bluuebunny/crossref_metadata_2025 huggingface dataset:
Two cases of left recurrent laryngeal nerve paralysis after right superior mediastinal node dissection
Authors: Nakamura Yasuyuki , Shindo Yuma , Arai Wataru , Tsuruta Kodai , Maki Ryunosuke , Miyajima Masahiro , Watanabe Atsushi
Published: June 2021

Background

Ipsilateral recurrent laryngeal nerve paralysis is one of the rare complications during the superior mediastinal node dissection for lung cancer. However, very few reports of contralateral recurrent laryngeal nerve paralysis during the procedure are available.

Case presentation

Two women aged 74 and 80 years developed hoarseness after undergoing right upper lobectomy and right superior mediastinal node dissection for primary lung cancer. Postoperative laryngoscopy in the two patients confirmed left vocal cord paralysis.

Conclusion

Node dissection is performed in the standard procedure for right upper lobe lung cancer. At this time, care must be taken not to cause damage not only to the recurrent laryngeal nerve on the ipsilateral side but also to the recurrent laryngeal nerve on the contralateral side.
Sleep Habits of Women With Infertility
Authors: Eisenberg Esther , Legro Richard S , Diamond Michael P , Huang Hao , O’Brien Louise M , Smith Yolanda R , Coutifaris Christos , Hansen Karl R , Santoro Nanette , Zhang Heping
Published: June 2021

Context

Sleep plays important roles in metabolic and reproductive function, and polycystic ovary syndrome (PCOS) is associated with sleep disturbances, including increased prevalence of obstructive sleep apnea.

Objective

We sought to evaluate sleep parameters in infertile women with PCOS compared with women with unexplained infertility (UI) and identify risk factors for disturbed sleep.

Methods

At private and academic ambulatory gynecology and infertility practices, we evaluated a prospective cohort of women diagnosed with PCOS or UI from 2 randomized clinical trials. We included 1603 infertile women enrolled in 2 concurrent randomized clinical trials. The main outcome measures were self-reported sleep measures.

Results

Sleep duration <6 hours (6.1% vs 2.7%; P < .001), habitual snoring (37.8% vs 19.0%; P < .001), and clinical sleepiness (12.0% vs 8.6%; P < .026) were more common in women with PCOS than those with UI. After adjusting for covariates, PCOS and elevated fasting insulin were associated (P = .010) with clinical symptoms of obstructive sleep apnea (OSA) diagnosis, whereas PCOS, elevated insulin (P = .003), WC >88 cm (P = .003), and current smoking (P = .012) were associated with habitual snoring. Clinical depression score (P < .001) and PCOS diagnosis (P = .002) were associated with perceived daytime sleepiness. Short sleep duration and clinical symptoms of OSA were not associated with conception and live birth rates.

Conclusion

Infertile women with PCOS more commonly report sleep disturbances than those with UI. Markers of insulin resistance are associated with previous diagnosis of OSA, habitual snoring, and short sleep duration. The presence of clinical symptoms of OSA or short sleep duration does not affect fertility treatment response.
Targeting Glucocorticoid Metabolism in Prostate Cancer
Authors: Valle Shelley , Sharifi Nima
Published: June 2021

In the treatment of metastatic prostate cancer, resistance to hormonal therapy is a major obstacle. With antiandrogen therapies that suppress androgen signaling through the androgen receptor (AR), the primary driver of prostate cancer, some malignancies are able take advantage of the closely related glucocorticoid receptor (GR). Escape from AR dependency often involves a simple functional switch from 1 steroid receptor to another. Recent research efforts have outlined the mechanism enabling this switch, which involves alterations in glucocorticoid metabolism that occur with antiandrogen therapy to increase tumor tissue glucocorticoids and enable GR signaling. Targeting this mechanism pharmacologically by blocking hexose-6-phosphate dehydrogenase shows promise in normalizing glucocorticoid metabolism and restoring responsiveness to antiandrogen therapy. This perspective reviews what we have learned about this resistance mechanism, examines potential implications, and considers how this knowledge might be harnessed for therapeutic benefit.
The β Cell in Diabetes: Integrating Biomarkers With Functional Measures
Authors: Kahn Steven E , Chen Yi-Chun , Esser Nathalie , Taylor Austin J , van Raalte Daniël H , Zraika Sakeneh , Verchere C Bruce
Published: June 2021

The pathogenesis of hyperglycemia observed in most forms of diabetes is intimately tied to the islet β cell. Impairments in propeptide processing and secretory function, along with the loss of these vital cells, is demonstrable not only in those in whom the diagnosis is established but typically also in individuals who are at increased risk of developing the disease. Biomarkers are used to inform on the state of a biological process, pathological condition, or response to an intervention and are increasingly being used for predicting, diagnosing, and prognosticating disease. They are also proving to be of use in the different forms of diabetes in both research and clinical settings. This review focuses on the β cell, addressing the potential utility of genetic markers, circulating molecules, immune cell phenotyping, and imaging approaches as biomarkers of cellular function and loss of this critical cell. Further, we consider how these biomarkers complement the more long-established, dynamic, and often complex measurements of β-cell secretory function that themselves could be considered biomarkers.
Investigating Music-Dance Relationships
Authors: Haugen Mari Romarheim
Published: June 2021

This article studies the rhythm of Norwegian telespringar, a tradition with an intimate relationship between music and dance that features a nonisochronous meter; that is, the durations between adjacent beats are unequal. A motion-capture study of a fiddler and dance couple revealed a long-medium-short duration pattern at the beat level in both the fiddler's and the dancers' periodic movements. The results also revealed a correspondence between how the fiddler and the dancers executed the motion patterns. This correspondence suggests that the performers share a common understanding of the underlying “feel” of the music. The results are discussed in light of recent theoretical perspectives on the multimodality of human perception. It is argued that the special feel of telespringar derives from embodied sensations related to the dance and how music and dance have developed in tandem over time. The study advocates a holistic view of music and dance, the importance of insider experience, and the role of embodied experience in guiding our understanding of the music as such.
A Network of Thrones: Kinship and Conflict in Europe, 1495–1918
Authors: Benzell Seth G. , Cooke Kevin
Published: June 2021

We construct a database linking European royal kinship networks, monarchies, and wars to study the effect of family ties on conflict. To establish causality, we exploit decreases in connection caused by apolitical deaths of rulers’ mutual relatives. These deaths are associated with substantial increases in the frequency and duration of war. We provide evidence that these deaths affect conflict only through changing the kinship network. Over our period of interest, the percentage of European monarchs with kinship ties increased threefold. Together, these findings help explain the well-documented decrease in European war frequency. (JEL D74, N33, N34, N43, N44, Z12, Z13)
Credit Rationing and Pass-Through in Supply Chains: Theory and Evidence from Bangladesh
Authors: Emran M. Shahe , Mookherjee Dilip , Shilpi Forhad , Uddin M. Helal
Published: June 2021

Traders are often blamed for high prices, prompting government regulation. We study the effects of a government ban of a layer of financing intermediaries in edible oil supply chain in Bangladesh during 2011–2012. Contrary to the predictions of a standard model of an oligopolistic supply chain, the ban caused downstream wholesale and retail prices to rise, and pass-through of the changes in imported crude oil price to fall. These results can be explained by an extension of the standard model to incorporate trade credit frictions, where intermediaries expand credit access of downstream traders. (JEL L13, L14, L66, O13, Q11, Q13, Q17)
Communication Infrastructure and Stabilizing Food Prices: Evidence from the Telegraph Network in China
Authors: Gao Pei , Lei Yu-Hsiang
Published: June 2021

This paper exploits a unique historical setting—the expansion of the telegraph network in nineteenth-century China when railroads were limited—to examine whether the reduction of information frictions stabilizes grain prices. Employing a difference-in-difference (DID) strategy, we find that the telegraph access (i) reduced both the magnitude and the incidence of extreme prices; (ii) mitigated price responses to local weather shocks but increased the responsiveness to shocks in other telegraph-connected regions; (iii) affected the price volatility in a mean-reverting pattern; i.e., volatility rose in previously price-stable regions, and volatility decreased in price-unstable regions. (JEL D83, L96, N55, N75, O13, O18, Q11)
Uber versus Taxi: A Driver’s Eye View
Authors: Angrist Joshua D. , Caldwell Sydnee , Hall Jonathan V.
Published: June 2021

Rideshare drivers pay a proportion of their fares to a ride-hailing platform operator, a commission-based compensation model used by many service providers. To Uber drivers, this commission is known as the Uber fee. By contrast, traditional taxi drivers in most US cities make a fixed payment independent of their earnings, usually a weekly or daily medallion lease, keeping every fare dollar net of lease costs and other expenses. We assess these compensation models using an experiment that offered random samples of Boston Uber drivers opportunities to lease a virtual taxi medallion that eliminates the Uber fee. Some drivers were offered a negative fee. Drivers’ labor supply response to our offers reveals a large intertemporal substitution elasticity, on the order of 1.2, and higher for those who accept lease contracts. At the same time, our virtual lease program was undersubscribed: many drivers who would have benefited from buying an inexpensive lease chose to sit out. We use these results to compute the average compensation required to make drivers indifferent between rideshare and taxi-style compensation contracts. The results suggest that rideshare drivers gain considerably from the opportunity to drive without leasing. (JEL J22, J31, L84, L92)
Narratives of Value in Richard Brome’s Dispute with the Salisbury Court
Authors: Ryner Bradley
Published: June 2021

The bill and answer for the 1640 court of request proceedings constitute the extant evidence of the terms of two contracts between Richard Brome and the Salisbury Court, one signed in 1635 and the other drafted in 1638 but unsigned. Inferring from these documents key differences between the contracts, this essay argues that the first contract left crucial ambiguities about the value of Brome’s labour, and the company attempted to resolve these ambiguities to its advantage through the second contract and the bill of complaint. This evidence suggests a primarily antagonistic relationship between Brome and the Salisbury Court from 1636.
Music, Community, and Middleton's Anti-Masque in The Witch
Authors: Loeb Andrew
Published: June 2021

This essay argues that the music in Middleton’s The Witch (c.1616), largely dismissed as unsophisticated spectacle by critics, is one of the play’s most innovative features. The witches’ songs implicitly critique the patriarchal order that has led to the dysfunctional intrigues of the courtly world from which they are excluded and offer the audience an alternative centred on a joyful, supportive community of women. To do this, Middleton’s play subverts the musical dynamics of Ben Jonson’s Masque of Queens (1609), deconstructing conventional associations between music and social harmony, and inviting the audience to explore alternative social formations.
‘Noe Place to Talk In’: Two More Brawling Playgoers and the 1626 Attempt to Close the Blackfriars Playhouse
Authors: Pangallo Matteo
Published: June 2021

Drawing on two previously unnoticed documents, this note identifies two new named early modern playgoers and connects their playgoing to the 1626 petition to close the Blackfriars theatre.
The Personation of John Suckling, 1635
Authors: Doelman James
Published: June 2021

The letters of Anthony Mingay indicate that in early 1635 Sir John Suckling was satirically personated in an unnamed play. This article considers Richard Brome’s The Sparagus Garden and James Shirley’s The Lady of Pleasure as possible candidates to be this play. It concludes, however, that the cowardly braggart soldier Sucket in Henry Glapthorne’s The Lady Mother is the most likely personation of Suckling, as the humiliating beating of that character most closely aligns with the attack on Suckling by Sir John Digby as described in Mingay’s letters.
Development of a Large Pneumatocele in a Patient Recovering from COVID-19 Pneumonitis
Authors: Hampson Frances , Salih Waleed , Jennifer Helm Jennifer Helm
Published: June 2021

A 39-year-old man presented with severe COVID-19 pneumonitis requiring hospital admission. He represented three days following discharge with sudden onset breathlessness and chest pain. Initial imaging suggested the presence of a left pneumothorax. Following further clinical decline a plan was made to insert a CT guided chest drain. However, imaging in the prone position for the procedure unexpectedly revealed a large left lower lobe pneumatocele with only a very small pneumothorax. Events and appearances suggest that this is a rare case of delayed COVID-19 pneumonitis-related pneumatocele formation. We will discuss the clinical significance of this entity.
Research Roundup
Authors: Cook Neal F
Published: June 2021

Neal Cook provides a synopsis and brief review of a selection of recently published research articles that are of interest to neuroscience nurses, highlighting key points to keep you up to date; a full reference is provided for those who wish to read the research in more detail
The importance of lavage in wound care
Authors: Bell Samantha
Published: June 2021

Open wound management in veterinary practice is commonplace, with the aim to provide the optimum wound condition to help aid healing and closure of the wound. There are four main principles of wound management needed to provide a healing environment. There needs to be identification and control of any infection and contamination, and wound necrosis needs to be controlled, any ongoing deterioration in the wound controlled and acted on and any further damage to the wound needs to be prevented. This article looks at lavage, one of the most important firstline methods in controlling infection and discusses how it is performed.
An evaluation into the effectiveness of surgical safety checklists in veterinary procedures
Authors: Orjefelt Ebba
Published: June 2021

Background:

Extensive research has been conducted evaluating surgical safety checklists in human medicine, but comparative research is lacking within veterinary medicine.

Aim

To evaluate the possible benefits of applying a surgical safety checklist to veterinary procedures.

Methods:

The checklist, created by the Association of Veterinary Anaesthetists (AVA), was applied to roughly 50% of patients undergoing surgical procedures in a veterinary practice in Edinburgh, Scotland during an 8-week period in 2020. The remaining 50% was not subjected to a checklist and was therefore used as a control group.

Results:

With the application of the checklist, the practices participating in the study experienced a 4% decrease in postoperative complications, although this was not statistically significant.

Conclusion:

The frequency of postoperative complications after surgical procedures reduced following the introduction of surgical safety checklists.
The contribution of the histopathological examination to the diagnosis of adverse local tissue reactions in arthroplasty
Authors: Perino Giorgio , De Martino Ivan , Zhang Lingxin , Xia Zhidao , Gallo Jiri , Natu Shonali , Langton David , Huber Monika , Rakow Anastasia , Schoon Janosch , Gomez-Barrena Enrique , Krenn Veit
Published: June 2021

The histopathological examination of the periprosthetic soft tissue and bone has contributed to the identification and description of the morphological features of adverse local tissue reactions (ALTR)/adverse reactions to metallic debris (ARMD). The need of a uniform vocabulary for all disciplines involved in the diagnosis and management of ALTR/ARMD and of clarification of the parameters used in the semi-quantitative scoring systems for their classification has been considered a pre-requisite for a meaningful interdisciplinary evaluation. This review of key terms used for ALTR/ARMD has resulted in the following outcomes: (a) pseudotumor is a descriptive term for ALTR/ARMD, classifiable in two main types according to its cellular composition defining its clinical course; (b) the substitution of the term metallosis with presence of metallic wear debris, since it cannot be used as a category of implant failure or histological diagnosis; (c) the term aseptic lymphocytic-dominated vasculitis- associated lesion (ALVAL) should be replaced due to the absence of a vasculitis with ALLTR/ALRMD for lymphocytic-predominant and AMLTR/AMRMD for macrophage-predominant reaction. This review of the histopathological classifications of ALTR/ARMD has resulted in the following outcomes: (a) distinction between cell death and tissue necrosis; (b) the association of corrosion metallic debris with adverse local lymphocytic reaction and tissue necrosis; (c) the importance of cell and particle debris for the viscosity and density of the lubricating synovial fluid; (d) a consensus classification of lymphocytic infiltrate in soft tissue and bone marrow; (e) evaluation of the macrophage infiltrate in soft tissues and bone marrow; (f) classification of macrophage induced osteolysis/aseptic loosening as a delayed type of ALTR/ARMD; (g) macrophage motility and migration as possible driving factor for osteolysis; (h) usefulness of the histopathological examination for the natural history of the adverse reactions, radiological correlation, post-marketing surveillance, and implant registries. The review of key terms used for the description and histopathological classification of ALTR/ARMD has resulted in a comprehensive, new standard for all disciplines involved in their diagnosis, clinical management, and long-term clinical follow-up.

Cite this article: EFORT Open Rev 2021;6:399-419. DOI: 10.1302/2058-5241.6.210013
Complications of hip preserving surgery
Authors: Hanke Markus S. , Lerch Till D. , Schmaranzer Florian , Meier Malin K. , Steppacher Simon D. , Siebenrock Klaus A.
Published: June 2021

Preoperative evaluation of the pathomorphology is crucial for surgical planning, including radiographs as the basic modality and magnetic resonance imaging (MRI) and case-based additional imaging (e.g. 3D-CT, abduction views). Hip arthroscopy (HAS) has undergone tremendous technical advances, an immense increase in use and the indications are getting wider. The most common indications for revision arthroscopy are labral tears and residual femoroacetabular impingement (FAI). Treatment of borderline developmental dysplastic hip is currently a subject of controversy. It is paramount to understand the underlining problem of the individual hip and distinguish instability (dysplasia) from FAI, as the appropriate treatment for unstable hips is periacetabular osteotomy (PAO) and for FAI arthroscopic impingement surgery. PAO with a concomitant cam resection is associated with a higher survival rate compared to PAO alone for the treatment of hip dysplasia. Further, the challenge for the surgeon is the balance between over- and undercorrection. Femoral torsion abnormalities should be evaluated and evaluation of femoral rotational osteotomy for these patients should be incorporated to the treatment plan.

Cite this article: EFORT Open Rev 2021;6:472-486. DOI: 10.1302/2058-5241.6.210019
Stable directional emission in active optical waveguides shielding external environmental influences
Authors: Chen Yikai , Kong Zhuoran , Chen Fulian , Ding Binxuan , Zhang Lu , Cui Shan , Zhang Hongchao
Published: June 2021

The skillful confinement of light brought by the composite waveguide structure has shown great possibilities in the development of photonic devices. It has greatly expanded the application range of an on-chip system in dark-field imaging and confined the laser when containing an active medium. Here we experimentally proved a stable directional emission in an active waveguide composed of metal and photonic crystal, which is almost completely unaffected by the external environment and different from the common local light field that is seriously affected by the structure. When the refractive index of samples on the surface layer changes, it can ensure the constant emission intensity of the internal mode, while still retaining the external environmental sensitivity of the surface mode. It can also be used for imaging and sensing as a functional slide. This research of chip-based directional emission is very promising for various applications including quantitative detection of biological imaging, coupled emission intensity sensing, portable imaging equipment, and tunable micro lasers.
Dynamically stable single frequency ring resonator from diode pumped Nd:YAG modules with 55.6 W of output power
Authors: Bereczki Allan , Ferreira Amauri Agostinho , Wetter Niklaus Ursus
Published: June 2021

A Nd:YAG rod single-frequency ring laser based on side-pumped commercial modules is presented. Thermally induced birefringence compensation was applied in a dynamically stable resonator providing 55.6 W of continuous, linearly polarized, TEM00 output. The particular case of a symmetric ring resonator containing one or two focusing rods and a pair of curved mirrors was analyzed and a design technique is presented, allowing for easy, continuous shaping of the stability limits by changing only the distances in the resonator.
Rigorous signal reconstruction in terahertz emission spectroscopy
Authors: Zhang Wentao , Turchinovich Dmitry
Published: June 2021

Terahertz (THz) emission spectroscopy is a powerful method that allows one to measure the ultrafast dynamics of polarization, current, or magnetization in a material based on THz emission from the material. However, the practical implementation of this method can be challenging, and can result in significant errors in the reconstruction of the quantity of interest. Here, we experimentally and theoretically demonstrate a rigorous method of signal reconstruction in THz emission spectroscopy, and describe the main experimental and theoretical sources of reconstruction error. We identify the linear line-of-sight geometry of the THz emission spectrometer as the optimal configuration for accurate, fully calibrated THz signal reconstruction. As an example, we apply our reconstruction method to ultrafast THz magnetometry experiment, where we recover the ultrafast magnetization dynamics in a photoexcited iron film, including both its temporal shape and absolute magnitude.
Optical random speckle encoding based on hybrid wavelength and phase modulation
Authors: Shi Wanxin , Hu Chengyang , Yang Sigang , Chen Minghua , Chen Hongwei
Published: June 2021

Optical random speckle encoding suffers from a contradiction between the generation speed and pattern amount. Spatial light modulators are commonly used for random speckle generation at relatively low speeds. Wavelength scanning combined with a scattering medium has a fast speed, while the pattern amount is limited by the optical bandwidth. To increase the performance of optical random speckle encoding, a novel, to the best of our knowledge, scheme combining wavelength and phase hybrid modulation is proposed and demonstrated. Through optical encoding in the two dimensions of wavelength and phase, the number of speckle patterns can reach one million, which is over 10,000 times that generated by only wavelength scanning. This scheme can be used in ghost imaging systems to increase the resolution of reconstructed images.
Formation of a three-dimensional bottle beam via an engineered microsphere
Authors: Zhou Yan , Hong Minghui
Published: June 2021

In this work, we propose a novel approach to produce three-dimensional (3D) optical trapping with sub-wavelength size through an engineered microsphere, under linear polarization states of an incident light. The engineered microsphere is designed to contain the segmented regions of diffractive patterns and made by focused ion beam fabrication. We simulate and experimentally characterize the focus performance of the engineered microsphere. The emitted light field from the exit surface of the engineered microsphere forms a pair of axially arranged focused beams, and they are connected with a continuous optical field embracing a 3D optical null at the center, forming the so-called optical bottle beam. Experimental results and numerical simulation are in good agreement. Such micro-optics can be used for precise and localized optical trapping.
Technologieauswahl im DigitalPakt: Wie werden Entscheidungen im Bildungssektor getroffen?
Authors: Petry Lukas , Lins Sebastian , Thiebes Scott , Sunyaev Ali
Published: June 2021

Der DigitalPakt Schule soll das deutsche Bildungswesen flächendeckend modernisieren, zeigt jedoch bisher Anlaufschwierigkeiten. Die bereitgestellten Fördermittel werden zögerlich abgerufen und die Kritiker:innen des Programms werden immer lauter. Diese Arbeit setzt genau an diesem Punkt an und diskutiert Ursachen und Einflüsse, die dazu beitragen, dass verfügbare Technologien bisher von Schulen nicht oder nur unzureichend angenommen werden. Diese Diskussion ist insbesondere wichtig, da das Schulsystem des Landes zurzeit durch die pandemie-bedingte Krise im Fokus steht. Dafür wurden semi-strukturierte Expert:inneninterviews mit Schulvertreter:innen durchgeführt und mit Hilfe von wissenschaftlichen Kodierungsmethoden analysiert. Die Ergebnisse geben einen Einblick in den Technologieauswahlprozess, um herauszufinden, wie Auswahlentscheidungen im Bildungssektor getroffen werden, und zu verstehen, warum der öffentliche Bereich eine Sonderstellung einnimmt und nicht so funktioniert, wie ein wirtschaftsdenkendes Unternehmen.
Topological data analysis distinguishes parameter regimes in the Anderson-Chaplain model of angiogenesis
Authors: Nardini John T. , Stolz Bernadette J. , Flores Kevin B. , Harrington Heather A. , Byrne Helen M.
Published: June 2021

Angiogenesis is the process by which blood vessels form from pre-existing vessels. It plays a key role in many biological processes, including embryonic development and wound healing, and contributes to many diseases including cancer and rheumatoid arthritis. The structure of the resulting vessel networks determines their ability to deliver nutrients and remove waste products from biological tissues. Here we simulate the Anderson-Chaplain model of angiogenesis at different parameter values and quantify the vessel architectures of the resulting synthetic data. Specifically, we propose a topological data analysis (TDA) pipeline for systematic analysis of the model. TDA is a vibrant and relatively new field of computational mathematics for studying the shape of data. We compute topological and standard descriptors of model simulations generated by different parameter values. We show that TDA of model simulation data stratifies parameter space into regions with similar vessel morphology. The methodologies proposed here are widely applicable to other synthetic and experimental data including wound healing, development, and plant biology.
De novo mutational signature discovery in tumor genomes using SparseSignatures
Authors: Lal Avantika , Liu Keli , Tibshirani Robert , Sidow Arend , Ramazzotti Daniele
Published: June 2021

Cancer is the result of mutagenic processes that can be inferred from tumor genomes by analyzing rate spectra of point mutations, or “mutational signatures”. Here we present SparseSignatures, a novel framework to extract signatures from somatic point mutation data. Our approach incorporates a user-specified background signature, employs regularization to reduce noise in non-background signatures, uses cross-validation to identify the number of signatures, and is scalable to large datasets. We show that SparseSignatures outperforms current state-of-the-art methods on simulated data using a variety of standard metrics. We then apply SparseSignatures to whole genome sequences of pancreatic and breast tumors, discovering well-differentiated signatures that are linked to known mutagenic mechanisms and are strongly associated with patient clinical features.
Regulating synchronous oscillations of cerebellar granule cells by different types of inhibition
Authors: Tang Yuanhong , An Lingling , Wang Quan , Liu Jian K.
Published: June 2021

Synchronous oscillations in neural populations are considered being controlled by inhibitory neurons. In the granular layer of the cerebellum, two major types of cells are excitatory granular cells (GCs) and inhibitory Golgi cells (GoCs). GC spatiotemporal dynamics, as the output of the granular layer, is highly regulated by GoCs. However, there are various types of inhibition implemented by GoCs. With inputs from mossy fibers, GCs and GoCs are reciprocally connected to exhibit different network motifs of synaptic connections. From the view of GCs, feedforward inhibition is expressed as the direct input from GoCs excited by mossy fibers, whereas feedback inhibition is from GoCs via GCs themselves. In addition, there are abundant gap junctions between GoCs showing another form of inhibition. It remains unclear how these diverse copies of inhibition regulate neural population oscillation changes. Leveraging a computational model of the granular layer network, we addressed this question to examine the emergence and modulation of network oscillation using different types of inhibition. We show that at the network level, feedback inhibition is crucial to generate neural oscillation. When short-term plasticity was equipped on GoC-GC synapses, oscillations were largely diminished. Robust oscillations can only appear with additional gap junctions. Moreover, there was a substantial level of cross-frequency coupling in oscillation dynamics. Such a coupling was adjusted and strengthened by GoCs through feedback inhibition. Taken together, our results suggest that the cooperation of distinct types of GoC inhibition plays an essential role in regulating synchronous oscillations of the GC population. With GCs as the sole output of the granular network, their oscillation dynamics could potentially enhance the computational capability of downstream neurons.
Molecular signatures of silencing suppression degeneracy from a complex RNA virus
Authors: Ambrós Silvia , Gómez-Muñoz Neus , Giménez-Santamarina Silvia , Sánchez-Vicente Javier , Navarro-López Josep , Martínez Fernando , Daròs José-Antonio , Rodrigo Guillermo
Published: June 2021

As genomic architectures become more complex, they begin to accumulate degenerate and redundant elements. However, analyses of the molecular mechanisms underlying these genetic architecture features remain scarce, especially in compact but sufficiently complex genomes. In the present study, we followed a proteomic approach together with a computational network analysis to reveal molecular signatures of protein function degeneracy from a plant virus (as virus-host protein-protein interactions). We employed affinity purification coupled to mass spectrometry to detect several host factors interacting with two proteins ofCitrus tristeza virus(p20 and p25) that are known to function as RNA silencing suppressors, using an experimental system of transient expression in a model plant. The study was expanded by considering two different isolates of the virus, and some key interactions were confirmed by bimolecular fluorescence complementation assays. We found that p20 and p25 target a common set of plant proteins including chloroplastic proteins and translation factors. Moreover, we noted that even specific targets of each viral protein overlap in function. Notably, we identified argonaute proteins (key players in RNA silencing) as reliable targets of p20. Furthermore, we found that these viral proteins preferentially do not target hubs in the host protein interactome, but elements that can transfer information by bridging different parts of the interactome. Overall, our results demonstrate that two distinct proteins encoded in the same viral genome that overlap in function also overlap in their interactions with the cell proteome, thereby highlighting an overlooked connection from a degenerate viral system.
Neofunctionalization of a second insulin receptor gene in the wing-dimorphic planthopper, Nilaparvata lugens
Authors: Xue Wen-Hua , Xu Nan , Chen Sun-Jie , Liu Xin-Yang , Zhang Jin-Li , Xu Hai-Jun
Published: June 2021

A single insulin receptor (InR) gene has been identified and extensively studied in model species ranging from nematodes to mice. However, most insects possess additional copies of InR, yet the functional significance, if any, of alternate InRs is unknown. Here, we used the wing-dimorphic brown planthopper (BPH) as a model system to query the role of a second InR copy in insects. NlInR2 resembled the BPH InR homologue (NlInR1) in terms of nymph development and reproduction, but revealed distinct regulatory roles in fuel metabolism, lifespan, and starvation tolerance. Unlike a lethal phenotype derived from NlInR1 null, homozygous NlInR2 null mutants were viable and accelerated DNA replication and cell proliferation in wing cells, thus redirecting short-winged–destined BPHs to develop into long-winged morphs. Additionally, the proper expression of NlInR2 was needed to maintain symmetric vein patterning in wings. Our findings provide the first direct evidence for the regulatory complexity of the two InR paralogues in insects, implying the functionally independent evolution of multiple InRs in invertebrates.
RNA-binding protein Maca is crucial for gigantic male fertility factor gene expression, spermatogenesis, and male fertility, in Drosophila
Authors: Zhu Li , Fukunaga Ryuya
Published: June 2021

During spermatogenesis, the process in which sperm for fertilization are produced from germline cells, gene expression is spatiotemporally highly regulated. In Drosophila, successful expression of extremely large male fertility factor genes on Y-chromosome spanning some megabases due to their gigantic intron sizes is crucial for spermatogenesis. Expression of such extremely large genes must be challenging, but the molecular mechanism that allows it remains unknown. Here we report that a novel RNA-binding protein Maca, which contains two RNA-recognition motifs, is crucial for this process. maca null mutant male flies exhibited a failure in the spermatid individualization process during spermatogenesis, lacked mature sperm, and were completely sterile, while maca mutant female flies were fully fertile. Proteomics and transcriptome analyses revealed that both protein and mRNA abundance of the gigantic male fertility factor genes kl-2, kl-3, and kl-5 (kl genes) are significantly decreased, where the decreases of kl-2 are particularly dramatic, in maca mutant testes. Splicing of the kl-3 transcripts was also dysregulated in maca mutant testes. All these physiological and molecular phenotypes were rescued by a maca transgene in the maca mutant background. Furthermore, we found that in the control genetic background, Maca is exclusively expressed in spermatocytes in testes and enriched at Y-loop A/C in the nucleus, where the kl-5 primary transcripts are localized. Our data suggest that Maca increases transcription processivity, promotes successful splicing of gigantic introns, and/or protects transcripts from premature degradation, of the kl genes. Our study identified a novel RNA-binding protein Maca that is crucial for successful expression of the gigantic male fertility factor genes, spermatogenesis, and male fertility.
Determining seropositivity—A review of approaches to define population seroprevalence when using multiplex bead assays to assess burden of tropical diseases
Authors: Chan YuYen , Fornace Kimberly , Wu Lindsey , Arnold Benjamin F. , Priest Jeffrey W. , Martin Diana L. , Chang Michelle A. , Cook Jackie , Stresman Gillian , Drakeley Chris
Published: June 2021

Background

Serological surveys with multiplex bead assays can be used to assess seroprevalence to multiple pathogens simultaneously. However, multiple methods have been used to generate cut-off values for seropositivity and these may lead to inconsistent interpretation of results. A literature review was conducted to describe the methods used to determine cut-off values for data generated by multiplex bead assays.

Methodology/Principal findings

A search was conducted in PubMed that included articles published from January 2010 to January 2020, and 308 relevant articles were identified that included the terms “serology”, “cut-offs”, and “multiplex bead assays”. After application of exclusion of articles not relevant to neglected tropical diseases (NTD), vaccine preventable diseases (VPD), or malaria, 55 articles were examined based on their relevance to NTD or VPD. The most frequently applied approaches to determine seropositivity included the use of presumed unexposed populations, mixture models, receiver operating curves (ROC), and international standards. Other methods included the use of quantiles, pre-exposed endemic cohorts, and visual inflection points.

Conclusions/Significance

For disease control programmes, seropositivity is a practical and easily interpretable health metric but determining appropriate cut-offs for positivity can be challenging. Considerations for optimal cut-off approaches should include factors such as methods recommended by previous research, transmission dynamics, and the immunological backgrounds of the population. In the absence of international standards for estimating seropositivity in a population, the use of consistent methods that align with individual disease epidemiological data will improve comparability between settings and enable the assessment of changes over time.
Anti-chikungunya virus seroprevalence in Indigenous groups in the São Francisco Valley, Brazil
Authors: Nicacio Jandir Mendonça , Khouri Ricardo , da Silva Antônio Marconi Leandro , Barral-Netto Manoel , Lima João Augusto Costa , Ladeia Ana Marice Teixeira , do Carmo Rodrigo Feliciano , Armstrong Anderson da Costa
Published: June 2021

Background

Chikungunya fever (CHIKF) is a serious public health problem with a high rate of infection and chronic disabling manifestations that has affected more than 2 million people worldwide since 2005. In spite of this, epidemiological data on vulnerable groups such as Indigenous people are scarce, making it difficult to implement public policies in order to prevent this disease and assist these populations.

Objective

To describe the serological and epidemiological profile of chikungunya virus (CHIKV) in two Indigenous populations in Northeast Brazil, as well as in an urbanized control community, and to explore associations between CHIKV and anthropometric variables in these populations.

Methodology/Principal findings

This is a cross-sectional ancillary study of the Project of Atherosclerosis among Indigenous Populations (PAI) that included people 30 to 70 years old, recruited from two Indigenous tribes (the less urbanized Fulni-ô and the more urbanized Truká people) and an urbanized non-Indigenous control group from the same area. Subjects underwent clinical evaluation and were tested for anti-CHIKV IgG by enzyme-linked immunosorbent assay. Serological profile was described according to ethnicity, sex, and age. The study population included 433 individuals distributed as follows: 109 (25·2%) Truká, 272 (62·8%) Fulni-ô, and 52 (12%) from the non-Indigenous urbanized control group. Overall prevalence of CHIKV IgG in the study sample was 49.9% (216; 95% CI: 45·1–54·7). When the sample was stratified, positive CHIKV IgG was distributed as follows: no individuals in the Truká group, 78·3% (213/272; 95% CI: 72·9–83·1) in the Fulni-ô group, and 5.8% (3/52; 95% CI: 1.21–16) in the control group.

Conclusions/Significance

Positive tests for CHIKV showed a very high prevalence in a traditional Indigenous population, in contrast to the absence of anti-CHIKV serology in the Truká people, who are more urbanized with respect to physical landscape, socio-cultural, and historical aspects, as well as a low prevalence in the non-Indigenous control group, although all groups are located in the same area.
Effects of intravenous magnesium sulfate on serum calcium-regulating hormones and plasma and urinary electrolytes in healthy horses
Authors: Schumacher Stephen A. , Kamr Ahmed M. , Lakritz Jeffrey , Burns Teresa A. , Bertone Alicia L. , Toribio Ramiro E.
Published: June 2021

Intravenous magnesium sulfate (MgSO4) is used in equine practice to treat hypomagnesemia, dysrhythmias, neurological disorders, and calcium dysregulation. MgSO4 is also used as a calming agent in equestrian events. Hypercalcemia affects calcium-regulating hormones, as well as plasma and urinary electrolytes; however, the effect of hypermagnesemia on these variables is unknown. The goal of this study was to investigate the effect of hypermagnesemia on blood parathyroid hormone (PTH), calcitonin (CT), ionized calcium (Ca2+), ionized magnesium (Mg2+), sodium (Na+), potassium (K+), chloride (Cl-) and their urinary fractional excretion (F) after intravenous administration of MgSO4 in healthy horses. Twelve healthy female horses of 4–18 years of age and 432–600 kg of body weight received a single intravenous dose of MgSO4 (60 mg/kg) over 5 minutes, and blood and urine samples were collected at different time points over 360 minutes. Plasma Mg2+ concentrations increased 3.7-fold over baseline values at 5 minutes and remained elevated for 120 minutes (P < 0.05), Ca2+ concentrations decreased from 30–60 minutes (P < 0.05), but Na+, K+ and Cl- concentrations did not change. Serum PTH concentrations dropped initially to rebound and remain elevated from 30 to 60 minutes, while CT concentrations increased at 5 minutes to return to baseline by 10 minutes (P < 0.05). The FMg, FCa, FNa, FK, and FCl increased, while urine osmolality decreased from 30–60 minutes compared baseline (P < 0.05). Short-term experimental hypermagnesemia alters calcium-regulating hormones (PTH, CT), reduces plasma Ca2+ concentrations, and increases the urinary excretion of Mg2+, Ca2+, K+, Na+ and Cl- in healthy horses. This information has clinical implications for the short-term effects of hypermagnesemia on calcium-regulation, electrolytes, and neuromuscular activity, in particular with increasing use of Mg salts to treat horses with various acute and chronic conditions as well as a calming agent in equestrian events.
Framing the potential of public frameshift peptides as immunotherapy targets in colon cancer
Authors: Spaanderman Ide T. , Peters Fleur S. , Jongejan Aldo , Redeker Egbert J. W. , Punt Cornelis J. A. , Bins Adriaan D.
Published: June 2021

Approximately 15% of Colon Cancers are Microsatellite Instable (MSI). Frameshift Peptides (FPs) formed in MSI Colon Cancer are potential targets for immunotherapeutic strategies. Here we comprehensively characterize the mutational landscape of 71 MSI Colon Cancer patients from the cancer genome atlas (TCGA). We confirm that the mutations in MSI Colon Cancers are frequently frameshift deletions (23% in MSI; 1% in microsatellite stable), We find that these mutations cluster at specific locations in the genome which are mutated in up to 41% of the patients. We filter these for an adequate variant allele frequency, a sufficient mean mRNA level and the formation of a Super Neo Open Reading Frame (SNORF). Finally, we check the influence of Nonsense Mediated Decay (MMD) by comparing RNA and DNA sequencing results. Thereby we identify a set of 20 NMD-escaping Public FPs (PFPs) that cover over 90% of MSI Colon, 62.2% of MSI Endometrial and 58.8% of MSI Stomach cancer patients and 3 out of 4 Lynch patients in the TCGA-COAD. This underlines the potential for PFP directed immunotherapy, both in a therapeutic and a prophylactic setting in multiple types of MSI cancers.
Real-time computer-aided diagnosis of focal pancreatic masses from endoscopic ultrasound imaging based on a hybrid convolutional and long short-term memory neural network model
Authors: Udriștoiu Anca Loredana , Cazacu Irina Mihaela , Gruionu Lucian Gheorghe , Gruionu Gabriel , Iacob Andreea Valentina , Burtea Daniela Elena , Ungureanu Bogdan Silviu , Costache Mădălin Ionuț , Constantin Alina , Popescu Carmen Florina , Udriștoiu Ștefan , Săftoiu Adrian
Published: June 2021

Differential diagnosis of focal pancreatic masses is based on endoscopic ultrasound (EUS) guided fine needle aspiration biopsy (EUS-FNA/FNB). Several imaging techniques (i.e. gray-scale, color Doppler, contrast-enhancement and elastography) are used for differential diagnosis. However, diagnosis remains highly operator dependent. To address this problem, machine learning algorithms (MLA) can generate an automatic computer-aided diagnosis (CAD) by analyzing a large number of clinical images in real-time. We aimed to develop a MLA to characterize focal pancreatic masses during the EUS procedure. The study included 65 patients with focal pancreatic masses, with 20 EUS images selected from each patient (grayscale, color Doppler, arterial and venous phase contrast-enhancement and elastography). Images were classified based on cytopathology exam as: chronic pseudotumoral pancreatitis (CPP), neuroendocrine tumor (PNET) and ductal adenocarcinoma (PDAC). The MLA is based on a deep learning method which combines convolutional (CNN) and long short-term memory (LSTM) neural networks. 2688 images were used for training and 672 images for testing the deep learning models. The CNN was developed to identify the discriminative features of images, while a LSTM neural network was used to extract the dependencies between images. The model predicted the clinical diagnosis with an area under curve index of 0.98 and an overall accuracy of 98.26%. The negative (NPV) and positive (PPV) predictive values and the corresponding 95% confidential intervals (CI) are 96.7%, [94.5, 98.9] and 98.1%, [96.81, 99.4] for PDAC, 96.5%, [94.1, 98.8], and 99.7%, [99.3, 100] for CPP, and 98.9%, [97.5, 100] and 98.3%, [97.1, 99.4] for PNET. Following further validation on a independent test cohort, this method could become an efficient CAD tool to differentiate focal pancreatic masses in real-time.
Hydroxychloroquine (HCQ) decreases the benefit of anti-PD-1 immune checkpoint blockade in tumor immunotherapy
Authors: Krueger Janna , Santinon Francois , Kazanova Alexandra , Issa Mark E. , Larrivee Bruno , Kremer Richard , Milhalcioiu Catalin , Rudd Christopher E.
Published: June 2021

Immunotherapy using checkpoint blockade (ICB) with antibodies such as anti-PD-1 has revolutionised the treatment of many cancers. Despite its use to treat COVID-19 patients and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, the effect of hydroxychloroquine (HCQ) on cancer immunotherapy has not been examined. In this study, remarkably, we find that HCQ alone, or in combination with azithromycin (AZ), at doses used to treat patients, decreased the therapeutic benefit of anti-PD-1 in cancer immunotherapy. No deleterious effect was seen on untreated tumors. Mechanistically, HCQ and HCQ/AZ inhibited PD-L1 expression on tumor cells, while specifically targeting the anti-PD-1 induced increase in progenitor CD8+CD44+PD-1+TCF1+tumor infiltrating T cells (TILs) and the generation of CD8+CD44+PD-1+effectors. Surprisingly, it also impaired the appearance of a subset of terminally exhausted CD8+TILs. No effect was seen on the presence of CD4+T cells, FoxP3+regulatory T cells (Tregs), thymic subsets, B cells, antibody production, myeloid cells, or the vasculature of mice. This study indicates for the first time that HCQ and HCQ/AZ negatively impact the ability of anti-PD-1 checkpoint blockade to promote tumor rejection.