bluuebunny/crossref_metadata_2025 huggingface dataset:
A case of pembrolizumab induced distal renal tubular acidosis
Authors: Atiq Saad O , Gokhale Tanmay , Atiq Zainab , Holmes Racquel , Sparks Matthew A
Published: February 2021

Immunotherapy has become a mainstay therapeutic in a variety of malignancies. Checkpoint inhibitors are used to enhance the endogenous immune response to target malignancy. The primary targets of checkpoint inhibitors include programed cell death receptor 1 (PD-1), programed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Despite clinical benefits, immune checkpoint inhibitors are associated with side effects termed immune-related adverse events (irAEs). We report a case of the PD-1 inhibitor (pembrolizumab) causing severe distal renal tubular acidosis (RTA). The patient presented with altered mental status and was found to have a severe non-anion gap metabolic acidosis after other potential etiologies were ruled out. We review the etiology of immune checkpoint inhibitor-induced RTA and review the case reports that have been described in the literature.
Longitudinal Follow‐up of Superior Laryngeal Nerve Block for Chronic Neurogenic Cough
Authors: Dhillon Vaninder K.
Published: February 2021

Objective

To demonstrate longitudinal follow‐up for patients who underwent in‐office superior laryngeal nerve (SLN) block with lidocaine and steroids for chronic neurogenic cough.

Study Design

Longitudinal follow‐up study over 10 months.

Setting

Clinical.

Methods

A retrospective review of 30 patients who underwent in‐office nerve block to the SLN for neurogenic cough, including the 10 patients whose outcomes were originally published in 2019.

Results

Thirty patients in this study who underwent a series of SLN blocks showed significant improvement in cough severity index (CSI). The average number of blocks was 3 (range, 2‐8). Twelve patients underwent initial SLN block to the left side and 18 patients underwent initial SLN block to the right side. The mean follow‐up from the first SLN block was 5.3 months. The mean pretreatment and posttreatment CSI scores were 27 and 11, respectively, for all 30 patients who underwent an SLN block. A Wilcoxon signed rank test shows that there is a significant effect on CSI (W = 2, z = −4.659, P <. 05). The mean longitudinal follow‐up for the original 10 patients was 10 months from the first SLN block, with none of these patients receiving any further treatment for their cough.

Conclusion

Superior laryngeal nerve block is an effective long‐term treatment for neurogenic cough. No additional treatment was required within 10 months of the SLN block.

Level of Evidence

Level IV.
Sonographic Evaluation of Peripheral Sciatic Nerve Injury: A Case Study
Authors: Franceschina Kirstie
Published: February 2021

Traumatic peripheral nerve injury is not a common finding in the general population but is increasingly being recognized and diagnosed in trauma and emergency medicine settings. Peripheral nerve injury can cause temporary or long-term motor and sensory loss, as well as intense pain and disability, if left untreated. The cause of peripheral nerve injury is diverse and often involves soft tissue damage, fractures, and hemorrhage in cases of traumatic injury. Peripheral nerve injury does not always heal spontaneously and, depending on severity, may warrant surgical intervention and repair. Although electrodiagnosic testing and surgical exploration are considered gold standards for peripheral nerve injury, high-resolution sonographic examination supplemented by clinical findings may be of value. The use of sonography demonstrated utility in determining a strategic management timeline and the efficacy of a surgical intervention.
Building a Harmonized Datamart by Integrating Cross-Institutional Systems of Clinical, Outcome, and Genomic Data: The Pediatric Patient Informatics Platform (PPIP)
Authors: Ma Clement , Sridharan Madhumitha , Al-Sayegh Hasan , Li Anran , Guo Dongjing , Auclair Mark , Kuragayala Vani , Bandaru Chandini , Milne Dana , Cruse Hugh , Beaudoin Ron , Orechia John , Bickel Jonathan , London Wendy B.
Published: February 2021

PURPOSE

Siloed electronic medical data limits utility and accessibility. At the Dana-Farber/Boston Children's Cancer and Blood Disorders Center, cross-institutional data were inconsistent and difficult to access. To unify data for clinical operations, administration, and research, we developed the Pediatric Patient Informatics Platform ( PPIP), an integrated datamart harmonizing multiple source systems across two institutions into a common technology.

PATIENTS AND METHODS

Starting in 2009, user requirements were gathered and data sources were prioritized. Project teams, including biostatisticians, database developers, and an external contractor, were formed. Read-access to source systems was established. The 3-layer PPIP architecture was developed: STAGING, a near-exact copy of source data; INTEGRATION, where data were reorganized into domains; and, CONSUMPTION, where data were optimized for rapid retrieval. The diverse systems were integrated into a common IBM Netezza technology. Data filters were defined to accurately capture the Center's patients, and derived data items were created for harmonization across sources. An interactive online query tool, PPIP360, was developed using Microstrategy Analytics.

RESULTS

Driven by scientific objectives, the PPIP datamart was created, including 33,674 patients, 2,983 protocols, and 3.6 million patient visits from 14 source databases, 164 source tables, and 2,622 source data items. The PPIP360 has 605 data items and 33 metrics across 11 reports and dashboards. Dana-Farber and Boston Children's established a legal data-sharing agreement. The PPIP has supported hundreds of faculty, staff, and projects, including planning clinical trials and informing strategic planning.

CONCLUSION

The PPIP has successfully harmonized and integrated diagnostic, demographic, laboratory, treatment, clinical outcome, pathology, transplant, meta-protocol, and –omics data, for efficient, daily operational and research activities at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, and future external sharing.
Prolactin Drives a Dynamic STAT5A/HDAC6/HMGN2Cis-Regulatory Landscape Exploitable in ER+ Breast Cancer
Authors: Craig Justin M , Turner Tia H , Harrell J Chuck , Clevenger Charles V
Published: February 2021

The hormone prolactin has been implicated in breast cancer pathogenesis and regulates chromatin engagement by the transcription factor, STAT5A. STAT5A is known to inducibly bind promoters and cis-regulatory elements genome-wide, though the mechanisms by which it exerts specificity and regulation of target gene expression remain enigmatic. We previously identified HDAC6 and HMGN2 as cofactors that facilitate prolactin-induced, STAT5A-mediated gene expression. Here, multicondition STAT5A, HDAC6, and HMGN2 chromatin immunoprecipitation and sequencing with parallel condition RNA-seq are utilized to reveal the cis-regulatory landscape and cofactor dynamics underlying prolactin-stimulated gene expression in breast cancer. We find that prolactin-regulated genes are significantly enriched for cis-regulatory elements bound by HDAC6 and HMGN2, and that inducible STAT5A binding at enhancers, rather than promoters, conveys specificity for prolactin-regulated genes. The selective HDAC6 inhibitor, ACY-241, blocks prolactin-induced STAT5A chromatin engagement at cis-regulatory elements as well as a significant proportion of prolactin-stimulated gene expression. We identify functional pathways known to contribute to the development and/or progression of breast cancer that are activated by prolactin and inhibited by ACY-241. Additionally, we find that the DNA sequences underlying shared STAT5A and HDAC6 binding sites at enhancers are differentially enriched for estrogen response elements (ESR1 and ESR2 motifs) relative to enhancers bound by STAT5A alone. Gene set enrichment analysis identifies significant overlap of ERα-regulated genes with genes regulated by prolactin, particularly prolactin-regulated genes with promoters or enhancers co-occupied by both STAT5A and HDAC6. Lastly, the therapeutic efficacy of ACY-241 is demonstrated in in vitro and in vivo breast cancer models, where we identify synergistic ACY-241 drug combinations and observe differential sensitivity of ER+ models relative to ER– models.
Differential effects of commensal bacteria on progenitor cell adhesion, division symmetry and tumorigenesis in the Drosophila intestine
Authors: Ferguson Meghan , Petkau Kristina , Shin Minjeong , Galenza Anthony , Fast David , Foley Edan
Published: February 2021

Microbial factors influence homeostatic and oncogenic growth in the intestinal epithelium. However, we know little about immediate effects of commensal bacteria on stem cell division programs. In this study, we examined the effects of commensal Lactobacillus species on homeostatic and tumorigenic stem cell proliferation in the female Drosophila intestine. We identified Lactobacillus brevis as a potent stimulator of stem cell divisions. In a wild-type midgut, L.brevis activates growth regulatory pathways that drive stem cell divisions. In a Notch-deficient background, L.brevis-mediated proliferation causes rapid expansion of mutant progenitors, leading to accumulation of large, multi-layered tumors throughout the midgut. Mechanistically, we showed that L.brevis disrupts expression and subcellular distribution of progenitor cell integrins, supporting symmetric divisions that expand intestinal stem cell populations. Collectively, our data emphasize the impact of commensal microbes on division and maintenance of the intestinal progenitor compartment.
Protein manipulation using single copies of short peptide tags in cultured cells and in Drosophila melanogaster
Authors: Vigano M. Alessandra , Ell Clara-Maria , Kustermann Manuela M. M. , Aguilar Gustavo , Matsuda Shinya , Zhao Ning , Stasevich Timothy J. , Affolter Markus , Pyrowolakis George
Published: February 2021

Cellular development and function rely on highly dynamic molecular interactions among proteins distributed in all cell compartments. Analysis of these interactions has been one of the main topics in cellular and developmental research, and has been mostly achieved by the manipulation of proteins of interest (POIs) at the genetic level. Although genetic strategies have significantly contributed to our current understanding, targeting specific interactions of POIs in a time- and space-controlled manner or analysing the role of POIs in dynamic cellular processes, such as cell migration or cell division, would benefit from more-direct approaches. The recent development of specific protein binders, which can be expressed and function intracellularly, along with advancement in synthetic biology, have contributed to the creation of a new toolbox for direct protein manipulations. Here, we have selected a number of short-tag epitopes for which protein binders from different scaffolds have been generated and showed that single copies of these tags allowed efficient POI binding and manipulation in living cells. Using Drosophila, we also find that single short tags can be used for POI manipulation in vivo.
Temporally regulated cell migration is sensitive to variation in body size
Authors: Dubois Clément , Gupta Shivam , Mugler Andrew , Félix Marie-Anne
Published: February 2021

Few studies have measured the robustness to perturbations of the final position of a long-range migrating cell. In the nematode Caenorhabditis elegans, the QR neuroblast migrates anteriorly, while undergoing three division rounds. We study the final position of two of its great-granddaughters, the end of migration of which was previously shown to depend on a timing mechanism. We find that the variance in their final position is similar to that of other long-range migrating neurons. As expected from the timing mechanism, the position of QR descendants depends on body size, which we varied by changing maternal age or using body size mutants. Using a mathematical model, we show that body size variation is partially compensated for. Applying environmental perturbations, we find that the variance in final position increased following starvation at hatching. The mean position is displaced upon a temperature shift. Finally, highly significant variation was found among C. elegans wild isolates. Overall, this study reveals that the final position of these neurons is quite robust to stochastic variation, shows some sensitivity to body size and to external perturbations, and varies in the species.

This article has an associated ‘The people behind the papers’ interview.
Investigation of the accessory maxillary ostium: a congenital variation or acquired defect?
Authors: Orhan Soylemez Umut Percem , Atalay Basak
Published: February 2021

Objective:

We sought to determine whether an accessory maxillary ostium (AMO) is a congenital or acquired condition and we investigated concomitant sinus pathologies associated with this structure.

Methods:

Paranasal sinus CT examinations of individuals aged ≥13 years and <13 years were compared retrospectively. In total, 552 sinuses of 276 patients aged ≥13 years (Group 1) and 284 maxillary sinuses of 142 children aged <13 years (Group 2) were evaluated. Patients were classified as AMO-positive or -negative. The following features were evaluated in Group 1: AMO presence, mucus retention cysts, mucosal thickening, sinusitis of the maxillary sinus, nasal septum deviation, concha hypertrophy, concha bullosa, primary ostium obstruction, uncinate process atelectasis, paradox concha, Agger nasi and Haller cells, and sinus hypoplasia. The sizes and locations of AMOs were also evaluated. The presence of an AMO and sinusitis were evaluated in Group 2.

Results:

AMOs were detected in 122 sinuses in Group 1. In the AMO-positive group, sinusitis, mucosal thickening, and primary ostium obstruction were significantly more common than in the AMO-negative group (p < 0.00001). Statistically significant associations were not observed between AMO presence and other parameters. AMOs were present in two sinuses in Group 2.

Conclusion:

Our results suggest that AMOs are acquired defects caused by sinus diseases. The rare occurrence of these structures in patients aged <13 years suggests that they may be a perforation or secondary drainage pathway in patients with sinusitis or primary ostium obstruction.
ANALYSIS OF THE TECHNOLOGY FOR THE PRODUCTION OF GRANULAR GLASS-CERAMIC FOAM AND THE DEVELOPMENT OF MEASURES FOR DUST CLEANING OF WORKING AREAS IN CONSTRUCTION
Authors: Ivanova Viktoriya , Nikolenko S. , Sazonova Svetlana
Published: February 2021

The system of dust cleaning at the enterprises of the construction industry is considered, in particular, at the production of granulated glass ceramic foam. The analysis of the work of construction industry enterprises and their harmful emissions. The applied methods of protecting working areas from dust, their effectiveness and the need for their use in various industries have been studied. It is proposed to make changes to the dust cleaning system used in the production of granulated glass ceramic foam. To increase the degree of cleaning, it is proposed to install a Venturi scrubber instead of a cyclone.
SYSTEM ANALYSIS OF THE PROBLEMS OF THE SCIENCE AND TECHNOLOGY FIELD «MEDICAL COMPUTER-AIDED DESIGN»
Authors: Nasyrov Rashit , Tiunov Oleg , Tiunov Igor
Published: February 2021

The article provides a system analysis of many problems that hinder the development of medical computer-aided design systems (CAD), in order to identify the most important problems of the subject area. An analysis is made of the key participant roles of the development and practical use process of medical CAD systems in order to determine the degree of their contribution to the final comprehensive result. The structure of business processes is being developed to ensure the completeness and relevance of the developed problematic model. The results can be useful for researchers and developers of medical computer-aided design systems, for experts of related specialties and potential consumers; for doctors studying or actively using computer modeling in the medical diagnostic process; for students studying medical informatics and students of biotechnological specialties, as well as teachers of relevant disciplines.
METHODOLOGY FOR SYNTHESIZING AN INFORMATION-MEASURING AND CONTROL SYSTEM WITH A CUSTOMIZABLE STRUCTURE AND FLEXIBLE SENSITIVE ELEMENTS USING THE EXAMPLE OF A PHASED ANTENNA ARRAY
Authors: Zhukov V. , Muromcev D. , Lavlinskiy V.
Published: February 2021

A new class of information-measuring and control systems with a configurable structure and flexible sensing elements is introduced and justified. The basics of the methodology for the synthesis of such systems are developed, including the synthesis of meters and algorithms for functioning, the development of mathematical support and a method for studying the stability of the system, aimed at increasing its energy efficiency by achieving the required accuracy and speed.
De jueces autoritarios y defensores progresistas: activismo judicial y controversias sociojurídicas en la ejecución de una sentencia ambiental
Authors: Scharager Andrés
Published: February 2021

A partir del caso de una sentencia que condenó al Poder Ejecutivo a construir un camino a la vera de un río de Buenos Aires, este artículo examina las controversias sociojurídicas desatadas entre un juez y los defensores públicos que patrocinaron a la población ribereña afectada. Se hallará que aquél, al conducir el proceso de implementación de políticas, actúa en detrimento de la protección de derechos sociales, mientras que éstos apelan a la construcción de conflicto para convertir dichos derechos en el eje de la causa. El trabajo, basado en un diseño cualitativo que incluyó entrevistas en profundidad y análisis de documentos, permite examinar las características que asume la puesta en práctica del activismo judicial en sus distintas facetas.
Recomendações de atividade física e exercício físico durante a pandemia Covid-19: revisão de escopo sobre publicações no Brasil
Authors: Mattos Samuel Miranda , Pereira Déborah Santana , Moreira Thereza Maria Magalhães , Cestari Virna Ribeiro Feitosa , Gonzalez Ricardo Hugo
Published: February 2021

No ano de 2020 a história mundial ficou marcada pela Covid-19, doença que causou inúmeros casos e óbitos, de interesse internacional à saúde pública. Esta revisão objetivou mapear as publicações brasileiras sobre recomendações de atividade física e exercício físico durante a pandemia Covid-19. Trata-se de uma revisão de escopo realizada de 22 estudos oriundos de três bases de dados, que continham recomendações expressas sobre prática de atividade física e exercício físico pela população brasileira durante a pandemia Covid-19. A análise dos dados se deu com a descrição das características dos artigos e de seus principais resultados em tabela, atrelada à análise textual dos artigos via software IRaMuTeQ. O corpus textual revelou o conceito de atividade física ligado à saúde, bem como orientações para atividade física e exercício físico com utilização de recursos tecnológicos, além da previsão de programas de exercício físico. A prática regular de atividade física e exercício físico durante a pandemia Covid-19 mostrou-se essencial à manutenção da saúde, sobretudo se regular e orientada, havendo possibilidade de utilização de tecnologias em abordagem individual ou grupal em vários cenários, sobretudo dentro de casa e ao ar livre.
Predictability and the Cross-Section of Expected Returns: A Challenge for Asset Pricing Models
Authors: Schlag Christian , Semenischev Michael , Thimme Julian
Published: February 2021

Many modern macro finance models imply that excess returns on arbitrary assets are predictable via the price-dividend ratio and the variance risk premium of the aggregate stock market. We propose a simple empirical test for the ability of such a model to explain the cross-section of expected returns by sorting stocks based on the sensitivity of expected returns to these quantities. Models with only one uncertainty-related state variable, like the habit model or the long-run risks model, cannot pass this test. However, even extensions with more state variables mostly fail. We derive conditions under which models would be able to produce expected return patterns in line with the data and discuss various examples.

This paper was accepted by David Simchi-Levi, finance.
A Network-Design Analysis of Airline Business Model Adaptation in the Face of Competition and Consolidation
Authors: de Oliveira Renan P. , Oliveira Alessandro V. M. , Lohmann Gui
Published: February 2021

By focusing on the intrinsic relationship between business models and network configurations in the airline industry, this paper develops a two-stage methodology to estimate the strategic drivers of network design of the major carriers in Brazil. The empirical approach decomposes their domestic network-building rationales into the ones adopted by virtual archetypical carriers. We consider the previously conceived low-cost, full-service, and regional carrier archetypes. Our main contribution is the development of a model that allows airlines’ networks to be strategically designed in a time-evolving pattern, reflecting a dynamically chosen blend of these archetypes. Moreover, we also consider the effects that mergers and acquisitions may have had in inducing changes in these blends. Our results suggest that all analyzed airlines have repositioned themselves through their trajectories to adopt a hybrid configuration, aiming at the intersection of at least two archetypical network-design rationales. Besides, the effects of consolidations point to certain diversions of the acquiring airlines’ domestic network-building rationales toward the ones of the acquired carriers, providing evidence that the consolidations may have served as stepping stones for market-repositioning moves.
Know the symptoms: diagnosing a brain tumour early is key
Authors: Lindsell Sarah
Published: February 2021

Everyone has a role to play in reducing diagnosis times for childhood brain tumours, the biggest cancer killer of children and adults under 40 years old in the UK. The Brain Tumour Charity's HeadSmart campaign aims to inform parents and healthcare professionals about the key early signs and symptoms of brain tumours.
Al-Khumasiya: Syria's Industrial Conglomerate of the 1950s
Authors: Moubayed Sami
Published: February 2021

Al-Khumasiya was a highly influential industrial complex that operated in Syria from 1946 until its nationalization in 1961. During the 1950s, it was the pride and joy of Syrian government officials, who took dignitaries on tours of its premises, boasting of the quality of its products. President Nasser of Egypt praised its achievements, before seizing the company in 1961 and transferring its ownership to the state, where it remains as of 2020. Many consider the nationalization of al-Khumasiya as the beginning of the end of the Syrian economy. And yet, nothing has been written about it, either in English or Arabic. Its records were destroyed, and its five founders died without leaving behind a written account of their experience. This article looks at the company, how it was founded, and what was so important for Syria throughout the 1940s and 1950s.
Efficient implementation of optical scanning holography in cancelable biometrics
Authors: Abd El-Samie Fathi E. , Nassar Rana M. , Safan Mohamed , Abdelhamed Mohamed A. , Khalaf Ashraf A. M. , El Banby Ghada M. , Zahran Osama , El-Rabaie El-Sayed M. , Mohamed Abdelnaser A. , El-Dokany Ibrahim M. , H. Ahmed HossamElDin , El-Khamy Said , Ramadan Noha , Soliman Randa F. , El-Shafai Walid
Published: February 2021

This paper presents a new trend in biometric security systems, which is cancelable multi-biometrics. In general, traditional biometric systems depend on a single biometric for identification. These traditional systems are subject to different types of attacks. In addition, a biometric signature may be lost in hacking scenarios; for example, in the case of intrusion, biometric signatures can be stolen forever. To reduce the risk of losing biometric signatures, the trend of cancelable biometrics has evolved by using either deformed or encrypted versions of biometrics for verification. In this paper, several biometric traits for the same person are treated to obtain a single cancelable template. First, optical scanning holography (OSH) is applied during the acquisition of each biometric. The resulting outputs are then compressed simultaneously to generate a unified template based on the energy compaction property of the discrete cosine transform (DCT). Hence, the OSH is used in the proposed approach as a tool to generate deformed versions of human biometrics in order to get the unified biometric template through DCT compression. With this approach, we guarantee the possibility of using multiple biometrics of the same user to increase security, as well as privacy of the new biometric template through utilization of the OSH. Simulation results prove the robustness of the proposed cancelable multi-biometric approach in noisy environments.
Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes
Authors: Jæger Karoline Horgmo , Wall Samuel , Tveito Aslak
Published: February 2021

Short QT (SQT) syndrome is a genetic cardiac disorder characterized by an abbreviated QT interval of the patient’s electrocardiogram. The syndrome is associated with increased risk of arrhythmia and sudden cardiac death and can arise from a number of ion channel mutations. Cardiomyocytes derived from induced pluripotent stem cells generated from SQT patients (SQT hiPSC-CMs) provide promising platforms for testing pharmacological treatments directly in human cardiac cells exhibiting mutations specific for the syndrome. However, a difficulty is posed by the relative immaturity of hiPSC-CMs, with the possibility that drug effects observed in SQT hiPSC-CMs could be very different from the corresponding drug effect in vivo. In this paper, we apply a multistep computational procedure for translating measured drug effects from these cells to human QT response. This process first detects drug effects on individual ion channels based on measurements of SQT hiPSC-CMs and then uses these results to estimate the drug effects on ventricular action potentials and QT intervals of adult SQT patients. We find that the procedure is able to identify IC50 values in line with measured values for the four drugs quinidine, ivabradine, ajmaline and mexiletine. In addition, the predicted effect of quinidine on the adult QT interval is in good agreement with measured effects of quinidine for adult patients. Consequently, the computational procedure appears to be a useful tool for helping predicting adult drug responses from pure in vitro measurements of patient derived cell lines.
Arrhythmogenic effects of ultra-long and bistable cardiac action potentials
Authors: Heitmann Stewart , Shpak Anton , Vandenberg Jamie I. , Hill Adam P.
Published: February 2021

Contemporary accounts of the initiation of cardiac arrhythmias typically rely on after-depolarizations as the trigger for reentrant activity. The after-depolarizations are usually triggered by calcium entry or spontaneous release within the cells of the myocardium or the conduction system. Here we propose an alternative mechanism whereby arrhythmias are triggered autonomously by cardiac cells that fail to repolarize after a normal heartbeat. We investigated the proposal by representing the heart as an excitable medium of FitzHugh-Nagumo cells where a proportion of cells were capable of remaining depolarized indefinitely. As such, those cells exhibit bistable membrane dynamics. We found that heterogeneous media can tolerate a surprisingly large number of bistable cells and still support normal rhythmic activity. Yet there is a critical limit beyond which the medium is persistently arrhythmogenic. Numerical analysis revealed that the critical threshold for arrhythmogenesis depends on both the strength of the coupling between cells and the extent to which the abnormal cells resist repolarization. Moreover, arrhythmogenesis was found to emerge preferentially at tissue boundaries where cells naturally have fewer neighbors to influence their behavior. These findings may explain why atrial fibrillation typically originates from tissue boundaries such as the cuff of the pulmonary vein.
LZP is required for hepatic triacylglycerol transportation through maintaining apolipoprotein B stability
Authors: Wu Jiao-Xiang , He Kun-Yan , Zhang Zhuang-Zhuang , Qu Yu-Lan , Su Xian-Bin , Shi Yi , Wang Na , Wang Lan , Han Ze-Guang
Published: February 2021

The conserved zona pellucida (ZP) domain is found in hundreds of extracellular proteins that are expressed in various organs and play a variety of roles as structural components, receptors and tumor suppressors. A liver-specific zona pellucida domain-containing protein (LZP), also named OIT3, has been shown to be mainly expressed in human and mouse hepatocytes; however, the physiological function of LZP in the liver remains unclear. Here, we show thatLzpdeletion inhibited very low-density lipoprotein (VLDL) secretion, leading to hepatic TG accumulation and lower serum TG levels in mice. The apolipoprotein B (apoB) levels were significantly decreased in the liver, serum, and VLDL particles of LZP-deficient mice. In the presence of LZP, which is localized to the endoplasmic reticulum (ER) and Golgi apparatus, the ER-associated degradation (ERAD) of apoB was attenuated; in contrast, in the absence of LZP, apoB was ubiquitinated by AMFR, a known E3 ubiquitin ligase specific for apoB, and was subsequently degraded, leading to lower hepatic apoB levels and inhibited VLDL secretion. Interestingly, hepatic LZP levels were elevated in mice challenged with a high-fat diet and humans with simple hepatic steatosis, suggesting that LZP contributes to the physiological regulation of hepatic TG homeostasis. In general, our data establish an essential role for LZP in hepatic TG transportation and VLDL secretion by preventing the AMFR-mediated ubiquitination and degradation of apoB and therefore provide insight into the molecular function of LZP in hepatic lipid metabolism.
Estimated impact of the pneumococcal conjugate vaccine on pneumonia mortality in South Africa, 1999 through 2016: An ecological modelling study
Authors: Kleynhans Jackie , Tempia Stefano , Shioda Kayoko , von Gottberg Anne , Weinberger Daniel M. , Cohen Cheryl
Published: February 2021

Background

Data on the national-level impact of pneumococcal conjugate vaccine (PCV) introduction on mortality are lacking from Africa. PCV was introduced in South Africa in 2009. We estimated the impact of PCV introduction on all-cause pneumonia mortality in South Africa, while controlling for changes in mortality due to other interventions.

Methods and findings

We used national death registration data in South Africa from 1999 to 2016 to assess the impact of PCV introduction on all-cause pneumonia mortality in all ages, with the exclusion of infants aged <1 month. We created a composite (synthetic) control using Bayesian variable selection of nondiarrheal, nonpneumonia, and nonpneumococcal deaths to estimate the number of expected all-cause pneumonia deaths in the absence of PCV introduction post 2009. We compared all-cause pneumonia deaths from the death registry to the expected deaths in 2012 to 2016. We also estimated the number of prevented deaths during 2009 to 2016. Of the 9,324,638 deaths reported in South Africa from 1999 to 2016, 12·6% were pneumonia-related.

Compared to number of deaths expected, we estimated a 33% (95% credible interval (CrI) 26% to 43%), 23% (95%CrI 17% to 29%), 25% (95%CrI 19% to 32%), and 23% (95%CrI 11% to 32%) reduction in pneumonia mortality in children aged 1 to 11 months, 1 to 4 years, 5 to 7 years, and 8 to 18 years in 2012 to 2016, respectively. In total, an estimated 18,422 (95%CrI 12,388 to 26,978) pneumonia-related deaths were prevented from 2009 to 2016 in children aged <19 years. No declines were estimated observed among adults following PCV introduction. This study was mainly limited by coding errors in original data that could have led to a lower impact estimate, and unmeasured factors could also have confounded estimates.

Conclusions

This study found that the introduction of PCV was associated with substantial reduction in all-cause pneumonia deaths in children aged 1 month to <19 years. The model predicted an effect of PCV in age groups who were eligible for vaccination (1 months to 4 years), and an indirect effect in those too old (8 to 18 years) to be vaccinated. These findings support sustaining pneumococcal vaccination to reduce pneumonia-related mortality in children.
A mathematical model for zoonotic transmission of malaria in the Atlantic Forest: Exploring the effects of variations in vector abundance and acrodendrophily
Authors: Medeiros-Sousa Antônio Ralph , Laporta Gabriel Zorello , Coutinho Renato Mendes , Mucci Luis Filipe , Marrelli Mauro Toledo
Published: February 2021

Transmission foci of autochthonous malaria caused byPlasmodium vivax-like parasites have frequently been reported in the Atlantic Forest in Southeastern and Southern Brazil. Evidence suggests that malaria is a zoonosis in these areas as human infections by simianPlasmodiumspecies have been detected, and the main vector of malaria in the Atlantic Forest,Anopheles(Kerteszia)cruzii, can blood feed on human and simian hosts. In view of the lack of models that seek to predict the dynamics of zoonotic transmission in this part of the Atlantic Forest, the present study proposes a new deterministic mathematical model that includes a transmission compartment for non-human primates and parameters that take into account vector displacement between the upper and lower forest strata. The effects of variations in the abundance and acrodendrophily ofAn.cruziion the prevalence of infected humans in the study area and the basic reproduction number (R0) for malaria were analyzed. The model parameters are based on the literature and fitting of the empirical data. Simulations performed with the model indicate that (1) an increase in the abundance of the vector in relation to the total number of blood-seeking mosquitoes leads to an asymptotic increase in both the proportion of infected individuals at steady state and R0; (2) the proportion of infected humans at steady state is higher when displacement of the vector mosquito between the forest strata increases; and (3) in most scenarios,Plasmodiumtransmission cannot be sustained only between mosquitoes and humans, which implies that non-human primates play an important role in maintaining the transmission cycle. The proposed model contributes to a better understanding of the dynamics of malaria transmission in the Atlantic Forest.
Nucleotide sugar biosynthesis occurs in the glycosomes of procyclic and bloodstream form Trypanosoma brucei
Authors: Sampaio Guther Maria Lucia , Prescott Alan R. , Kuettel Sabine , Tinti Michele , Ferguson Michael A. J.
Published: February 2021

InTrypanosoma brucei, there are fourteen enzymatic biotransformations that collectively convert glucose into five essential nucleotide sugars: UDP-Glc, UDP-Gal, UDP-GlcNAc, GDP-Man and GDP-Fuc. These biotransformations are catalyzed by thirteen discrete enzymes, five of which possess putative peroxisome targeting sequences. Published experimental analyses using immunofluorescence microscopy and/or digitonin latency and/or subcellular fractionation and/or organelle proteomics have localized eight and six of these enzymes to the glycosomes of bloodstream form and procyclic formT.brucei, respectively. Here we increase these glycosome localizations to eleven in both lifecycle stages while noting that one, phospho-N-acetylglucosamine mutase, also localizes to the cytoplasm. In the course of these studies, the heterogeneity of glycosome contents was also noted. These data suggest that, unlike other eukaryotes, all of nucleotide sugar biosynthesis inT.bruceiis compartmentalized to the glycosomes in both lifecycle stages. The implications are discussed.
The late Holocene demise of a sublittoral oyster bed in the North Sea
Authors: Sander Lasse , Hass H. Christian , Michaelis Rune , Groß Christopher , Hausen Tanja , Pogoda Bernadette
Published: February 2021

A fossil oyster bed (Ostrea edulis) was recently encountered offshore Helgoland (German Bight). Oysters are important filter feeders in marine environments and their habitat structure supports a large associated biodiversity. The European flat oyster Ostrea edulis has historically occurred in vast populations in the North Sea, but declined massively in the early 20th century. The ecological restoration of Ostrea habitats is a current focal point in the North Sea. To better understand the mechanisms that caused the local collapse of the oyster population, this study investigated the size structure, weight, and age of the shells, along with the spatial dimensions, seafloor properties, and environmental context of the oyster bed. The results show that the demise of the population occurred around 700 CE, ruling out excessive harvest as a driver of decline. Synchronicity of increased geomorphological activity of rivers and concurrent major land use changes in early medieval Europe suggest that increased sedimentation was a viable stressor that reduced the performance of the oysters. The shells provided no indication of a demographically poor state of the oyster bed prior to its demise, but manifested evidence of the wide-spread occurrence of the boring sponge Cliona sp. Our study challenges the assumption of a stable preindustrial state of the European flat oyster in the North Sea, and we conclude that the long-term variability of environmental conditions needs to be addressed to benchmark success criteria for the restoration of O. edulis.
Satellite tracking of rehabilitated sea turtles suggests a high rate of short-term survival following release
Authors: Robinson David P. , Hyland Kevin , Beukes Gerhard , Vettan Abdulkareem , Mabadikate Aneeshkumar , Jabado Rima W. , Rohner Christoph A. , Pierce Simon J. , Baverstock Warren
Published: February 2021

The rehabilitation of wildlife can contribute directly to the conservation of threatened species by helping to maintain wild populations. This study focused on determining the post-rehabilitation survival and spatial ecology of sea turtles and on comparing the movements of individuals with flipper amputations (amputees) to non-amputee animals. Our aims were to assess whether rehabilitated sea turtles survive after release, to compare and contrast the movement characteristics of the different species of sea turtles we tracked, and to examine whether amputees and non-amputees within species behaved similarly post-release. Twenty-six rehabilitated sea turtles from four species, including hawksbillEretmochelys imbricata(n = 12), loggerheadCaretta caretta(n = 11), greenChelonia mydas(n = 2), and olive ridleyLepidochelys olivacea(n = 1) sea turtles from the United Arab Emirates were fitted with satellite tags before release. Rehabilitation times ranged from 89 to 817 days (mean 353 ± 237 days). Post-release movements and survival were monitored for 8 to 387 days (mean 155 ± 95 days) through satellite tracking. Tag data suggested that three tracked sea turtles died within four days of release, one after 27 days, and one after 192 days from what are thought to be anthropogenic factors unrelated to their pre-rehabilitation ailments. We then compared habitat use and movement characteristics among the different sea turtle species. Although half of all turtles crossed one or more international boundaries, dispersal varied among species. Loggerhead turtles had a high dispersal, with 80% crossing an international boundary, while hawksbill turtles displayed higher post-release residency, with 66% remaining within UAE territorial waters. Amputee turtles moved similarly to non-amputee animals of the same species. Loggerhead turtles travelled faster (mean ± sd = 15.3 ± 8 km/day) than hawksbill turtles (9 ± 7 km/day). Both amputee and non-amputee sea turtles within a species moved similarly. Our tracking results highlight that rehabilitated sea turtles, including amputees, can successfully survive in the wild following release for up to our ~one-year monitoring time therefore supporting the suitability for release of sea turtles that have recovered from major injuries such as amputations. However, more broadly, the high mortality from anthropogenic factors in the Arabian Gulf region is clearly a serious issue and conservation challenge.
Evaluation of two automated low-cost RNA extraction protocols for SARS-CoV-2 detection
Authors: Lázaro-Perona Fernando , Rodriguez-Antolín Carlos , Alguacil-Guillén Marina , Gutiérrez-Arroyo Almudena , Mingorance Jesús , García-Rodriguez Julio ,   on behalf of the SARS-CoV-2 Working Group
Published: February 2021

Background

Two automatable in-house protocols for high-troughput RNA extraction from nasopharyngeal swabs for SARS-CoV-2 detection have been evaluated.

Methods

One hundred forty one SARS-CoV-2 positive samples were collected during a period of 10-days. In-house protocols were based on extraction with magnetic beads and designed to be used with either the Opentrons OT-2 (OT-2in-house) liquid handling robot or the MagMAXTMExpress-96 system (MMin-house). Both protocols were tested in parallel with a commercial kit that uses the MagMAXTMsystem (MMkit). Nucleic acid extraction efficiencies were calculated from a SARS-CoV-2 DNA positive control.

Results

No significant differences were found between both in-house protocols and the commercial kit in their performance to detect positive samples. The MMkitwas the most efficient although the MMin-housepresented, in average, lower Cts than the other two. In-house protocols allowed to save between 350€ and 400€ for every 96 extracted samples compared to the commercial kit.

Conclusion

The protocols described harness the use of easily available reagents and an open-source liquid handling system and are suitable for SARS-CoV-2 detection in high throughput facilities.
Decreasing trends in cholangiocarcinoma incidence and relative survival in Khon Kaen, Thailand: An updated, inclusive, population-based cancer registry analysis for 1989–2018
Authors: Kamsa-ard Supot , Santong Chalongpon , Kamsa-ard Siriporn , Luvira Vor , Luvira Varisara , Suwanrungruang Krittika , Bhudhisawasdi Vajarabhongsa
Published: February 2021

Background

Cholangiocarcinoma (CCA) is a leading cause of cancer death in northeastern Thailand. We reported on the incidence of CCA using only one method. In the current study, we used three different statistical methods to forecast future trends and estimate relative survival.

Methods

We reviewed the CCA cases diagnosed between 1989 and 2018 recorded in the population-based Khon Kaen Cancer Registry (KKCR). Annual percent change (APC) was calculated to quantify the incidence rate trends using Joinpoint regression. Age-period-cohort models (APC model) were used to examine the temporal trends of CCA by age, calendar year, and birth cohort. We projected the incidence of CCA up to 2028 using three independent approaches: the Joinpoint, Age-period-cohort, and Nordpred models. Survival assessments were based on relative survival (RS).

Results

The respective APC in males and females decreased significantly (-3.1%; 95%CI: -4.0 to -2.1 and -2.4%; 95%CI: -3.6 to -1.2). The APC model—AC-P for male CCA—decreased according to a birth-cohort. The CCA incidence for males born in 1998 was 0.09 times higher than for those born in 1966 (Incidence rate ratios, IRR = 0.09; 95%CI: 0.07 to 0.12). The relative incidence for female CCA similarly decreased according to a birth-cohort (IRR = 0.11; 95%CI: 0.07 to 0.17). The respective projection for the age-standardized rate for males and females for 2028 will be 7.6 per 100,000 (102 patients) and 3.6 per 100,000 (140 patients). The five-year RS for CCA was 10.9% (95%CI: 10.3 to 11.6).

Conclusion

The incidence rate of CCA has decreased. The projection for 2028 is that the incidence will continue to decline. Nevertheless, the survival of patients with CCA remains poor.
Global structures and local network mechanisms of knowledge-flow networks
Authors: Cugmas Marjan , Ferligoj Anuška , Škerlavaj Miha , Žiberna Aleš
Published: February 2021

Understanding the patterns and underlying mechanisms that come into play when employees exchange their knowledge is crucial for their work performance and professional development. Although much is known about the relationship between certain global network properties of knowledge-flow networks and work performance, less is known about the emergence of specific global network structures of knowledge flow. The paper therefore aims to identify a global network structure in blockmodel terms within an empirical knowledge-flow network and discuss whether the selected local network mechanisms are able to drive the network towards the chosen global network structure. Existing studies of knowledge-flow networks are relied on to determine the local network mechanisms. Agent-based modelling shows the selected local network mechanisms are able to drive the network towards the assumed hierarchical global structure.
β-carotene and Bacillus thuringiensis insecticidal protein differentially modulate feeding behaviour, mortality and physiology of European corn borer (Ostrinia nubilalis)
Authors: Girón-Calva Patricia Sarai , Lopez Carmen , Albacete Alfonso , Albajes Ramon , Christou Paul , Eizaguirre Matilde
Published: February 2021

Maize with enhanced β-carotene production was engineered to counteract pervasive vitamin A deficiency in developing countries. Second-generation biofortified crops are being developed with additional traits that confer pest resistance. These include crops that can produceBacillus thuringiensisBerliner (Bt) insecticidal proteins. Currently, it is unknown whether β-carotene can confer fitness benefits through to insect pests, specifically through alteringOstrinia nubilalisforaging behaviour or development in the presence of Bt insecticidal toxin. Therefore the effects of dietary β-carotene plus Bt insecticidal protein on feeding behaviour, mortality, and physiology in early and late instars ofO.nubilalislarvae were investigated. The results of two-choice experiments showed that irrespective of β-carotene presence, at day five 68%-90% of neonates and 69%-77% of fifth-instar larvae avoided diets with Cry1A protein. Over 65% of neonate larvae preferred to feed on diets with β-carotene alone compared to 39% of fifth-instar larvae. Higher mortality (65%-97%) in neonates fed diets supplemented with β-carotene alone and in combination with Bt protein was found, whereas <36% mortality was observed when fed diets without supplemented β-carotene or Bt protein. Diets with both β-carotene and Bt protein extended 25 days the larval developmental duration from neonate to fifth instar (compared to Bt diets) but did not impair larval or pupal weight. Juvenile hormone and 20-hydroxyecdysone regulate insect development and their levels were at least 3-fold higher in larvae fed diets with β-carotene for 3 days. Overall, these results suggest that the effects of β-carotene and Bt protein onO.nubilalisis dependent on larval developmental stage. This study is one of the first that provides insight on how the interaction of novel traits may modulate crop susceptibility to insect pests. This understanding will in turn inform the development of crop protection strategies with greater efficacy.