bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hax1 Is Indispensable for Neutrophil Development in Zebrafish
Authors: Doll Larissa , Aghaallaei Narges , Welte Karl , Skokowa Julia , Bajoghli Baubak 
Published: February 2020

Inherited deficiency of HCLS1-associated protein X1 (HAX1) in human leads to the development of severe congenital neutropenia (CN), which is characterized by impaired neutrophil development. Patients with HAX1 deficiency are prone to life-threatening infections beginning in their first months of life unless treated by recombinant human granulocyte colony-stimulating factor (rhG-CSF) or bone marrow transplantation. But approximately 10% of these patients do not respond to the rhG-CSF therapy. Therefore, there is an urgent need for new tailored therapeutic strategies for the treatment of this disease. However, there is a lack of an animal model that allows high-throughput compound screening for the HAX1 associated neutropenia. In this study, we sought to determine the role of hax1 in zebrafish hematopoiesis. We used two approaches to interfere with the zebrafish hax1. First, we injected antisense morpholino that efficiently blocked the translation of hax1 mRNA. As a second approach, we used the CRISPR-Cas9 technique to introduce mutations in the zebrafish hax1 gene. Both approaches were used in the in wild-type embryos and transgenic (mpo:gfp) reporter line, where the neutrophils are labeled with GFP. We found that hax1 knockdown reduced the number of neutrophils, without affecting the development of HSPCs and monocytes/macrophages. Compared with their wild-type counterparts, hax1 morphants exhibited reduced expression levels of hcls1 and cebpa. Whereas the expression level of cebpb, a marker of emergency granulopoiesis, was upregulated. Next, we examined whether hax1 knockdown impairs the cellular viability because CN patients who harbor HAX1 mutations exhibit increased apoptosis of myeloid progenitors. Although zebrafish hax1 morphants showed increased cell death throughout the embryo, apoptosis was not triggered in the hematopoietic site. Therefore, our results suggested that reduced neutrophil numbers in zebrafish hax1 morphants is due to decreased production of neutrophils rather than increased cell death. To determine whether our zebrafish model is suitable for discovering human drugs, we treated zebrafish hax1 morphants with human G-CSF and rescued the quantitative reduction of neutrophils. Overall, we have successfully established a novel in vivo model for studying the HAX-1 role in the granulopoiesis, which might open new avenues for developing therapeutic strategies for CN.

Disclosures
No relevant conflicts of interest to declare.
The Tetraspanin CD53 Regulates Early B Cell Development By Promoting IL-7R Signaling
Authors: Greenberg Zev J. , Monlish Darlene A. , Bartnett Rachel L. , Bednarski Jeffrey J. , Schuettpelz Laura G. 
Published: February 2020

The tetraspanin CD53 has been implicated in B cell development and function. Tetraspanins are a family of transmembrane proteins important for organization of the plasma membrane and regulation of cellular migration, adhesion, and activation. CD53 has been shown to be a transcriptional target of EBF1, a critical transcription factor for early B cell development. Additional signaling for early B cell development occurs through the IL-7 receptor (IL-7R), where ligation promotes continued B cell differentiation and pro-survival/anti-apoptotic gene expression. Human deficiency of CD53 results in recurrent infections and reduced serum immunoglobulins. While prior studies have implicated a role for CD53 in regulating mature B cells, its role in early B cell development is not well understood.
Herein, we show that CD53 expression rapidly increases throughout B cell development, beginning at the pre-pro-B cell stage. With a CRISPR-generated knockout mouse, we show that Cd53-/- mice have significantly reduced bone marrow (25% fewer, p&lt;0.005), splenic (35% fewer, p&lt;0.05), lymphatic (65% fewer, p&lt;0.0001), and peripheral (30% fewer, p&lt;0.005) B cells compared to wild-type (WT) littermate controls. Mirroring the human phenotype, Cd53-/- mice have significantly reduced serum IgG and IgM (40% reduced, p&lt;0.01). In addition, hematopoietic stem cells isolated from Cd53-/- mice give rise to 30% fewer B cells compared to controls in vitro (p=0.005). Analysis of bone marrow B cell development demonstrates that this loss of B cells originates with early B cell progenitors, which express nearly 50% less IL-7Ra than WT and reduced IL-7 signaling. Using mass cytometry, we identified differential signaling pathways downstream of IL-7R in B cell progenitors. Specifically, we observe impaired PI3K and STAT5 activation in pre-pro- and pro-B cells in the absence of CD53, with a consequent increase in apoptosis in these populations (p&lt;0.01). Decreased STAT5 phosphorylation was confirmed by western blot. Finally, co-immunoprecipitation studies demonstrate a physical interaction between CD53 and IL-7Ra, suggesting that these proteins associate at the cell surface. Together, these data suggest a novel role for CD53 during IL-7 signaling to promote early B cell development. Ongoing studies are focused on determining the CD53 residues required for interaction with IL-7R.

Disclosures
No relevant conflicts of interest to declare.
Dissimilarity of the gut–lung axis and dysbiosis of the lower airways in ventilated preterm infants
Authors: Gallacher David , Mitchell Emma , Alber Dagmar , Wach Richard , Klein Nigel , Marchesi Julian R. , Kotecha Sailesh 
Published: February 2020

BackgroundChronic lung disease of prematurity (CLD), also called bronchopulmonary dysplasia, is a major consequence of preterm birth, but the role of the microbiome in its development remains unclear. Therefore, we assessed the progression of the bacterial community in ventilated preterm infants over time in the upper and lower airways, and assessed the gut–lung axis by comparing bacterial communities in the upper and lower airways with stool findings. Finally, we assessed whether the bacterial communities were associated with lung inflammation to suggest dysbiosis.MethodsWe serially sampled multiple anatomical sites including the upper airway (nasopharyngeal aspirates), lower airways (tracheal aspirate fluid and bronchoalveolar lavage fluid) and the gut (stool) of ventilated preterm-born infants. Bacterial DNA load was measured in all samples and sequenced using the V3–V4 region of the 16S rRNA gene.ResultsFrom 1102 (539 nasopharyngeal aspirates, 276 tracheal aspirate fluid, 89 bronchoalveolar lavage, 198 stool) samples from 55 preterm infants, 352 (32%) amplified suitably for 16S RNA gene sequencing. Bacterial load was low at birth and quickly increased with time, but was associated with predominant operational taxonomic units (OTUs) in all sample types. There was dissimilarity in bacterial communities between the upper and lower airways and the gut, with a separate dysbiotic inflammatory process occurring in the lower airways of infants. Individual OTUs were associated with increased inflammatory markers.ConclusionsTaken together, these findings suggest that targeted treatment of the predominant organisms, including those not routinely treated, such asUreaplasmaspp., may decrease the development of CLD in preterm-born infants.
The modular nature of protein evolution: domain rearrangement rates across eukaryotic life
Authors: Dohmen Elias , Klasberg Steffen , Bornberg-Bauer Erich , Perrey Sören , Kemena Carsten 
Published: February 2020

Abstract
Background
Modularity is important for evolutionary innovation. The recombination of existing units to form larger complexes with new functionalities spares the need to create novel elements from scratch. In proteins, this principle can be observed at the level of protein domains, functional subunits which are regularly rearranged to acquire new functions.

Results
In this study we analyse the mechanisms leading to new domain arrangements in five major eukaryotic clades (vertebrates, insects, fungi, monocots and eudicots) at unprecedented depth and breadth. This allows, for the first time, to directly compare rates of rearrangements between different clades and identify both lineage specific and general patterns of evolution in the context of domain rearrangements. We analyse arrangement changes along phylogenetic trees by reconstructing ancestral domain content in combination with feasible single step events, such as fusion or fission. Using this approach we explain up to 70% of all rearrangements by tracing them back to their precursors. We find that rates in general and the ratio between these rates for a given clade in particular, are highly consistent across all clades. In agreement with previous studies, fusions are the most frequent event leading to new domain arrangements. A lineage specific pattern in fungi reveals exceptionally high loss rates compared to other clades, supporting recent studies highlighting the importance of loss for evolutionary innovation. Furthermore, our methodology allows us to link domain emergences at specific nodes in the phylogenetic tree to important functional developments, such as the origin of hair in mammals.

Conclusions
Our results demonstrate that domain rearrangements are based on a canonical set of mutational events with rates which lie within a relatively narrow and consistent range. In addition, gained knowledge about these rates provides a basis for advanced domain-based methodologies for phylogenetics and homology analysis which complement current sequence-based methods.
Optical coherence tomography features of retinal lesions in Chinese patients with endogenous Candida endophthalmitis
Authors: Zhuang Hong , Ding Xinyi , Gao Fengjuan , Zhang Ting , Ni Yingqin , Chang Qing , Xu Gezhi 
Published: February 2020

AbstractBackgroundTo evaluate the optical coherence tomography (OCT) features of retinal lesions in Chinese patients with endogenous Candida endophthalmitis (ECE).MethodsWe performed a retrospective review of patients diagnosed with ECE at one medical center. The medical records of the patients including predisposing risk factors, treatment and visual acuity were reviewed. And we focused on the analysis of OCT images of retinal lesions before and after treatment.ResultsA total of 16 Chinese patients (22 eyes) were included in this study. The most frequent predisposing risk factors were intravenous use of corticosteroids or antibiotics, lithotripsy for urinary calculi, and diabetes. After treatment, visual acuity was improved in 13 (59.1%) of the 22 eyes, and remained the same in the other 9 (40.9%) eyes. Pre-treatment OCT images obtained at presentation were available for 17 of the 22 eyes. Four types of the OCT manifestations of retinal lesions were identified: type 1 (subretinal macular lesions), type 2 (lesions are located in the inner retinal layer), type 3 (lesions involve the full-thickness retina and accompanied with macular edema), type 4 (sub-inner limiting membrane lesions). Pre-treatment OCT imaging of the 17 eyes revealed five as type 1, four as type 2, six as type 3, and two as type 4. After treatment, OCT images revealed epiretinal membrane and subretinal fibrosis as the most common post-treatment complications of ECE. Epiretinal membrane was detected in 2/4 type 2 lesions, in 4/6 type 3 lesions, and in 1/2 type 4 lesions, while subretinal fibrosis was mainly seen in type 1 lesions (4/5). Among the types, visual prognosis was best in eyes with type 2 lesions.ConclusionsIn this case series, the OCT manifestations of retinal lesions in ECE could be classified into four types. The post-treatment OCT manifestations were different in four types of lesions. We preliminarily found that the OCT morphology of retinal lesions was associated with the visual prognosis of ECE.
Better influenza vaccines: an industry perspective
Authors: Chen Juine-Ruey , Liu Yo-Min , Tseng Yung-Chieh , Ma Che 
Published: February 2020

AbstractVaccination is the most effective measure at preventing influenza virus infections. However, current seasonal influenza vaccines are only protective against closely matched circulating strains. Even with extensive monitoring and annual reformulation our efforts remain one step behind the rapidly evolving virus, often resulting in mismatches and low vaccine effectiveness. Fortunately, many next-generation influenza vaccines are currently in development, utilizing an array of innovative techniques to shorten production time and increase the breadth of protection. This review summarizes the production methods of current vaccines, recent advances that have been made in influenza vaccine research, and highlights potential challenges that are yet to be overcome. Special emphasis is put on the potential role of glycoengineering in influenza vaccine development, and the advantages of removing the glycan shield on influenza surface antigens to increase vaccine immunogenicity. The potential for future development of these novel influenza vaccine candidates is discussed from an industry perspective.
The efficacy and safety of pharmacological treatments for lymphangioleiomyomatosis
Authors: Wang Qi , Luo Mengqi , Xiang Bo , Chen Siyuan , Ji Yi 
Published: February 2020

Abstract
Background
Lymphangioleiomyomatosis (LAM) is a rare, low-grade multisystem neoplastic disease. Most LAM patients are at a high risk of losing lung function at an accelerated rate and developing progressive dyspnea. Recently, several studies have reported their experience with pharmacological treatments for LAM. Therefore, we conducted a systematic review and meta-analysis to assess the efficacy and safety of these therapies.

Methods
PubMed (Medline), EMBASE, Cochrane Library, Web of Science and EBSCO Host were searched (until March 31, 2019) for eligible prospective studies regarding LAM patients treated with pharmacological treatments. Random effect models were used for quantitative analysis.

Results
Fourteen prospective studies regarding five pharmacological treatments (including sirolimus, everolimus, doxycycline, triptorelin, and a combination therapy of sirolimus and hydroxychloroquine) were enrolled in our systematic review, and ten of them were used for the meta-analysis. Seven prospective studies reported that sirolimus was effective at improving or stabilizing lung function and alleviating renal angiomyolipoma (AML) in LAM patients. Subsequent quantitative analyses showed that during sirolimus treatment, the pooled values of lung function and 6-min walk distance (6MWD) were not significantly changed (P > 0.05), with the pooled response rate of AML being 0.62 (95% confidence intervals [CIs]: 0.43 to 0.82, I2 = 65%). Regarding everolimus, three prospective studies reported similar effects to those of sirolimus with regard to preserving lung function and reducing AMLs. The meta-analysis showed that the changes in lung function during everolimus treatment were not statistically significant (P > 0.05), while the pooled response rate of AML was 0.78 (95% CI: 0.68 to 0.88, I2 = 8%). Neither the qualitative nor the quantitative results confirmed the benefits of doxycycline or triptorelin treatment, and the effects of the combination therapy were unclear in LAM patients. Most of the adverse events during pharmacological treatments were low or moderate grade and tolerable.

Conclusions
Overall, sirolimus and everolimus were recommended for the treatment of LAM because they could stabilize lung function and alleviate renal AML. Doxycycline and triptorelin were not recommended for the treatment of LAM because no beneficial outcomes were consistently observed. The efficacy and safety of combination therapy remain to be further explored.
Epileptic seizure classifications using empirical mode decomposition and its derivative
Authors: Karabiber Cura Ozlem , Kocaaslan Atli Sibel , Türe Hatice Sabiha , Akan Aydin 
Published: February 2020

Abstract
Background
Epilepsy is one of the most common neurological disorders associated with disruption of brain activity. In the classification and detection of epileptic seizures, electroencephalography (EEG) measurements, which record the electrical activities of the brain, are frequently used. Empirical mode decomposition (EMD) and its derivative, ensemble EMD (EEMD) are recently developed methods used to decompose non-stationary and nonlinear signals such as EEG into a finite number of oscillations called intrinsic mode functions (IMFs). Our main objective in this study is to present a hybrid IMF selection method combining four different approaches (energy, correlation, power spectral distance, and statistical significance measures), and investigate the effect of selected IMFs extracted by EMD and EEMD on the classification. We have applied the proposed IMF selection approach on the classification of EEG signals recorded from epilepsy patients who are under treatment at our collaborator hospital. Multichannel EEG signals collected from epilepsy patients are decomposed into IMFs, and then IMF selection was performed. Finally, time- and spectral-domain, and nonlinear features are extracted and feature sets are created for the classification.

Results
The maximum classification accuracies obtained using various combinations of IMFs were 94.56%, 95.63%, 96.8%, and 96.25% for SVM, KNN, naive Bayes, and logistic regression classifiers, respectively, by using EMD analysis; whereas, the EEMD approach has provided maximum classification accuracies of 96.06%, 97%, 97%, and 96.25% for SVM, KNN, naive Bayes, and logistic regression, respectively. Classification performance with the same features obtained using direct EEG signals instead of the decomposed IMFs was worse than the aforementioned 2 approaches for every combination.

Conclusion
Simulation results demonstrate that the proposed IMF selection approach affects the classification results. Also, EEMD provides a robust method for feature extraction from EEG signals in order to classify pre-seizure and seizure segments.
Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis
Authors: Ospina-Tascón Gustavo A. , Hernandez Glenn , Alvarez Ingrid , Calderón-Tapia Luis E. , Manzano-Nunez Ramiro , Sánchez-Ortiz Alvaro I. , Quiñones Egardo , Ruiz-Yucuma Juan E. , Aldana José L. , Teboul Jean-Louis , Cavalcanti Alexandre Biasi , De Backer Daniel , Bakker Jan 
Published: February 2020

Abstract
Background
Optimal timing for the start of vasopressors (VP) in septic shock has not been widely studied since it is assumed that fluids must be administered in advance. We sought to evaluate whether a very early start of VP, even without completing the initial fluid loading, might impact clinical outcomes in septic shock.

Methods
A total of 337 patients with sepsis requiring VP support for at least 6 h were initially selected from a prospectively collected database in a 90-bed mixed-ICU during a 24-month period. They were classified into very-early (VE-VPs) or delayed vasopressor start (D-VPs) categories according to whether norepinephrine was initiated or not within/before the next hour of the first resuscitative fluid load. Then, VE-VPs (n = 93) patients were 1:1 propensity matched to D-VPs (n = 93) based on age; source of admission (emergency room, general wards, intensive care unit); chronic and acute comorbidities; and lactate, heart rate, systolic, and diastolic pressure at vasopressor start. A risk-adjusted Cox proportional hazard model was fitted to assess the association between VE-VPs and day 28 mortality. Finally, a sensitivity analysis was performed also including those patients requiring VP support for less than 6 h.

Results
Patients subjected to VE-VPs received significantly less resuscitation fluids at vasopressor starting (0[0–510] vs. 1500[650–2300] mL, p < 0.001) and during the first 8 h of resuscitation (1100[500–1900] vs. 2600[1600–3800] mL, p < 0.001), with no significant increase in acute renal failure and/or renal replacement therapy requirements. VE-VPs was related with significant lower net fluid balances 8 and 24 h after VPs. VE-VPs was also associated with a significant reduction in the risk of death compared to D-VPs (HR 0.31, CI95% 0.17–0.57, p < 0.001) at day 28. Such association was maintained after including patients receiving vasopressors for < 6 h.

Conclusion
A very early start of vasopressor support seems to be safe, might limit the amount of fluids to resuscitate septic shock, and could lead to better clinical outcomes.
Nutritional support in sepsis: when less may be more
Authors: van Niekerk Gustav , Meaker Charné , Engelbrecht Anna-Mart 
Published: February 2020

AbstractDespite sound basis to suspect that aggressive and early administration of nutritional support may hold therapeutic benefits during sepsis, recommendations for nutritional support have been somewhat underwhelming. Current guidelines (ESPEN and ASPEN) recognise a lack of clear evidence demonstrating the beneficial effect of nutritional support during sepsis, raising the question: why, given the perceived low efficacy of nutritionals support, are there no high-quality clinical trials on the efficacy of permissive underfeeding in sepsis? Here, we review clinically relevant beneficial effects of permissive underfeeding, motivating the urgent need to investigate the clinical benefits of delaying nutritional support during sepsis.
Seismic Hazard Function (SHF) study of coastal sources of Sumatra Island: SHF evaluation of Padang and Bengkulu cities
Authors: Triyoso Wahyu , Suwondo Aris , Yudistira Tedi , Sahara David P. 
Published: February 2020

AbstractSignificant earthquakes on the island of Sumatra, Indonesia, have predominantly been earthquakes with a thrust mechanism that occurred due to the subduction process and seismotectonics near coastal cities of West and South Sumatra, which could be affected by earthquakes triggered by these seismic sources. We compared the Seismic Hazard Function (SHF) of two coastal cities of Sumatra: Bengkulu and Padang. The results showed that the SHF of Bengkulu is higher than that of Padang. Estimated earthquake hazards are presented in the form of seismic hazard maps expressed as the PGA of 10% rate of exceedance probability in 50 years. In estimating the seismic potential in Sumatra, the seismic moment rate was jointly estimated from the smoothed mean seismicity rate and the pre-seismic subduction surface strain rate model. In this study, the island of Sumatra was chosen as a master model for Seismic Hazard Analysis (SHA). The motivation for choosing Sumatra for the SHA was because of the large body of complete historical earthquake data of the North Western Sunda Arc. The SHF is calculated based on a magnitude range of 6.0 to 9.0 during 50 years with the radius distance from the source less than or equal to 100 km.