-up. PrEP initiators were more likely to report particular sexual behaviors during the follow-up period that they commenced PrEP compared with the period immediately prior: receptive condomless anal intercourse with casual partners increased from 31.0% to 48.9% (McNemar < 0.001); mean partner number increased from 21.96 partners to 34.55 partners (p-trend < 0.001). Among the 1170 men who did not initiate PrEP, prevalence of these behaviors remained lower and stable. Sexual sensation-seeking and gay social engagement were both higher among men who commenced PrEP.

Conclusions:

GBM tended to increase their engagement in “adventurous” sexual behaviors after PrEP initiation. Sexual behaviors among men who did not initiate PrEP were less common and did not change over time.
18F FDG Uptake Due to Late-Onset Osteoradionecrosis for Tongue Base Carcinoma
Authors: Dholam Kanchan P. , Singh Gurkaran Preet , Agarwal Jai Prakash , Mahajan Abhishek
Published: February 2019

Differentiating osteoradionecrosis (ORN) from tumor recurrence is challenging. This report is rare documentation of false-positive 18F-FDG PET scan attributed to ORN in a patient previously treated for carcinoma of base of tongue (Ca BOT). Extraordinarily high 18F-FDG uptake was seen in right ramus (SUVmax, 17.4), left body mandible (SUVmax, 13.6) with left pleural deposits (SUVmax, 17.4). Tumor recurrence was suspected. Pleural fluid aspirate showed evidence of metastatic disease. However, CT-guided biopsy of mandibular lesions revealed necrotic tissue. Hence diagnosis of ORN was established. Patient was put on palliative chemotherapy. No mandibular recurrence was noted during 6-month follow-up period.
Multifocal Small Bowel Carcinoid
Authors: Clark Michael , Nathan Mark , Broski Stephen M.
Published: February 2019

Carcinoid is a subtype of neuroendocrine tumor, a rare group of tumors that are known to express somatostatin receptor 2. 68Ga-DOTATATE is a somatostatin analog that is specific for somatostatin receptor 2 and therefore allows visualization of neuroendocrine tumors. We present 2 cases of primary multifocal small bowel carcinoid evaluated using 68Ga-DOTATATE PET/CT, along with contrast-enhanced CT corollary findings. Given the increased sensitivity of 68Ga-DOTATATE PET/CT compared with CT and 111In-octreotide scintigraphy, we expect multifocal carcinoid to become increasingly recognized.
Meningeal Metastasis Relapse With Focal Involvement of Cranial Bone Flap
Authors: Louarn Nicolas , Dauta Aurélie , Lechapt-Zalcman Emmanuèle , Kauv Paul , Itti Emmanuel
Published: February 2019

A 63-year-old woman was referred to our PET/MRI platform to evaluate the possible relapse of a meningeal metastasis, complicating an invasive ductal carcinoma of the left breast. This metastasis was diagnosed on a left hemiparesis and treated by surgery and radiation therapy. One year later, the same symptoms led to another brain MRI examination that found a contrast-enhanced lesion in the operating site. We decided to perform a 18F-DOPA PET/MRI to document this lesion, which confirmed the diagnosis of a probable relapse and revealed a focal uptake on the bone flap.
Novel Functional Renal PET Imaging With 18F-FDS in Human Subjects
Authors: Werner Rudolf A. , Ordonez Alvaro A. , Sanchez-Bautista Julian , Marcus Charles , Lapa Constantin , Rowe Steven P. , Pomper Martin G. , Leal Jeffrey P. , Lodge Martin A. , Javadi Mehrbod S. , Jain Sanjay K. , Higuchi Takahiro
Published: February 2019

The novel PET probe 2-deoxy-2-18F-fluoro-d-sorbitol (18F-FDS) has demonstrated favorable renal kinetics in animals. We aimed to elucidate its imaging properties in 2 human volunteers. 18F-FDS was produced by a simple 1-step reduction from 18F-FDG. On dynamic renal PET, the cortex was delineated and activity gradually transited in the parenchyma, followed by radiotracer excretion. No adverse effects were reported. Given the higher spatiotemporal resolution of PET relative to conventional scintigraphy, 18F-FDS PET offers a more thorough evaluation of human renal kinetics. Due to its simple production from 18F-FDG, 18F-FDS is virtually available at any PET facility with radiochemistry infrastructure.
Prostate Cancer Pulmonary Metastasis Presenting as a Ground-Glass Pulmonary Nodule on 68Ga-PSMA-11 PET/CT
Authors: Lubin David J. , Holden Stuart B. , Rettig Matthew B. , Reiter Robert E. , King Christopher R. , Lee Jay M. , Wallace Dean W. , Calais Jeremie
Published: February 2019

68Ga–prostate-specific membrane antigen 11 (PSMA) PET/CT imaging accurately depicts metastatic prostate adenocarcinoma (PCa). Pulmonary metastases of PCa are often overlooked on follow-up imaging in patients after initial treatment and following androgen deprivation therapy. Here we present a rare case of biopsy-proven PCa pulmonary metastasis with a ground-glass appearance. The increased PSMA expression and the evolving CT features of the solid component of the ground-glass nodule detected by PSMA PET/CT imaging led to surgical resection and PET/CT-guided therapy.
An Isolated Osseous Rosai-Dorfman Disease Shown on FDG PET/CT
Authors: Zadeh Mahdi Zirakchian , Wen Zhe , States Lisa J. , Zhuang Hongming
Published: February 2019

Rosai-Dorfman disease is typically presented as lymphadenopathy, especially in the neck. Extranodal diseases also frequently occur but are generally concurrent with nodal disease. We report FDG PET/CT findings of solitary femoral Rosai-Dorfman disease without any lymphadenopathy in a pediatric patient.
Hyperfunctioning Papillary Microcarcinoma Diagnosed by 124I PET/Ultrasound Fusion Imaging
Authors: Seifert Philipp , Gühne Falk , Freesmeyer Martin
Published: February 2019

A 49-year-old woman presented with a multinodular goiter, causing local symptoms and hyperthyroisdism. Besides a hypofunctioning benign nodule (TIRADS 3, benign in FNAC), the conventional diagnostic revealed another small hyperfunctioning nodule with suspicious ultrasound features (TIRADS 4C). To rule out a trapping-only nodule and topographical misalignments, a 124I PET/ultrasound fusion was performed and confirmed elevated iodine uptake within the suspicious nodule. Further disseminated autonomous areas are suspected to be additionally responsible for the low TSH-level. Because of the local cervical symptoms and the hyperthyroidism, the patient underwent surgery. The small hyperfunctioning nodule turned out to be a classic papillary microcarcinoma.
Hospital Environmental Effects on Sleep in Adults With Traumatic Brain Injury in Rehabilitation
Authors: Amato Shelly , Anthony Mary K.
Published: February 2019

Purpose

The aim of this study was to describe sleep patterns of adults with traumatic brain injury and examine effects of environmental stressors (patient care activities and light) on patterns of sleep.

Design

A descriptive, correlational, explanatory design was used for this study.

Methods

Sixty-three subjects with traumatic brain injury (>18 years) on an acute traumatic brain injury rehabilitation unit wore an Actiwatch for 48 hours to collect light and sleep data. Patient care activity data were collected between 11 p.m. and 7 a.m.

Findings

Patient care activities and light occurred between 11 p.m. and 7 a.m. Nighttime sleep duration and sleep efficiency were explained by patient care activities, whereas light explained wake time after sleep onset.

Conclusion

Patient care activities and light serve as environmental stressors that affect sleep.

Clinical Relevance

Results necessitate examining the need and timing of nursing care activities and light during nighttime. Findings provide a basis for policy changes that optimize sleep.
Accuracy of Physical Examination, Transvaginal Sonography, Magnetic Resonance Imaging, and Rectal Endoscopic Sonography for Preoperative Evaluation of Rectovaginal Endometriosis
Authors: Chen Ying-Han , Wang Dan-Bo , Guo Cui-Shan
Published: February 2019

The aim of this study was to compare the effectiveness of physical examination, transvaginal sonography, magnetic resonance imaging, and rectal endoscopic sonography for the identification of rectovaginal endometriosis and potential rectal infiltration. Women with suspected rectovaginal endometriosis underwent physical examination, transvaginal sonography, magnetic resonance imaging, and rectal endoscopic sonography. Evaluation was performed for the presence of rectovaginal endometriotic foci and rectal infiltration. The findings obtained with these methods were compared with those of surgical and histopathological examination. Sensitivity, specificity, positive predictive values, and negative predictive values were evaluated for each method. Rectovaginal endometriosis was histologically confirmed in 21 (72.4%) of 29 women. With respect to diagnosis of rectovaginal endometriosis, the sensitivity, specificity, and accuracy of physical examination were 95.2%, 62.5%, and 86.2%; those of transvaginal sonography were 42.9%, 87.5%, and 55.2%; those of magnetic resonance imaging were 90.5%, 87.5%, and 89.7%; and those of rectal endoscopic sonography were 81.0%, 75.0%, and 79.3%, respectively. With respect to identification of rectal infiltration, the sensitivity, specificity, and accuracy of transvaginal sonography were 26.7%, 85.7%, and 55.2%; those of magnetic resonance imaging were 73.3%, 92.9%, and 82.8%; and those of rectal endoscopic sonography were 86.7%, 85.7%, and 86.2%, respectively. Magnetic resonance imaging combined with physical examination seem to be the main approach for the presurgical assessment of rectovaginal endometriosis. Rectal endoscopic sonography is a worthwhile method for the diagnosis of rectal infiltration.
Autologous Fibrin Glue With Collagen Carrier During Maxillary Sinus Lift Procedure
Authors: Leighton Yerko , Weber Benjamin , Rosas Eduardo , Pinto Nelson , Borie Eduardo
Published: February 2019

This study aimed to describe the use of autologous fibrin glue (AFG) with a collagen carrier during maxillary sinus lift procedures with immediate implants during 3 years of follow-up. Twelve patients who had lost their teeth in the region associated to maxillary sinus, with a bone remnant 3 to 5 mm in height, were selected to perform a maxillary sinus augmentation with AFG and collagen membrane, placing the implant immediately. After 5 months, the implants were connected and rehabilitated. The patients were followed-up for a 3-year period, being evaluated every 6 months. At the end of the 3-year follow-up period, 100% implant success was observed, with a mean of bone augmentation of 7.75 mm. Three maxillary sinus membranes were perforated and healed by using AFG and collagen membrane without identify any complication during the follow-up period. Finally, the use of collagen carrier combined with AFG as a filling material during the maxillary sinus lift procedure may be a low-cost and reliable alternative that allows bone formation.
The Role of Fat Grafting in the Treatment of Keloid Scars and Venous Ulcers
Authors: Williams Eva A. , Thaller Seth R.
Published: February 2019

Autologous fat grafting is an increasingly popular practice in the field of plastic surgery. Since the 1980s, it has become one of the most commonly performed procedures by plastic surgeons. Fat grafting has applications in a variety of clinical scenarios, ranging from breast reconstruction to facial volume loss. Recently, the benefit of fat grafting has been employed in wound healing and the treatment of troublesome scars. In this article, we describe the role of fat grafting in the treatment of keloid scars and venous ulcers.
A Case of Schizophrenia With Catatonia Resistant to Lorazepam and Olanzapine Monotherapy But Responsive to Combination Treatment: Is It Time to Consider Using Select Second-Generation Antipsychotics Earlier in the Treatment Algorithm for This Patient Type?
Authors: Spiegel David R. , Glad Rachel , Smith Melanie , Raja Uzair , Wade Ryan , Johnson Kelsey
Published: February 2019

Objective

Catatonia is a distinct psychomotor syndrome that involves a constellation of up to 40 different symptoms. Although conventionally responsive to benzodiazepines, the catatonic syndrome is much more resistant to benzodiazepine treatment when a feature of schizophrenia.

Method

We present a patient with schizophrenia with catatonic symptoms, marginally responsive to lorazepam challenge, lorazepam, and olanzapine monotherapy, but ultimately began combination treatment with these 2 medications.

Results

Our patient's score on the Bush-Francis Catatonia Rating Scale significantly decreased after 2 weeks of combination lorazepam and olanzapine without adverse effects.

Conclusion

We propose a modification to the standard treatment protocol for catatonia, especially in those patients with schizophrenia with catatonic features.
How Much Do Benzodiazepines Matter for Electroconvulsive Therapy in Patients With Major Depression?
Authors: Delamarre Lysandre , Galvao Filipe , Gohier Bénédicte , Poulet Emmanuel , Brunelin Jerome
Published: February 2019

Background

Electroconvulsive therapy (ECT) is one of the most effective treatments for major depressive disorder (MDD), especially in cases of treatment-resistant MDD. Because of their pharmacological profiles, benzodiazepines (BZDs) are suspected to decrease the efficacy of ECT. This study investigated the effect of BZDs on ECT-induced clinical outcomes and ECT course parameters in patients with MDD.

Method

The impact of BZDs on severity of depression (Montgomery-Asberg Depression Rating Scale scores) and on ECT course parameters (seizure threshold, clinical and electroencephalographic seizure duration) was investigated in 70 patients with MDD who received an ECT course using dose-titration method (22 received concomitant BZDs).

Results

Lower remission rates (52.0%) and smaller decreases in Montgomery-Asberg Depression Rating Scale scores were observed in the non-BZD group than in the BZD group (81.2%, P = 0.02). There were no significant differences between the 2 groups regarding seizure duration and seizure threshold.

Limitations

This was a retrospective study. Impact of BZDs on anxiety and cognition was not assessed.

Conclusions

Benzodiazepines increased the clinical efficacy of ECT when delivered using dose-titration method and bitemporal stimulation. Further studied are needed to understand the interaction between BZDs and ECT on clinical outcomes.
Microbial metabolites mediate bumble bee attraction and feeding
Authors: Schaeffer Robert N. , Rering Caitlin C. , Maalouf Isabelle , Beck John J. , Vannette Rachel L.
Published: February 2019

Animals such as bumble bees use chemosensory cues to localize and evaluate essential resources. Increasingly, it is recognized that microbes can alter the quality of foraged resources and produce metabolites that act as foraging cues. The distinct nature of these sensory cues however and their use in animal foraging remain poorly understood. Here, we test the hypothesis that species of nectar-inhabiting microbes differentially influence pollinator attraction and feeding via microbial metabolites in nectar. We examined electrophysiological potential of bumble bee antennae to respond to volatile microbial metabolites, followed by behavioral responses using choice assays. We assessed gustatory responses through both no-choice and choice feeding assays. Antennae responded to some microbial volatiles, and bees chose Asaia bacterial solutions compared to Metschnikowia yeast based on volatiles alone. However, B. impatiens consumed significantly more Metschnikowia-inoculated nectar, suggesting distinct roles for volatile and non-volatile microbial metabolites in mediating feeding decisions, with potential to affect associative learning and future foraging. Our results suggest that microbial metabolites may represent non-reinforcing cues with potential consequences for forager learning, economics and floral host reproduction.
Sensory neuron-derived Nav1.7 contributes to dorsal horn neuron excitability
Authors: Alles Sascha R.A. , Nascimento Filipe , Luján Rafael , Millet Queensta , Bangash Ali , Santana Sonia , Cox James J. , Beato Marco , Zhao Jing , Wood John N.
Published: February 2019

Expression of the voltage-gated sodium channel Nav1.7 in sensory neurons is required for pain sensation. We examined the role of Nav1.7 in the dorsal horn of the spinal cord using an epitope-tagged knock-in mouse. Immuno-electron microscopy showed the presence of Nav1.7 in dendrites of lamina II neurons, despite the absence of mRNA. Peripheral nervous system-specific Nav1.7 KO mice showed central deficits with lamina II dorsal horn tonic firing neurons more than halved and single spiking neurons more than doubled. Nav1.7 blocker PF05089771 diminished excitability in dorsal horn neurons, but had no effect on Nav1.7 KO mice. These data demonstrate an unsuspected functional role of peripherally generated Nav1.7 in dorsal horn neurons and an expression pattern that would not be predicted by transcriptomic analysis.
Metabolic Modulation Predicts Heart Failure Tests Performance
Authors: Contaifer Daniel , Buckley Leo F , Wohlford George , Kumar Naren G , Morriss Joshua M , Ranasinghe Asanga D , Carbone Salvatore , Canada Justin M , Trankle Cory , Abbate Antonio , Van Tassell Benjamin W , Wijesinghe Dayanjan
Published: February 2019

Cardiopulmonary testing (CPET) and biomarkers such as NT-proBNP, Galectin-3, and C-reactive protein (CRP) have shown great promise for characterizing the heart failure (HF) phenotypes. However, the underlying metabolic changes that cause, predict and accompany changes in these parameters are not well known. In depth knowledge of these metabolic changes has the ability to provide new insights towards the clinical management of HF as well as providing better biomarkers for the assessment of disease progression and measurement of success from clinical interventions. To address this knowledge gap, we undertook a deep metabolomic and lipidomic phenotyping of a cohort of HF patients and utilized Multiple Regression Analysis (MRA) to identify associations between the patients plasma metabolome and the lipidome to parameters of CPET and the above mentioned HF biomarkers (HFBio). A total of 49 subjects were submitted to CPET and HFBio evaluation with deep metabolomic and lipidomic profiling of the plasma. Stepwise MRA and Standard Least Squares methods were used to determine models of best fit. Metabolic Pathway Analysis was utilized to detect what metabolites were over-represented and significantly enriched, and Metabolite Set Enrichment Analysis was used to explore pre-existing biological knowledge from studies of human metabolism. The study cohort was predominantly males of African American decent, presenting a high frequency of diabetes, hyperlipidemia, and hypertension with a low mean left ventricular ejection fraction and a high left ventricular end-diastolic and end-systolic volume. VE/VCO2 and Peak VO2 (CV=0.07 and 0.08, respectively) showed the best metabolic predictive model for test performance, while CRP and NT-ProBNP (CV=0.31 and 0.29, respectively) were the least fitted models. Aminoacyl-tRNA and amino acid biosynthesis, amino acid metabolism, nitrogen metabolism, pantothenate and CoA biosynthesis, sphingolipid and glycerolipid metabolism, fatty acid biosynthesis, glutathione metabolism, and pentose phosphate pathway (PPP) were revealed to be the most relevant pathways. Principal related diseases were brain dysfunction and enzyme deficiencies associated with lactic acidosis. Considering the modulations in HF poor test performance, our results indicate an overall profile of oxidative stress, lactic acidosis, and metabolic syndrome coupled with mitochondria dysfunction. Overall, the insights resulting from this studys MRA coincides with what has previously been discussed in parts in existing literature thereby confirming the validity of our findings while at the same time thoroughly characterizing the metabolic underpinning of CPET and HFBio results.
Deep coverage microscopy exposes a pharmacological window for modifiers of neuronal network connectivity
Authors: Verschuuren Marlies , Verstraelen Peter , Garcia Gerardo , Cilissen Ines , Coninx Emma , Verslegers Mieke , Larsen Peter , Nuydens Rony , De Vos Winnok H.
Published: February 2019

Background

Therapeutic developments for neurodegenerative disorders are redirecting their focus to the mechanisms that contribute to synaptic plasticity and the loss thereof. Identification of novel regulators requires a method to quantify neuronal network connectivity with high accuracy and throughput. To meet this demand, we have established a microscopy-based pipeline that integrates morphological and functional correlates of connectivity in primary neuronal culture.

Results

We unveiled a connectivity signature that was specific to the cell type and culture age. We defined a score that accurately reports on the degree of neuronal connectivity and we validated this score by targeted perturbation of microtubule stability and selective depletion of anti-oxidants. With a focused compound screen, we discovered that inhibition of dual leucine zipper kinase activity increased neuronal connectivity in otherwise unperturbed cultures and exerted neuroprotective effects in cultures grown under sub-optimal or challenged conditions.

Conclusions

Our results illustrate that profiling microscopy images with deep coverage enables sensitive interrogation of neuronal connectivity and allows exposing a dose and time window for pharmacological interventions. Therefore, the current approach holds promise for identifying pathways and compounds that preserve or rescue neuronal connectivity in neurodegenerative disorders.
Depth-dependent PSF calibration and aberration correction for 3D single-molecule localization
Authors: Li Yiming , Wu Yu-Le , Hoess Philipp , Mund Markus , Ries Jonas
Published: February 2019

3D Single molecule localization microscopy relies on fitting of the individual molecules with a point spread function (PSF) model. The reconstructed images often show local squeezing or expansion in z. A common cause are depth-induced aberrations in conjunction with an imperfect PSF model calibrated from beads on a coverslip, resulting in a mismatch between measured PSF and real PSF. Here, we developed a strategy for accurate z-localization in which we use the imperfect PSF model for fitting, determine the fitting errors and correct for them in a post-processing step. We present an open-source software tool and a simple experimental calibration procedure that allow retrieving accurate z-positions in any PSF engineering approach or fitting modality, even at large imaging depths.
A novel human enteroid-anaerobe co-culture system to study microbial-host interaction under physiological hypoxia
Authors: Fofanova TY , Stewart CJ , Auchtung JM , Wilson RL , Britton RA , Grande-Allen KJ , Estes MK , Petrosino JF
Published: February 2019

Mechanistic investigations of host-microbe interactions in the human gut are limited by current co-culture model systems. The intestinal epithelium requires oxygen for viability, while gut bacteria are facultative or obligate anaerobes. The ability to model host-commensal interactions under dynamic oxygen conditions is critical to understanding host-pathogen interactions in the human gut. Here, we demonstrate a simple, cost-effective method for co-culturing obligate anaerobic bacteria with human intestinal enteroid monolayers under variable oxygen conditions. The Enteroid-Anaerobe Co-Culture (EACC) system is able to recapitulate the steep oxygen gradient seenin vivoand induce expression of hypoxia-associated phenotypes such as increased barrier integrity and expression of antimicrobial peptide genes. Using clinical strains of the commensal anaerobesBacteroides thetaiotaomicronandBlautiasp. on established patient-derived intestinal enteroid cell lines under physiological hypoxia, the EACC system can sustain host-anaerobe interactions for at least 24 hours. Following co-culture with anaerobic bacteria, we demonstrate patient-specific differences in epithelial response, reinforcing the potential to develop a personalized medicine approach to bacteriotherapy and host-microbe interaction investigations. Our innovative EACC system provides a robust model for investigating host-microbe interactions in complex, patient-derived intestinal tissues, that facilitates study of mechanisms underlying the role of the microbiome in health and disease.
Model-based integration of genomics and metabolomics reveals SNP functionality in Mycobacterium tuberculosis
Authors: Øyås Ove , Borrell Sonia , Trauner Andrej , Zimmermann Michael , Feldmann Julia , Gagneux Sebastien , Stelling Jörg , Sauer Uwe , Zampieri Mattia
Published: February 2019

Human tuberculosis is caused by members of the Mycobacterium tuberculosis complex (MTBC) and presents variable disease outcomes. The variation has primarily been attributed to host and environmental factors, but recent evidence indicates an additional role of genetic diversity among MTBC clinical strains. Here, we used metabolomics to unravel the potential role of genetic variations in conferring strain-specific adaptive capacity and vulnerability. To systematically identify functionality of single nucleotide polymorphisms (SNPs), we developed a constraint-based approach that integrates metabolomic and genomic data. Model-based predictions were systematically tested against independent metabolome data; they correctly classified SNP effects in pyruvate kinase and suggested a genetic basis for strain-specific sensitivity to the antibiotic para-aminosalicylic acid. Our method is broadly applicable to mutations in enzyme-encoding genes across microbial life, opening new possibilities for identifying strain-specific metabolic vulnerabilities that could lead to more selective treatment strategies.
A Recurrent Neural Network Model for Flexible and Adaptive Decision Making based on Sequence Learning
Authors: Zhang Zhewei , Cheng Huzi , Yang Tianming
Published: February 2019

The brain makes flexible and adaptive responses in the complicated and ever-changing environment for the organism’s survival. To achieve this, the brain needs to choose appropriate actions flexibly in response to sensory inputs. Moreover, the brain also has to understand how its actions affect future sensory inputs and what reward outcomes should be expected, and adapts its behavior based on the actual outcomes. A modeling approach that takes into account of the combined contingencies between sensory inputs, actions, and reward outcomes may be the key to understanding the underlying neural computation. Here, we train a recurrent neural network model based on sequence learning to predict future events based on the past event sequences that combine sensory, action, and reward events. We use four exemplary tasks that have been used in previous animal and human experiments to study different aspects of decision making and learning. We first show that the model reproduces the animals’ choice and reaction time pattern in a probabilistic reasoning task, and its units’ activities mimics the classical findings of the ramping pattern of the parietal neurons that reflects the evidence accumulation process during decision making. We further demonstrate that the model carries out Bayesian inference and may support meta-cognition such as confidence with additional tasks. Finally, we show how the network model achieves adaptive behavior with an approach distinct from reinforcement learning. Our work pieces together many experimental findings in decision making and reinforcement learning and provides a unified framework for the flexible and adaptive behavior of the brain.
Murburn concept explains the acutely lethal effect of cyanide
Authors: Manoj Kelath Murali , Ramasamy Surjith , Parashar Abhinav , Soman Vidhu , Pakshirajan Kannan
Published: February 2019

Cyanide (CN) toxicity is traditionally understood to result from its binding of hemeFe centers, thereby disrupting mitochondrial cytochrome oxidase function and oxygen utilization by other globin proteins. Recently, a diffusible reactive oxygen species (DROS) mediated reaction mechanism called murburn concept was proposed to explain mitochondrial ATP-synthesis and heat generation. Per this purview, it was theorized that CN ion-radical equilibrium dissipates the catalytically vital DROS into futile cycles, producing water. In the current study, a comparative quantitative assessment of the above two explanations is made for: (i) lethal dosage or concentrations of CN, (ii) thermodynamics and kinetics of the binding/reaction, and (iii) correlation of CN with the binding data and reaction chemistry of H2S/CO. The quantitative findings suggest that the hemeFe binding-based toxicity explanation is untenable. CN also inhibited the experimentalin vitroDROS-mediated coupling of inorganic phosphate with ADP. Further, pH-dependent inhibition profiles of heme enzyme catalyzed oxidation of a phenolic (wherein an -OH group reacts with DROS to form water, quite akin to the murburn model of ATP synthesis) indicated that- (i) multiple competitive reactions in milieu controlled outcomes and (ii) low concentrations of CN cannot disrupt activity via a coordination (binding) of cyanide at the distal hemeFe. Therefore, the μM-level IC50and the acutely lethal effect of CN on cellular respiration could be explained by the deleterious interaction of CN ion-radical equilibrium with DROS in matrix, disrupting mitochondrial ATP synthesis. This work supports the murburn explanation for cellular respiration.
TMS-EEG signatures of glutamatergic neurotransmission in human cortex
Authors: König Franca , Belardinelli Paolo , Liang Chen , Desideri Debora , Müller-Dahlhaus Florian , Gordon Pedro Caldana , Zipser Carl , Zrenner Christoph , Ziemann Ulf
Published: February 2019

Neuronal activity in the brain is regulated by an excitation-inhibition balance. Glutamate is the main excitatory neurotransmitter. Transcranial magnetic stimulation (TMS) evoked electroencephalographic (EEG) potentials (TEPs) represent a novel way to quantify pharmacological effects on neuronal activity in the human cortex. Here we tested TEPs under the influence of a single oral dose of two anti-glutamatergic drugs, perampanel, an AMPA-receptor antagonist, and dextromethorphan, an NMDA-receptor antagonist, and nimodipine, an L-type voltage-gated calcium channel blocker in 16 healthy adults in a pseudorandomized, double-blinded, placebo-controlled, crossover design. Single-pulse TMS was delivered to the left motor cortex and TEPs were obtained pre-and post-drug intake. Dextromethorphan specifically increased the amplitude of the N45, a negative potential around 45 ms after the TMS pulse, while perampanel reduced the P70 amplitude in the non-stimulated hemisphere. Nimodipine and placebo had no effect on TEPs. These data extend previous pharmaco-TMS-EEG studies by demonstrating that the N45 is regulated by a balance of GABAAergic inhibition and NMDA-receptor-mediated glutamatergic excitation. In contrast, AMPA-receptor-mediated glutamatergic neurotransmission contributes to interhemispherically propagated activity reflected in the P70. These data are important to understand the physiology of TEPs as markers of excitability and propagated activity in the human cortex in health and disease.
Ancient whole genome duplications and the evolution of the gene duplication and loss rate
Authors: Zwaenepoel Arthur , Van de Peer Yves
Published: February 2019

Gene tree - species tree reconciliation methods have been employed for studying ancient whole genome duplication (WGD) events across the eukaryotic tree of life. Most approaches have relied on using maximum likelihood trees and the maximum parsimony reconciliation thereof to count duplication events on specific branches of interest in a reference species tree. Such approaches do not account for uncertainty in the gene tree and reconciliation, or do so only heuristically. The effects of these simplifications on the inference of ancient WGDs are unclear. In particular the effects of variation in gene duplication and loss rates across the species tree have not been considered. Here, we developed a full probabilistic approach for phylogenomic reconciliation based WGD inference, accounting for both gene tree and reconciliation uncertainty using a method based on the principle of amalgamated likelihood estimation. The model and methods are implemented in a maximum likelihood and Bayesian setting and account for variation of duplication and loss rate across the species tree, using methods inspired by phylogenetic divergence time estimation. We applied our newly developed framework to ancient WGDs in land plants and investigate the effects of duplication and loss rate variation on reconciliation and gene count based assessment of these earlier proposed WGDs.
Structural Insights into Hearing Loss Genetics from Polarizable Protein Repacking
Authors: Tollefson M. R. , Litman J. M. , Qi G. , Marini R. J. , O’Connell C. E. , Wipfler M. J. , Bernabe H. V. , Tollefson W. T. A. , Casavant T. L. , Braun T. A. , Smith R. J. H. , Schnieders M. J.
Published: February 2019

Hearing loss is associated with ~8100 mutations in 152 genes, and within the coding regions of these genes are over 60,000 missense variants. The majority of these variants are classified as ‘variants of uncertain significance’ to reflect our inability to ascribe a phenotypic effect to the observed amino acid change. A promising source of pathogenicity information are atomic resolution simulations, although input protein structures often contain defects due to limitations in experimental data and/or only distant homology to a template. Here we combine the polarizable AMOEBA force field, many-body optimization theory and GPU acceleration to repack all deafness-associated proteins and thereby improve average structure resolution from 2.2 Å to 1.0 Å based on assessment with MolProbity. We incorporate these data into the Deafness Variation Database to inform deafness pathogenicity prediction, and show that advanced polarizable force fields could now be used to repack the entire human proteome using the Force Field X software.
Estimating the abundance of duiker (Cephalophus spp.) populations in African rainforests: an overview of relevant methods
Authors: Entanga Elenga Gaius Bolumbu , Gaillard Jean-Michel , Musibono Dieudonné Eyul’Anki , Bibula Ifuta Séraphin Ndey , Bonenfant Christophe
Published: February 2019

Duikers are among the most sought after antelope species for bush meat in central Africa. Estimates of population abundance of duikers based on reliable methods is therefore of prime importance for their sustainable management. Here we retrieved 31 studies from the literature and compared methods used to estimate the abundance of duiker populations in African rainforests. Implemented methods all derived from seven main combinations of sampling designs and population abundance estimators. We then evaluated the relevance of those seven methods by scoring them based on eight criteria selected according to their pros and cons reported in the litterature for large-scale population management of wildlife. For management purposes, methods derived from distance sampling offer the best compromise between the implementation costs and the biological information collected. In particular, both diurnal and nocturnal distance sampling can be recommended. Hunter calls and drive-netting are less reliable, but can be used in association with other measurements in the framework of indicators of ecological changes, a monitoring approach that has been successfully used in temperate ecosystems for managing large herbivores.

Funding information

Ministère de l’Environnement et du Développement Durable de la République Démocratique du Congo, Campus France and Centre National de la Recherche Scientifique (CNRS).

Les céphalophes sont parmi les espèces d’antilopes les plus recherchées pour la viande de brousse en Afrique centrale. L’estimation de l’abondance des populations de céphalophes revêt donc une importance primordiale pour leur gestion durable et adaptative. Nous avons extrait 31 études de la littérature et comparé les méthodes utilisées pour estimer l’abondance des populations de céphalophes dans les forêts tropicales africaines. Les méthodes employées dérivent de sept combinaisons principales de plans d’échantillonnage et d’estimateurs d’abondance. Nous avons évalué la pertinence de ces sept méthodes sur la base de critères sélectionnés en fonction de leurs avantages et inconvénients pour une gestion à grande échelle de la population. Les méthodes dérivées de l’échantillonnage par distance offrent le meilleur compromis entre les coûts de mise en œuvre et les informations biologiques collectées. Les méthodes d’échantillonnage diurne et nocturne se sont montrées les plus satisfaisantes. Les méthodes d’appel par les chasseurs et de battue au filet sont moins fiables, mais peuvent être utilisées en association avec d’autres mesures biologiques comme indicateurs de changements écologiques, une approche qui a été utilisée avec succès dans les écosystèmes tempérés pour la gestion des grands herbivores.

Mots-clés:

gestion durable, grands herbivores, indicateurs de changement écologique, méthode de recensement, viande de brousse
Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain
Authors: Leung Edward J.Y. , Abraham Antony D. , Wong Brenden A. , Kruse Lauren C. , Clark Jeremy J. , Land Benjamin B.
Published: February 2019

Chronic pain affects a significant percentage of the United States population, and available pain medications like opioids have drawbacks that make long-term use untenable. Cannabinoids show promise in the management of pain, but long-term treatment of pain with cannabinoids has been challenging to implement in preclinical models. We developed a voluntary, gelatin oral self-administration paradigm that allowed animals to consume Δ9-tetrahydrocannabinol, cannabidiol, or morphine ad libitum. Animals stably consumed these gelatins over 3 weeks, with detectable serum levels. We designed a real-time gelatin measurement system, and observed that mice consumed gelatin throughout the light and dark cycles, with THC-gelatin animals consuming less than the other groups. Consumption of all three gelatins reduced measures of allodynia in a chronic, neuropathic sciatic nerve injury model, but tolerance to morphine developed after one week while THC or CBD reduced allodynia over three weeks. Hyperalgesia took longer to develop after sciatic nerve injury, but by the last day of testing THC significantly reduced hyperalgesia responses, with a trend effect of CBD, and no effect of morphine. Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by both THC and CBD. This study demonstrates that mice will voluntarily consume both cannabinoids and opioids via gelatin, and that cannabinoids can provide long-term relief of chronic pain states. Additionally, ultrasonic clicks may objectively represent the pain status of a mouse and could be integrated into future pain models.
pyKNEEr: An image analysis workflow for open and reproducible research on femoral knee cartilage
Authors: Bonaretti Serena , Gold Garry E. , Beaupre Gary S.
Published: February 2019

Transparent research in musculoskeletal imaging is fundamental to reliably investigate diseases such as knee osteoarthritis (OA), a chronic disease impairing femoral knee cartilage. To study cartilage degeneration, researchers have developed algorithms to segment femoral knee cartilage from magnetic resonance (MR) images and to measure cartilage morphology and relaxometry. The majority of these algorithms are not publicly available or require advanced programming skills to be compiled and run. However, to accelerate discoveries and findings, it is crucial to have open and reproducible workflows. We presentpyKNEEr, a framework for open and reproducible research on femoral knee cartilage from MR images.pyKNEEris written in python, uses Jupyter notebook as a user interface, and is available on GitHub with a GNU GPLv3 license. It is composed of three modules: 1) image preprocessing to standardize spatial and intensity characteristics, 2) femoral knee cartilage segmentation for intersubject, multimodal, and longitudinal acquisitions, and 3) analysis of cartilage morphology and relaxometry. Each module contains one or more Jupyter notebooks with narrative, code, visualizations, and dependencies to reproduce computational environments.pyKNEErfacilitates transparent image-based research of femoral knee cartilage because of its ease of installation and use, and its versatility for publication and sharing among researchers. Finally, due to its modular structure,pyKNEErfavors code extension and algorithm comparison. We tested our reproducible workflows with experiments that also constitute an example of transparent research withpyKNEEr. We provide links to executed notebooks and executable environments for immediate reproducibility of our findings.
Adult emergence order in a community of cavity-nesting bees and wasps, and their parasites
Authors: MacIvor J Scott
Published: February 2019

Evaluating resource use and overlap through time and space among and within species having similar habitat requirements informs community-level conservation and coexistence, efforts to monitor species at-risk and biological invasions. Many species share common nesting requirements; one example are cavity-nest bees and wasps, which provision nests in dark and dry holes in wood, plant stems, or other plant-based materials that can be bundled together into ‘trap nests’. In this study, the adult emergence order of 47 species of solitary cavity-nesting bees and wasps, and their parasites (total N>8000 brood cells) were obtained from two hundred identical trap nests set up each year (over three years) to survey these populations across Toronto, Canada and the surrounding region. All brood cells collected were reared in a growth chamber under constant warming temperature and humidity to determine species identity, and adult emergence order. This order ranged from 0 to 38 days, with all mason bees (Osmiaspp.) emerging within the first two days, and the invasive resin bee species,Megachile sculpturalisSmith significantly later than all others. Late emerging species i) exhibited significantly greater intraspecific variation in mean emergence day and ii) were significantly larger in body size, compared to early emerging species. Detailing natural history information at the species- and community-level, such as the adult emergence order of coexisting cavity-nesting bees and wasps and their parasites, can inform the timing of deployment of trap nests to support and monitor target species, and refine experimental design to study these easily-surveyed and essential insect communities.