bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of Ear Molding in Infants using the EarWell Infant Correction System and Factors Affecting Outcome
Authors: Chan Stephanie L. S. , Lim Gale J. S. , Por Yong Chen , Chiang Ming Fang , Ho Shuxian , Saffari Seyed Ehsan , Chia Hui-Ling
Published: October 2019

Background:

One-third of infants have ear anomalies, and less than one-third self-correct. Correction of ear deformities by molding exploits the plasticity of the auricular cartilage because of circulating maternal estrogen during infancy. In this study, the authors assess the efficacy of the EarWell Infant Correction System in the correction of ear deformities and determine the factors that affect its outcome.

Methods:

The authors conducted a single-center prospective study over a 3-year period. Consecutive full-term infants who underwent ear molding with the EarWell system were recruited. Primary outcome was successful correction of ear anomaly. Secondary outcomes included complications and maintenance of ear shape. Factors identified included type of anomaly, age at application, duration of application, and breastfeeding.

Results:

Sixty-seven patients with a total of 105 ears were recruited. The anomalies were classified into deformations (66.7 percent) and malformations (33.3 percent). The median age group at presentation was 0 to 7 days (67 percent). Average duration of application was 4.1 weeks. Successful correction was achieved in 86 percent of patients. Ear deformations achieved a significantly higher rate of successful outcome (98 percent) compared with malformations (64 percent) (p < 0.001). Skin complications were common (46 percent) and attributed to our tropical climate. Patients with complications were of a higher mean age (22.1 days) compared with patients with no complications (10.6 days) (p = 0.037).

Conclusions:

The EarWell system is an effective nonsurgical option for the treatment of ear anomalies. The type of anomaly was the only predictor of successful correction, whereas age at application, duration of molding, and breastfeeding were not. Complications were more common in older infants.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
“Like a Normal Person Again”: A Qualitative Analysis of the Impact of Headache Surgery
Authors: Afifi Ahmed M. , Schwarze Margaret L. , Stilp Emmaline K. , Orne Jason , Smith Jeremy P. , Abd-Elsayed Alaa A. , Anderson Brooke M. , Salem Ahmed , Macdonald Cameron L. , Israel Jacqueline S.
Published: October 2019

Background:

Outcomes after migraine surgery have been previously assessed using quantitative measurements, including the migraine headache index. Qualitative methodologies offer the ability to analyze patients’ perceptions and pain experience, and may point to changes in domains not captured by quantitative instruments. The purpose of this study was to characterize individual patients’ experiences with migraines and to analyze how patients’ experience of headaches changes in relation to surgery.

Methods:

Patients who previously underwent migraine surgery performed by a single surgeon participated in semistructured interviews at least 1 year after surgery. Purposive sampling was used to recruit patients [n = 15 (73 percent female)]. Interviews were transcribed verbatim. A multidisciplinary team with backgrounds in surgery, pain management, medicine, and health services research coded and analyzed transcripts.

Results:

Participants reported improvements in one or more domains of pain following surgery, and changes in medication use and effectiveness. Even in individuals with persistent pain postoperatively, surgery appeared to facilitate an improvement in headache self-efficacy, including an ability to participate in daily activities. Migraineurs frequently described a new degree of control over at least one aspect of their pain.

Conclusions:

Migraine surgery appears to positively impact patients’ lives in ways that support and expand on previously published outcomes. Patients report benefiting from surgery in ways that are not currently captured in commonly used metrics. This study’s findings support the need for more specific patient-reported outcome measures to help clinicians and patients understand the impact of surgery and which outcomes matter most to patients.
Change Is Happening: An Evaluation of Gender Disparities in Academic Plastic Surgery
Authors: Smith Brandon T. , Egro Francesco M. , Murphy Carolyn P. , Stavros Alex G. , Kenny Elizabeth M. , Nguyen Vu T.
Published: October 2019

Background:

Gender disparities in academic plastic surgery are known; however, recently, professional societies have endorsed a culture of gender diversification. This study aims to evaluate the effects of these changes at faculty and leadership positions.

Methods:

A cross-sectional study was conducted in June of 2018 to evaluate gender representation among U.S. academic plastic surgery faculty, and compare career qualifications, years of experience, and faculty positions.

Results:

A total of 938 academic plastic surgeons were identified, of which only 19.8 percent were women. Female surgeons graduated more recently than men (2009 versus 2004; p < 0.0001) and predominantly from integrated residency programs (OR, 2.72; 95 percent CI, 1.87 to 3.96), were more likely to be an assistant professor (OR, 2.19; 95 percent CI, 1.58 to 3.05), and were less likely to be a full professor (OR, 0.20; 95 percent CI, 0.11 to 0.35) or program chair (OR, 0.32; 95 percent CI, 0.16 to 0.65). After adjustment for differences in years of postresidency experience, only disparities at the full professor position remained significant (OR, 0.34; 95 percent CI, 0.16 to 0.17), indicating that experience-independent gender inequality is prominent at the full professor level and that current differences in cohort experience are a significant contributor to many of the observed positional disparities. Lastly, programs led by a female chair employed significantly more female faculty (32.5 percent versus 18.2 percent; p = 0.016).

Conclusions:

Gender diversity in academic plastic surgery remains a significant issue, but may see improvement as the disproportionately high number of junior female academics advance in their careers. However, leadership and promotion disparities between men and women still exist and must be addressed.
Recognizing Racial Heterogeneity in the Latino Nose: Aesthetic Concepts for an Individualized Approach
Authors: Perez Justin L. , Mohan Raja , Rohrich Rod J.
Published: October 2019

Background:

Latinos are one of the fastest growing ethnic groups in the United States, and there is a growing demand for aesthetic rhinoplasty in these patients. The authors provide an individualized, systematic approach for evaluation and improvement of surgical outcomes in Latino patients.

Methods:

A retrospective review of patients identified as Latino who underwent primary rhinoplasty and those who did not but had documented nasal photographs was performed. Photographs and operative records were reviewed in detail. Specific aesthetic nasal characteristics, individualized surgical techniques, and aesthetic results were recorded.

Results:

The Latino nose has some characteristic nasal traits, including thick soft-tissue envelope, bulbous and underrotated tips, fatty hanging alae with propensity for anterior notching, weak underlying cartilaginous structures, and a propensity for alar flare worsened by depressor septi hyperactivity. Case review, however, demonstrates that there is moderate variability, with some patients demonstrating features more consistent with a European Caucasian nose and others displaying features more congruent with the black nose.

Conclusions:

Addressing the Latino nose requires a firm understanding of the racial heterogeneity that exists within this patient population, ranging from features more consistent with the black nose to features more congruent with a European Caucasian nose. A patient’s aesthetic goals should be thoroughly discussed to avoid racial incongruity. The authors provide an individualized, component approach to improving aesthetic outcomes in Latino rhinoplasty.
FDG PET/CT Image for a Rosai-Dorfman Disease With Pituitary and Bone Involvement in a Pediatric Patient
Authors: Kong Ziren , Wang Yu , Ma Wenbin , Cheng Xin
Published: October 2019

Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy, is a rare nonneoplastic histiocytic disorder that often involves the lymph nodes and occasionally the central nervous system or skeleton. However, the presence of extranodal Rosai-Dorfman lesions without lymphadenopathy is extremely rare. Here we present a case of a pathological confirmed Rosai-Dorfman disease with pituitary and skeletal involvement without lymph nodes involvement.
Excellent Response to 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy in a Patient With Progressive Metastatic Castration-Resistant Prostate Cancer With Neuroendocrine Differentiation After 177Lu-PSMA Therapy
Authors: Liu Chen , Liu Teli , Zhang Jingjing , Baum Richard P. , Yang Zhi
Published: October 2019

Prostate cancer with neuroendocrine differentiation is associated with a poor prognosis, rapid disease progression, and treatment resistance, and constitutes a diagnostic and therapeutic dilemma. We present images of 177Lu-DOTATATE scan and 68Ga-DOTATATE PET/CT scan conducted on a 65-year-old man with prostate cancer with neuroendocrine differentiation, whose disease progressed despite conventional treatment and 177Lu-PSMA radioligand therapy; however, an extraordinary radiographic tumor remission, biochemical response, and improvement of clinical symptoms were observed after the patient underwent 177Lu-DOTATATE peptide receptor radionuclide therapy.
Contemporary Concepts of Primary Dynamic Facial Nerve Reconstruction in the Oncologic Patient
Authors: Klein Holger Jan , Guedes Tiago , Tzou Chieh-Han John , Rodriguez-Lorenzo Andrés
Published: October 2019

Transection of the facial nerve and its branches during extensive ablative procedures in the oncologic patient causes loss of control of facial mimetic muscles with severe functional and aesthetic sequelae. In such patients with advanced tumorous disease, copious comorbidities, and poor prognosis, rehabilitation of the facial nerve has long been considered of secondary priority. However, recent advances in primary facial nerve reconstruction after extensive resection demonstrated encouraging results focusing on rapid and reliable restoration of facial functions. The authors summarize 3 innovative approaches of primary dynamic facial nerve reconstruction by using vascularized nerve grafts, dual innervation concepts, and intra-facial nerve transfers.
A Relationship Between the Supratrochlear Nerve and Trochlea: Anatomical Study and Application to Migraine Headaches
Authors: Kikuta Shogo , Iwanaga Joe , Watanabe Koichi , Kusukawa Jingo , Tubbs R. Shane
Published: October 2019

Supratrochlear nerve (STN) is a terminal branch of the frontal nerve arising from the ophthalmic nerve (V1). Compression of the STN by adjacent structures might result in migraine headaches. The aim of this study was to explore the relationship of the STN and trochlea for a better understanding of potential entrapment of the STN. Nineteen orbits from ten fresh-frozen cadaveric heads were dissected. The relationship of the STN and the trochlea was classified into three types: In type I, the STN passed lateral to the trochlea; In type II, the STN passed through the trochlea; In type III, the STN passed medial to the trochlea. Type I was found in 52.6% (10/19 sides), type II was found in 42.1% (8/19 sides), and type III was seen in 3.4% (1/19 sides). In type III, both the STN and infratrochlear nerve were identified as separate branches. The authors propose a new classification of the pathway of the STN based on its relationship with the trochlea. This study might shed light on headaches emanating from this region.
Fabrication of Nasoalveolar Molding Devices for the Treatment of Cleft Lip and Palate, Using Stereolithography Additive Manufacturing Processes and Computer-Aided Design Manipulation Software
Authors: Ahmed Mairaj K. , Ahsanuddin Sofia , Retrouvey Jean-Marc , Koka Krishna Sai , Qureshi Haider , Bui Anthony H. , Taub Peter J.
Published: October 2019

Introduction:

Nasoalveolar molding (NAM) is a presurgical orthopedic treatment modality that attempts to reorient misaligned bony and soft tissue structures in patients with clefting of the lip and palate. The NAM devices are implemented prior to surgical intervention in order to minimize the gap across the cleft and thereby reduce tension across the eventual repair. Currently, NAM devices are fabricated in a laboratory and then refined chairside by the provider. The present article describes the potential of three-dimensional (3D) printing and computer-aided design (CAD) software for the fabrication of NAM devices.

Material and methods:

A workflow was developed to demonstrate the use of 3D printing and CAD software to design NAM devices. This workflow encompasses scanning an impression into CAD software, performing a series of manipulations, and then printing the digital model.

Results:

To test the workflow, a cleft palate plaster model was scanned into CAD software. Through a series of linear and angular freeform manipulations of the body, the model was modified to display a cleft with a reduced alveolar gap. Sequential molding devices were produced which would gradually apply pressure to targeted areas of hard and soft tissue until the cleft is minimized. The resulting devices are printed using a stereolithography printer.

Conclusions:

The use of 3D printing and CAD software shows promise in improving the accuracy, speed, and cost-effectiveness of designing NAM devices. The accuracy and flexibility from digitally visualizing the manipulations made to an appliance before its creation can result in a more personalized device for the patient.
The Transareola Endoscopic Approach Yields Adequate Oncological Dissection as Open Approach in the Treatment of Papillary Thyroid Carcinoma
Authors: Gao Hengyuan , Chen Chen , Liu Xinjie , Xu Nan , Wang Yuanyang , Qu Rui , Yu Xiaofang
Published: October 2019

Objective:

This study aimed to evaluate and discuss whether the transareola endoscopic surgery has similar outcome outcomes to open surgery in the treatment of papillary thyroid carcinoma (PTC).

Method:

A total of 102 patients with PTC were enrolled in this study. Among them, 53 patients were treated by transareola endoscopic surgery (endoscopic group) and 49 patients were treated by open surgery (open group). Some specific factors, including thyroglobulin (Tg), radioactive iodine uptake (RAIU), postoperative nuclide imaging in thyroid area, postoperative nuclide imaging of lymph nodes suspicious for metastasis (PNILNSM), etc. were analyzed and compared between the 2 groups.

Results:

There were no significant differences between the 2 groups regarding body mass index (22.9±3.4 vs. 24.0±3.3, P=0.103), operation time (173.3±43.2 vs. 158.8±47.9 min, P=0.110), intraoperative blood loss (41.8±19.4 vs. 35.8±31.0 mL, P=0.251, P=0.251), tumor diameter (19.0±6.8 vs. 20.2±7.2 mm, P=0.400), and overall complications (11.3% vs. 10.2%, P=0.868). No significant difference was found in the specific factors between the 2 groups concerning RAIU-2h/24h (2.44±1.34 vs. 2.58±1.65%/2.83±3.75 vs. 2.35±3.44%, P=0.646/ P=0.506), number of dissected lymph nodes (4.4±1.4 vs. 4.6±1.5, P=0.595), Tg before radioiodine therapy (4.46±5.50 vs. 5.60±8.36; P=0.495), Tg after radioiodine therapy (1.03±1.93 vs. 1.11±1.61, P=0.812, P=0.812), postoperative nuclide imaging in thyroid area (1.76±1.50 vs. 2.19±1.85 cm2, P=0.195), PNILNSM before radioiodine (none: 79.2% vs. 83.7%, P=0.566; central: 17.0% vs. 12.2%, P=0.653; lateral: 1.9% vs. 4.1%, P=0.450; central+lateral: 1.9% vs. 0%, P=1.000), and PNILNSM after radioiodine (none: 94.3% vs. 95.9%, P=0.111; central: 3.8% vs. 2.0%, P=1.000; lateral: 0 vs. 2.0%, P=0.480; central+lateral: 1.9% vs. 0%, P=1.000).

Conclusions:

Transareola endoscopic total thyroidectomy and central lymph nodes dissection are safe and effective. According to the evaluated postoperative specific factors, this technique achieves similar outcomes to open surgery in selected patients with PTC.
Characterizing species interactions that contribute to biofilm formation in a multispecies model of a potable water bacterial community
Authors: Thompson Alex F. , English Erika L. , Nock Adam M. , Willsey Graham G. , Eckstrom Korin , Cairns Brynn , Bavelock Matthew , Tighe Scott W. , Foote Andrea , Shulman Hannah , Pericleous Androulla , Gupta Shilpi , Kadouri Daniel E. , Wargo Matthew J.
Published: October 2019

Microbial biofilms are ubiquitous in drinking water systems, yet our understanding of drinking water biofilms lags behind our understanding of those in other environments. Here, a six-member model bacterial community was used to identify the interactions and individual contributions of each species to community biofilm formation. These bacteria were isolated from the International Space Station potable water system and include

Cupriavidus metallidurans

,

Chryseobacterium gleum

, Ralstonia insidiosa, Ralstonia pickettii,

Methylorubrum

(Methylobacterium) populi and

Sphingomonas paucimobilis

, but all six species are common members of terrestrial potable water systems. Using reconstituted assemblages, from pairs to all 6 members, community biofilm formation was observed to be robust to the absence of any single species and only removal of the

C. gleum

/

S. paucimobilis

pair, out of all 15 possible 2-species subtractions, led to loss of community biofilm formation. In conjunction with these findings, dual-species biofilm formation assays supported the view that the contribution of

C. gleum

to community biofilm formation was dependent on synergistic biofilm formation with either

R. insidiosa

or

C. metallidurans

. These data support a model of multiple, partially redundant species interactions to generate robustness in biofilm formation. A bacteriophage and multiple predatory bacteria were used to test the resilience of the community to the removal of individual members in situ, but the combination of precise and substantial depletion of a single target species was not achievable. We propose that this assemblage can be used as a tractable model to understand the molecular bases of the interactions described here and to decipher other functions of drinking water biofilms.
Ocular hypertension drives remodeling of AMPA receptors in select populations of retinal ganglion cells
Authors: Sladek Asia L. , Nawy Scott
Published: October 2019

AMPA receptors in the CNS are normally impermeable to Ca2+ but aberrant expression of Ca2+-permeable AMPA receptors (CP-AMPARs) occurs in pathological conditions such as ischemia or epilepsy, or in degenerative diseases such as ALS. Here we show that select populations of retinal ganglion cells (RGCs) similarly express high levels of CP-AMPARs in a mouse model of glaucoma. CP-AMPAR expression increased dramatically in both α On and α transient Off RGCs, and this increase was prevented by genomic editing of the GluA2 Q/R site. α On RGCs with elevated CP-AMPAR levels displayed profound synaptic depression, which was reduced by selectively blocking CP-AMPARs, buffering Ca2+ with BAPTA, or with the CB1 antagonist AM251, suggesting that depression was mediated by a retrograde transmitter which might be triggered by influx of Ca2+ through CP-AMPARs. Thus OHT alters the composition of AMPARs and modulates patterns of synaptic activity in select populations of RGCs.
Rapid disruption of the cortical microcirculation after mild traumatic brain injury
Authors: Witkowski Ellen D. , Erdener Şefik Evren , Kılıç Kıvılcım , Kura Sreekanth , Tang Jianbo , Postnov Dmitry D. , Lee Esther , Kong Sunnie , Boas David A. , Davison Ian G.
Published: October 2019

Traumatic brain injury (TBI) is a major source of cognitive deficits affecting millions annually. The bulk of human injuries are mild, causing little or no macroscopic damage to neural tissue, yet can still lead to long-term neuropathology manifesting months or years later. Although the cellular stressors that ultimately lead to chronic pathology are poorly defined, one notable candidate is metabolic stress due to reduced cerebral blood flow (CBF), which is common to many forms of TBI. Here we used high-resolution in vivo intracranial imaging in a rodent injury model to characterize deficits in the cortical microcirculation during both acute and chronic phases after mild TBI. We found that CBF dropped precipitously during immediate post-injury periods, decreasing to less than half of baseline levels within minutes and remaining suppressed for 1.5-2 hours. Repeated time-lapse imaging of the cortical microvasculature revealed further striking flow deficits in the capillary network, where 18% of vessels were completely occluded for extended periods after injury, and an additional >50% showed substantial stoppages. Decreased CBF was paralleled by extensive vasoconstriction that is likely to contribute to loss of flow. Our data indicate a major role for vascular dysfunction in even mild forms of TBI, and suggest that acute post-injury periods may be key therapeutic windows for interventions that restore flow and mitigate metabolic stress.
Temporal contiguity training does not affect size-tolerant representations in object-selective cortex
Authors: Van Meel Chayenne , de Beeck Hans P. Op
Published: October 2019

The human visual system has a remarkable ability to reliably identify objects across variations in appearance, such as variations in viewpoint, lighting and size. Here we used fMRI in humans to test whether temporal contiguity training with natural and altered image dynamics can respectively build and break neural size tolerance for objects. Participants (N = 23) were presented with sequences of images of “growing” and “shrinking” objects. In half of the trials, the object also changed identity when the size change happened. According to the temporal contiguity hypothesis, and studies with a similar paradigm in monkeys, this training process should alter size tolerance. After the training phase, BOLD responses to each of the object images were measured in the scanner. Neural patterns in LOC and V1 contained information on size, similarity and identity. In LOC, the representation of object identity was partially invariant to changes in size. However, temporal contiguity training did not affect size tolerance in LOC. Size tolerance in human object-selective cortex is more robust to variations in input statistics than expected based on prior work in monkeys supporting the temporal contiguity hypothesis.
A quantitative narrative on movement, disease and patch exploitation in nesting agent groups
Authors: Getz Wayne M. , Salter Richard , Tallam Krti
Published: October 2019

Animal relocation data has recently become considerably more ubiquitous, finely structured (collection frequencies measured in minutes) and co-variate rich (physiology of individuals, environmental and landscape information, and accelerometer data). To better understand the impacts of ecological interactions, individual movement and disease on global change ecology, including wildlife management and conservation, it is important to have simulators that will provide demographic, movement, and epidemiology null models against which to compare patterns observed in empirical systems. Such models may then be used to develop quantitative narratives that enhance our intuition and understanding of the relationship between population structure and generative processes: in essence, along with empirical and experimental narratives, quantitative narratives are used to advance ecological epistemology. Here we describe a simulator that accounts for the influence of consumer-resource interactions, existence of social groups anchored around a central location, territoriality, group-switching behavior, and disease dynamics on population size. We use this simulator to develop new and reinforce existing quantitative narratives and point out areas for future study.

Author summary

The health and viability of species are of considerable concern to all nature lovers. Population models are central to our efforts to assess the numerical and ecological status of species and threats posed by climate change. Models, however, are crude caricatures of complex ecological systems. So how do we construct reliable assessment models able to capture processes essential to predicating the impacts of global change on population viability without getting tied up in their vast complexities? We broach this question and demonstrate how models focusing at the level of the individual (i.e., agent-based models) are tools for developing robust, narratives to augment narratives arising purely from empirical data sources and experimental outcomes. We do this in the context of nesting social groups, foraging for food, while exhibiting territoriality and group-switching behavior; and, we evaluate the impact of disease on the viability of such populations.
Brain Differences in the Prefrontal Cortex, Amygdala, and Hippocampus in Youth with Congenital Adrenal Hyperplasia
Authors: Herting Megan M. , Azad Anisa , Kim Robert , Geffner Mitchell E. , Kim Mimi S.
Published: October 2019

Context

Classical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency results in hormone imbalances present both prenatally and postnatally that may impact the developing brain.

Objective

To characterize gray matter morphology in the prefrontal cortex and subregion volumes of the amygdala and hippocampus in youth with CAH, compared to age- and sex-matched controls.

Design

A cross-sectional study of 27 CAH youth (16 female; 12.6 ± 3.4 year) and 35 typically developing, age- and sex-matched healthy controls (20 female; 13.0 ± 2.8 year) with 3-T magnetic resonance imaging scans. Brain volumes of interest included bilateral prefrontal cortex, and eight amygdala and six hippocampal subregions. Between-subject effects of group (CAH vs control) and sex, and their interaction (group-by-sex) on brain volumes were studied, while controlling for intracranial volume (ICV) and group differences in body mass index and bone age.

Results

CAH youth had smaller ICV and increased cerebrospinal fluid volume compared to controls. In fully-adjusted models, CAH youth had smaller bilateral, superior and caudal middle frontal volumes, and smaller left lateral orbito-frontal volumes compared to controls. Medial temporal lobe analyses revealed the left hippocampus was smaller in fully-adjusted models. CAH youth also had significantly smaller lateral nucleus of the amygdala and hippocampal subiculum and CA1 subregions.

Conclusions

This study replicates previous findings of smaller medial temporal lobe volumes in CAH patients, and suggests that lateral nucleus of the amygdala, as well as subiculum and subfield CA1 of the hippocampus are the most affected regions in CAH youth.

Précis

We collected brain scans of 27 youth with classical CAH and 35 healthy controls. Portions of the prefrontal cortex, amygdala, and hippocampus were smaller in CAH youth compared to controls.

Disclosure Summary

MEG receives grant support from Novo Nordisk; consultant fees from Daiichi Sankyo, Ferring, Novo Nordisk, Nutrition & Growth Solutions, Pfizer, Sandoz, and Spruce Biosciences; serves on data safety monitoring boards for Ascendis, Millendo, and Tolmar; and receives royalties from McGraw-Hill and UpToDate.
A role of hypoxia inducible factor 1 alpha in Mouse Gammaherpesvirus 68 (MHV68) lytic replication and reactivation from latency
Authors: López-Rodríguez Darlah M. , Kirillov Varvara , Krug Laurie T. , Mesri Enrique A. , Andreansky Samita
Published: October 2019

The hypoxia inducible factor 1 alpha (HIFIα) protein and the hypoxic microenvironment are critical for infection and pathogenesis by the oncogenic gammaherpesviruses (γHV) such as Kaposi’ Sarcoma-associated Herpes Virus (KSHV) and Epstein-Barr virus (EBV). However, understanding the role of HIFIα during the virus life cycle and its biological relevance in the context of host pathogenesis has been challenging due to the lack of animal models for human γHV. To study the role of HIFIα we employed the murine gammaherpesvirus 68 (MHV68), a rodent pathogen that readily infects laboratory mice. We show that MHV68 infection induces HIFIα protein and HIFIα-responsive gene expression in permissive cells. Deletion of HIFIα reduces virus production due to a global downregulation of viral gene expression. Most notable was the marked decrease in many viral genes bearing hypoxia regulatory element (HRE) such as viral G-Protein Coupled Receptor (vGPCR), which is known to activate HIF1α transcriptional activity during KSHV infection. Intranasal infection of HIF1αLoxP/LoxPmice with MHV68 expressing Cre-recombinase impaired virus expansion during early acute infection and affected lytic reactivation in the splenocytes explanted from mice. Moreover, low oxygen conditions accelerated lytic reactivation and enhanced virus production in MHV68 infected splenocytes. Thus, we conclude that HIFIα plays a critical role to promote virus replication. Our results highlight the importance of the mutual interactions of the oxygen-sensing machinery and gammaherpesviruses in viral replication and pathogenesis.

AUTHOR SUMMARY

The host oxygen sensing machinery including the HIF1α pathway is important during the viral life cycle of oncogenic gammaherpesviruses such as KSHV and EBV. However, due to the host specificity, the effects of HIF1α in herpes biology is limited to studies within vitrosystems. Here, we study the role of HIF1α using the mouse gammaherpesvirus 68 (MHV68) that readily infects laboratory mice. We demonstrate that MHV68 infection upregulates HIF1α during replication and inactivation of HIF1α transcriptional activity significantly decreased viral genes expression which results in impaired virus productionin vitro. In vivo deletion of HIF1α impaired viral expansion during acute infection and affected reactivation from latency. These results show the importance of the interplay with the oxygen-sensing machinery in gammaherpesvirus infection and pathogenesis, placing the MHV68 mouse model as a unique platform to gain insight into this important aspect of oncogenic gamma-herpesviruses biology and to test HIF1α targeted therapeutics.
Pollinators in food webs: Mutualistic interactions increase diversity, stability, and function in multiplex networks
Authors: Hale Kayla R. S. , Valdovinos Fernanda S. , Martinez Neo D.
Published: October 2019

Ecosystems are composed of complex networks of many species interacting in different ways. While ecologists have long studied food webs of feeding interactions, recent studies increasingly focus on mutualistic networks including plants that exchange food for reproductive services provided by animals such as pollinators. Here, we synthesize both types of consumer-resource interactions to better understand the controversial effects of mutualism on ecosystems at the species, guild, and whole-community levels. We find that consumer-resource mechanisms underlying plant-pollinator mutualisms can increase the persistence, productivity, abundance, and temporal stability of both mutualists and non-mutualists in food webs. These effects strongly increase with floral reward productivity and are qualitatively robust to variation in the prevalence of mutualism and pollinators feeding upon resources in addition to rewards. This work advances the ability of mechanistic network theory to synthesize different types of interactions and illustrates how mutualism can enhance the diversity, stability, and function of complex ecosystems.
Multiplex in situ hybridization within a single transcript: RNAscope reveals dystrophin mRNA dynamics
Authors: Hildyard J.C.W. , Rawson F. , Wells D.J. , Piercy R.J.
Published: October 2019

Dystrophin plays a vital role in maintaining muscle health, yet low mRNA expression, lengthy transcription time and the limitations of traditional in-situ hybridization (ISH) methodologies mean that the dynamics of dystrophin transcription remain poorly understood. RNAscope is highly sensitive ISH method that can be multiplexed, allowing detection of individual transcripts at sub-cellular resolution, with different target mRNAs assigned to distinct fluorophores. We present a novel approach, instead using RNAscope probes targeted to 5’ and 3’ regions of the same transcript: labelling muscle dystrophin mRNA in this manner allows transcriptional dynamics to be deciphered in health and disease, resolving both nascent myonuclear transcripts and exported mature mRNAs (the latter absent in dystrophic muscle, yet restored following therapeutic intervention). We show that even in healthy muscle, immature dystrophin mRNA predominates (60-80% of total), with the surprising implication that the half-life of a mature transcript is markedly shorter than the time invested in transcription: at the transcript level, supply may exceed demand. Our findings provide unique spatiotemporal insight into the behaviour of this long transcript (with implications for therapeutic approaches), and further suggests this modified multiplex ISH approach is well-suited to long genes, offering a highly tractable means to reveal complex transcriptional dynamics.
Distributed and Retinotopically Asymmetric Processing of Coherent Motion in Mouse Visual Cortex
Authors: Sit Kevin K. , Goard Michael J.
Published: October 2019

Perception of visual motion is important for a range of ethological behaviors in mammals. In primates, specific higher visual cortical regions are specialized for processing of coherent visual motion. However, the distribution of motion processing among visual cortical areas in mice is unclear, despite the powerful genetic tools available for measuring population neural activity. Here, we used widefield and 2-photon calcium imaging of transgenic mice expressing a calcium indicator in excitatory neurons to measure mesoscale and cellular responses to coherent motion across the visual cortex. Imaging of primary visual cortex (V1) and several higher visual areas (HVAs) during presentation of natural movies and random dot kinematograms (RDKs) revealed heterogeneous responses to coherent motion. Although coherent motion responses were observed throughout visual cortex, particular HVAs in the putative dorsal stream (PM, AL, AM) exhibited stronger responses than ventral stream areas (LM and LI). Moreover, beyond the differences between visual areas, there was considerable heterogeneity within each visual area. Individual visual areas exhibited an asymmetry across the vertical retinotopic axis (visual elevation), such that neurons representing the inferior visual field exhibited greater responses to coherent motion. These results indicate that processing of visual motion in mouse cortex is distributed unevenly across visual areas and exhibits a spatial bias within areas, potentially to support processing of optic flow during spatial navigation.
Division of labour promotes the spread of information in colony emigrations by the antTemnothorax rugatulus
Authors: Valentini Gabriele , Masuda Naoki , Shaffer Zachary , Hanson Jake R. , Sasaki Takao , Walker Sara Imari , Pavlic Theodore P. , Pratt Stephen C.
Published: October 2019

The fitness of group-living animals often depends on how well members share information needed for collective decision-making. Theoretical studies have shown that collective choices can emerge in a homogeneous group of individuals following identical rules, but real animals show much evidence for heterogeneity in the degree and nature of their contribution to group decisions. In social insects, for example, the transmission and processing of information is influenced by a well-organized division of labour. Studies that accurately quantify how this behavioural heterogeneity affects the spread of information among group members are still lacking. In this paper, we look at nest choices during colony emigrations of the antTemnothorax rugatulusand quantify the degree of behavioural heterogeneity of workers. Using methods from both machine learning and network analysis, we identify and characterize four behavioural castes of workers – primary, secondary, passive, and wandering – covering distinct roles in the spread of information during each emigration. This detailed characterization of the contribution of each worker can improve models of collective decision-making in this species and promises a deeper understanding of behavioural variation at the colony level.
Cortico-cortical feedback from V2 exerts a powerful influence over the visually evoked local field potential and associated spike timing in V1
Authors: Hartmann Till S. , Raja Sruti , Lomber Stephen G. , Born Richard T.
Published: October 2019

The local field potential (LFP) is generally thought to be dominated by synaptic activity within a few hundred microns of the recording electrode. The sudden onset of a visual stimulus causes a large downward deflection of the LFP recorded in primary visual cortex, known as a visually evoked potential (VEP), followed by rhythmic oscillations in the gamma range (30-80 Hz) that are often in phase with action potentials of nearby neurons. By inactivating higher visual areas that send feedback projections to V1, we produced a large decrease in amplitude of the VEP, and a strong attenuation of gamma rhythms in both the LFP and multi-unit activity, despite an overall increase in neuronal spike rates. Our results argue that much of the recurrent, rhythmic activity measured in V1 is strongly gated by feed-back from higher areas, consistent with models of coincidence detection that result in burst firing by layer 5 pyramidal neurons.
N-Acetyl Cysteine Abrogates Silver-Induced Reactive Oxygen Species in Human Cells Without Altering Silver-based Antimicrobial Activity
Authors: Shah Kush N. , Shah Parth N. , Mullen Andrew R. , Chen Qingquan , DeBerardinis Ralph J. , Cannon Carolyn L.
Published: October 2019

Silver-based antimicrobials are widely used topically to treat infections associated with multi-drug resistant (MDR) pathogens. Expanding this topical use to aerosols to treat lung infections requires understanding and preventing silver toxicity in the respiratory tract. A key mechanism resulting in silver-induced toxicity is the production of reactive oxygen species (ROS). In this study, we have verified ROS generation in silver-treated bronchial epithelial (16HBE) cells prompting evaluation of three antioxidants, N-acetyl cysteine (NAC), ascorbic acid, and melatonin, to identify potential prophylactic agents. Among them, NAC was the only candidate that abrogated the ROS generation in response to silver exposure resulting in the rescue of these cells from silver-associated toxicity. Further, this protective effect directly translated to restoration of metabolic activity, as demonstrated by the normal levels of citric acid cycle metabolites in NAC-pretreated silver-exposed cells. As a result of the normalized citric acid cycle, cells pre-incubated with NAC demonstrated significantly higher levels of adenosine triphosphate (ATP) levels compared with NAC-free controls. Moreover, we found that this prodigious capacity of NAC to rescue silver-exposed cells was due not only to its antioxidant activity, but also to its ability to directly bind silver. Despite binding to silver, NAC did not alter the antimicrobial activity of silver.

Importance

Although silver is a potent, broad-spectrum antibiotic, silver-induced toxicity, primarily due to generation of ROS, remains a concern limiting its use beyond treatment of wounds. NAC has been widely used as an antioxidant to rescue eukaryotic cells from metal-associated toxicity. Thus, we have evaluated the capacity of NAC to abrogate silver toxicity in a human bronchial epithelial cell line (16HBE) as a step towards expanding the use of silver-based antimicrobials to treat lung infections. We found that NAC pre-incubation resurrects a healthy metabolic state in bronchial epithelial cells exposed to silver ions via a combination of its antioxidant and metal-binding properties. Finally, this ability of NAC to rescue silver-exposed eukaryotic cells does not alter the antimicrobial activity of silver. Thus, a silver-NAC combination holds tremendous potential as a future, non-toxic antimicrobial agent.
Evaluation of IL-1 blockade as an adjunct to linezolid therapy for tuberculosis in mice and macaques
Authors: Winchell Caylin G. , Mishra Bibhuti B. , Phuah Jia Yao , Saqib Mohd , Nelson Samantha J. , Maiello Pauline , Causgrove Chelsea M. , Ameel Cassaundra L. , Stein Brianne , Borish H. Jacob , White Alexander G. , Klein Edwin C. , Zimmerman Matthew D. , Dartois Véronique , Lin Philana Ling , Sassetti Christopher M. , Flynn JoAnne L.
Published: October 2019

In 2017 over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) occurred, emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic for drug-resistant Gram-positive infections and is an effective treatment for TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. LZD toxicities may be mediated by IL-1, an inflammatory pathway important for early immunity during M. tuberculosis infection. However, IL-1 can contribute to pathology and disease severity late in TB progression. Since IL-1 may contribute to LZD toxicity and does influence TB pathology, we targeted this pathway with a potential host-directed therapy (HDT). We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce bone marrow toxicity and TB associated-inflammation. We used two animal models of TB to test our hypothesis, a TB-susceptible mouse model and clinically relevant cynomolgus macaques. Antagonizing IL-1 in mice with established infection reduced lung neutrophil numbers and partially restored the erythroid progenitor populations that are depleted by LZD. In macaques, we found no conclusive evidence of bone marrow suppression associated with LZD, indicating our treatment time may have been short enough to avoid the toxicities observed in humans. Though treatment was only 4 weeks (the FDA approved regimen at the time of study), we observed sterilization of the majority of granulomas regardless of co-administration of the FDA-approved IL-1 receptor antagonist (IL-1Rn), also known as Anakinra. However total lung inflammation was significantly reduced in macaques treated with IL-1Rn and LZD compared to LZD alone. Importantly, IL-1Rn administration did not impair the host response against Mtb or LZD efficacy in either animal model. Together, our data support that inhibition of IL-1 in combination with LZD has potential to be an effective HDT for TB and the need for further research in this area.
Cell-to-cell expression dispersion of B-cell surface proteins displays genetic variation among humans
Authors: Triqueneaux Gérard , Burny Claire , Symmons Orsolya , Janczarski Stéphane , Gruffat Henri , Yvert Gaël
Published: October 2019

Variability in gene expression across a population of homogeneous cells is known to influence various biological processes. In model organisms, natural genetic variants were found that modify expressiondispersion(variability at a fixed mean) but whether such effects exist in humans has not been fully demonstrated. Here, we analyzed single-cell expression of four proteins (CD23, CD55, CD63 and CD86) across cell lines derived from individuals of the Yoruba population. Using data from over 30 million cells, we found substantial inter-individual variation of dispersion. We demonstrate, viade novocell line generation and subcloning experiments, that this variation exceeds the variation associated with cellular immortalization. By association mapping, we linked the expression dispersion of CD63 to thers971SNP. Our results show that human DNA variants can have inherently-probabilistic effects on gene expression. Such subtle genetic effects may participate to phenotypic variation and disease predisposition.
PRMT5 in T helper lymphocytes is essential for cholesterol biosynthesis-mediated Th17 responses and autoimmunity
Authors: Webb Lindsay M. , Sengupta Shouvonik , Edell Claudia , Amici Stephanie A. , Narvaez-Miranda Janiret , Kennemer Austin , Guerau-de-Arellano Mireia
Published: October 2019

Protein Arginine Methyltransferase (PRMT) 5 catalyzes symmetric dimethylation of arginine, a post-translational modification involved in cancer and embryonic development. However, the role of PRMT5 in T helper (Th) cell polarization and Th cell-mediated disease has not yet been elucidated. Here we report that PRMT5 is necessary for Th17 differentiation and EAE, via enhancement of cholesterol biosynthesis and activation of ROR-γt. PRMT5 additionally controls thymic and peripheral homeostasis in the CD4 Th cell life cycle, as well as iNK T and CD8 T cell development or maintenance, respectively. Overall, our two conditional PRMT5 KO models that selectively delete PRMT5 in all T cells (T-PRMT5Δ/Δ) or Th cells (iCD4-PRMT5Δ/Δ) unveil a crucial role for PRMT5 in T cell proliferation, Th17 responses and disease. These results point to Th PRMT5 and its downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17-mediated diseases.
Daughterless, theDrosophilaorthologue of TCF4, is required for associative learning and maintenance of synaptic proteome
Authors: Tamberg Laura , Jaago Mariliis , Säälik Kristi , Shubina Anastassia , Kiir Carl Sander , Sirp Alex , Timmusk Tõnis , Palgi Mari
Published: October 2019

Mammalian Transcription Factor 4 (TCF4) has been linked to schizophrenia and intellectual disabilities like Pitt-Hopkins syndrome (PTHS). Here we show that similarly to mammalian TCF4, fruit fly orthologue Daughterless (Da) is expressed in theDrosophilabrain structures associated with learning and memory, the mushroom bodies. Furthermore, silencing ofdain mushroom body neurons impairs appetitive associative learning of the larvae and leads to decreased levels of the synaptic proteins Synapsin (Syn) and discs large 1 (dlg1) suggesting the involvement of Da in memory formation. Here we demonstrate thatSynanddlg1are direct target genes of Da in adultDrosophilaheads, since Da binds to the regulatory regions of these genes and the modulation of Da levels alter the levels ofSynanddlg1mRNA. Silencing ofdaalso affects negative geotaxis of the adult flies suggesting the impairment of locomotor function. Overall, our findings suggest that Da regulatesDrosophilalarval memory and adult negative geotaxis possibly via its synaptic target genesSynanddlg1. These behavioural phenotypes can be further used as a PTHS model to screen for therapeutics.

Summary statement

Human TCF4, a bHLH transcription factor, is associated with intellectual disability and schizophrenia. Here we propose aDrosophilamodel for human disease studies using TCF4 orthologue in fruit fly, Daughterless.
A vast resource of allelic expression data spanning human tissues
Authors: Castel Stephane E. , Aguet François , Mohammadi Pejman ,   GTEx Consortium, Ardlie Kristin G. , Lappalainen Tuuli
Published: October 2019

Allele specific expression (ASE) analysis robustly measurescisregulatory effects. Here, we present a vast ASE resource generated from the GTEx v8 release, containing 15,253 samples spanning 54 human tissues for a total of 431 million measurements of ASE at the SNP-level and 153 million measurements at the haplotype-level. In addition, we developed an extension of our tool phASER that allows effect sizes ofcisregulatory variants to be estimated using haplotype-level ASE data. This ASE resource is the largest to date and we are able to make haplotype-level data publicly available. We anticipate that the availability of this resource will enable future studies of regulatory variation across human tissues.