bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling gain-of-function and loss-of-function components ofSPAST-based hereditary spastic paraplegia using transgenic mice
Authors: Piermarini Emanuela , Akarsu Seyma , Connors Theresa , Kneussel Matthias , Lane Michael A , Morfini Gerardo , Karabay Arzu , Baas Peter W , Qiang Liang 
Published: December 2021

AbstractHereditary spastic paraplegia (HSP) is a disease in which dieback degeneration of corticospinal tracts, accompanied by axonal swellings, leads to gait deficiencies. SPG4-HSP, the most common form of the disease, results from mutations of human spastin gene (SPAST), which is the gene that encodes spastin, a microtubule-severing protein. The lack of a vertebrate model that recapitulates both the etiology and symptoms of SPG4-HSP has stymied the development of effective therapies for the disease. hSPAST-C448Y mice, which express human mutant spastin at the ROSA26 locus, display corticospinal dieback and gait deficiencies but not axonal swellings. On the other hand, mouse spastin gene (Spast)-knockout (KO) mice display axonal swellings but not corticospinal dieback or gait deficiencies. One possibility is that reduced spastin function, resulting in axonal swellings, is not the cause of the disease but exacerbates the toxic effects of the mutant protein. To explore this idea, Spast-KO and hSPAST-C448Y mice were crossbred, and the offspring were compared with the parental lines via histological and behavioral analyses. The crossbred animals displayed axonal swellings as well as earlier onset, worsened gait deficiencies and corticospinal dieback compared with the hSPAST-C448Y mouse. These results, together with observations on changes in histone deacetylases 6 and tubulin modifications in the axon, indicate that each of these three transgenic mouse lines is valuable for investigating a different component of the disease pathology. Moreover, the crossbred mice are the best vertebrate model to date for testing potential therapies for SPG4-HSP.
Development of a Personalized Intestinal Fibrosis Model Using Human Intestinal Organoids Derived From Induced Pluripotent Stem Cells
Authors: Estrada Hannah Q , Patel Shachi , Rabizadeh Shervin , Casero David , Targan Stephan R , Barrett Robert J 
Published: December 2021

Abstract

Background
Intestinal fibrosis is a serious complication of Crohn’s disease. Numerous cell types including intestinal epithelial and mesenchymal cells are implicated in this process, yet studies are hampered by the lack of personalized in vitro models. Human intestinal organoids (HIOs) derived from induced pluripotent stem cells (iPSCs) contain these cell types, and our goal was to determine the feasibility of utilizing these to develop a personalized intestinal fibrosis model.

Methods
iPSCs from 2 control individuals and 2 very early onset inflammatory bowel disease patients with stricturing complications were obtained and directed to form HIOs. Purified populations of epithelial and mesenchymal cells were derived from HIOs, and both types were treated with the profibrogenic cytokine transforming growth factor β (TGFβ). Quantitative polymerase chain reaction and RNA sequencing analysis were used to assay their responses.

Results
In iPSC-derived mesenchymal cells, there was a significant increase in the expression of profibrotic genes (Col1a1, Col5a1, and TIMP1) in response to TGFβ. RNA sequencing analysis identified further profibrotic genes and demonstrated differential responses to this cytokine in each of the 4 lines. Increases in profibrotic gene expression (Col1a1, FN, TIMP1) along with genes associated with epithelial-mesenchymal transition (vimentin and N-cadherin) were observed in TGFβ -treated epithelial cells.

Conclusions
We demonstrate the feasibility of utilizing iPSC-HIO technology to model intestinal fibrotic responses in vitro. This now permits the generation of near unlimited quantities of patient-specific cells that could be used to reveal cell- and environmental-specific mechanisms underpinning intestinal fibrosis.
A mathematical model to describe antibody-dependent enhancement and assess the effect of limiting cloning for plasma cells in heterologous secondary dengue infection
Authors: Alves Rubio Felipe , Mo Yang Hyun 
Published: December 2021

AbstractWe propose a mathematical model to study the antibody-dependent enhancement (ADE) phenomenon. Here, we explore the interaction between macrophages, dengue virus and plasma cells, especially the effect of a limitation on plasma cell proliferation, which occurs due to immunological memory. The model has up to three equilibrium points: one virus-free equilibrium and two virus-presence equilibrium, depending on the value of two thresholds. We determine the existence regions for the model equilibrium points and their stability, a sensitivity analysis was performed in the model thresholds. Numerical simulations illustrate that ADE can occur even when the basic reproduction number is less than one.
Supplementation With Fish Oil in Pregnancy Reduces Gastroenteritis in Early Childhood
Authors: Horner David , Hjelmsø Mathis Hjort , Thorsen Jonathan , Rasmussen Morten , Eliasen Anders , Vinding Rebecca Kofod , Schoos Ann-Marie Malby , Brustad Nicklas , Sunde Rikke Bjersand , Bønnelykke Klaus , Chawes Bo L , Stokholm Jakob , Bisgaard Hans 
Published: December 2021

Abstract

Background
We hypothesized that insufficient intake of fish oil–derived omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) during pregnancy is a contributing factor to gastroenteritis in early childhood. We examined the effect of n-3 LCPUFA supplementation on gastroenteritis symptoms in the offspring’s first 3 years of life.

Methods
This was a double-blinded, randomized controlled trial whereby 736 mothers were administered n-3 LCPUFA or control from pregnancy week 24 until 1 week after birth. We measured the number of days with gastroenteritis, number of episodes with gastroenteritis, and the risk of having a gastroenteritis episode in the first 3 years of life.

Results
A median reduction of 2.5 days with gastroenteritis (P = .018) was shown, corresponding to a 14% reduction in the n-3 LCPUFA group compared with controls in the first 3 years of life (P = .037). A reduction in the number of gastroenteritis episodes (P = .027) and a reduced risk of having an episode (hazard ratio, 0.80 [95% confidence interval, .66–.97]; P = .023) were also shown.

Conclusions
Fish oil supplementation from the 24th week of pregnancy led to a reduction in the number of days and episodes with gastroenteritis symptoms in the first 3 years of life. The findings suggest n-3 LCPUFA supplementation as a preventive measure against gastrointestinal infections in early childhood.

Clinical Trials Registration
NCT00798226.
Maize PHYTOMELATONIN RECEPTOR1 functions in plant tolerance to osmotic and drought stress
Authors: Wang Lin-Feng , Lu Kai-Kai , Li Ting-Ting , Zhang Yu , Guo Jia-Xing , Song Ru-Feng , Liu Wen-Cheng 
Published: December 2021

Abstract
Phytomelatonin is a universal signal molecule that regulates plant growth and stress responses; however, only one receptor that can directly bind with and perceive melatonin signaling has been identified so far, namely AtPMTR1/CAND2 in Arabidopsis. Whether other plants contain a similar receptor and, if so, how it functions is still unknown. In this study, we identified a new phytomelatonin receptor in the monocot maize (Zea mays), and investigated its role in plant responses to osmotic and drought stress. Using homology searching, we identified a plasma membrane-localized protein, Zm00001eb214610/ZmPMTR1, with strong binding activity to melatonin as a potential phytomelatonin receptor in maize. Overexpressing ZmPMTR1 in Arabidopsis Col-0 promoted osmotic stress tolerance, and rescued osmotic stress sensitivity of the Arabidopsis cand2-1 mutant. Furthermore, ZmPMTR1 also largely rescued defects in melatonin-induced stomatal closure in the cand2-1 mutant, thereby reducing water loss rate and increasing tolerance to drought stress. In addition, we identified a maize mutant of ZmPMTR1, EMS4-06e2fl, with a point-mutation causing premature termination of protein translation, and found that this mutant had lower leaf temperatures, increased rate of water loss, and enhanced drought stress sensitivity. Thus, we present ZmPMTR1 as the first phytomelatonin receptor to be identified and examined in a monocot plant, and our results indicate that it plays an important function in the response of maize to drought stress.
Oncology Patients Who Develop Transfusion-Associated Circulatory Overload: An Observational Study
Authors: Maldonado Marisol , Villamin Colleen E , Murphy Leah E , Dasgupta Amitava , Bassett Roland L , Correa Medina Mayrin , Bates Tonita S , Martinez Fernando , Knopfelmacher Couchonal Adriana M , Klein Kimberly , Kelley James M 
Published: December 2021

Abstract

Background
Transfusion-associated circulatory overload (TACO) is a largely preventable transfusion complication that results in significant morbidity and mortality. Cancers, related treatments, and comorbidities are among the factors that can predispose patients to TACO, but currently there are limited data on this topic in the literature.

Methods
We collected data retrospectively from the electronic health records of 93 adult patients with cancer who met Centers for Disease Control and Prevention (CDC) criteria for TACO from July 1, 2019, through October 31, 2020. The parameters we studied included demographics, comorbidities, treatment modalities, transfusion practices, and outcomes. We summarized data by means and ranges for continuous variables, and proportions for categorical variables.

Results
During the study period, the incidence of TACO among oncology patients was 0.84 per 1000 transfusions (95% CI, 0.68–1.02), representing 6.6% of all reactions. This percentage is high, compared with 1%–6% among other populations. Unique characteristics such as hematology malignancy (75.3%), receipt of cardiotoxic chemotherapy (87.1%), pneumonia (57.0%), preexisting oxygen use (59.1%), dyspnea (62.4%), hypertension (55.9%), renal insufficiency (46.2%), daily use of corticosteroids (43.0%), daily use of diuretics (40.9%), daily use of beta-blockers (36.6%), and elevated NT-proBNP (33.3%) were frequently observed in these group of oncology patients.

Conclusions
Our study indicates that oncology patients have unique factors that may lead to diagnosis of TACO. Developing appropriate guidelines that apply to oncology patients, in addition to those set forth by the CDC, should be considered. Implementation by ordering healthcare providers of a tools that can predict TACO can help in early recognition and mitigation of TACO.
Concussion Knowledge and Attitudes in Reserve Officers’ Training Corps Cadets
Authors: Radzak Kara N , Hunzinger Katherine J , Costantini Katelyn M , Swanik C Buz , Buckley Thomas A 
Published: December 2021

ABSTRACT

Introduction
Military members’ knowledge of concussion signs and symptoms may be critical to appropriate concussion identification and health-seeking behavior, particularly for those in leadership roles. The current study aimed to characterize concussion knowledge and attitudes among future military officers undergoing U.S.-based Reserve Officers’ Training Corps (ROTC) training.

Materials and Methods
Army and Air Force ROTC cadets at 2 large, public universities were utilized for a survey-based observational study. The study was approved by the institutional review board at both university research sites. Cadets completed a modified Rosenbaum Concussion Knowledge and Attitude Survey to obtain cadets’ Concussion Knowledge Index and Concussion Attitude Index, where higher scores are preferable. Cadets’ concussion knowledge and attitudes were characterized via descriptive statistics.

Results
Cadets (n = 110) had a mean Concussion Knowledge Index of 18.8 ± 3.2 (range = 9–23, out of 25). Potentially detrimental misconceptions included: belief that typically concussion symptoms no longer persist after 10 days (79.1%) and brain imaging shows visible physical damage following concussion (74.5%). Mean Concussion Attitude Index was 60.6 ± 7.4 (range = 46–75, out of 75). In general, cadets reported higher agreement with safe concussion behavior than what they believe peers would report.

Conclusions
Cadets were found to have a high concussion knowledge, yet common misconceptions remained. Cadets consistently reported safe choices but were less sure that peers felt similarly; future investigations should evaluate ROTC concussion social norms and education should note peers’ beliefs supporting safe concussion attitudes.
The evolution of the oxygen abundance gradients in star-forming galaxies in the eagle simulations
Authors: Tissera Patricia B , Rosas-Guevara Yetli , Sillero Emanuel , Pedrosa Susana E , Theuns Tom , Bignone Lucas 
Published: December 2021

ABSTRACT
We analyse the evolution of the oxygen abundance gradient of star-forming galaxies with stellar mass ${\rm M_{\ast }}\ge 10^{9}\rm M_{\odot }$ in the eagle simulation over the redshift range z = [0, 2.5]. We find that the median metallicity gradient of the simulated galaxies is close to zero at all z, whereas the scatter around the median increases with z. The metallicity gradients of individual galaxies can evolve from strong to weak and vice versa, since mostly low-metallicity gas accretes on to the galaxy, resulting in enhanced star formation and ejection of metal-enriched gas by energy feedback. Such episodes of enhanced accretion, mainly dominated by major mergers, are more common at higher z and hence contribute to increasing the diversity of gradients. For galaxies with negative metallicity gradients, we find a redshift evolution of $\rm \sim -0.03~dex~kpc^{-1}/\delta z$. A positive mass dependence is found at z ≤ 0.5, which becomes slightly stronger for higher redshifts and, mainly, for ${\rm M_{\ast }}\lt 10^{9.5} \rm M_{\odot }$. Only galaxies with negative metallicity gradients define a correlation with galaxy size, consistent with an inside-out formation scenario. Our findings suggest that major mergers and/or significant gas accretion can drive strong negative or positive metallicity gradients. The first ones are preferentially associated with disc-dominated galaxies, and the second ones with dispersion-dominated systems. The comparison with forthcoming observations at high redshift will allow a better understanding of the potential role of metallicity gradients as a chemical probe of galaxy formation.
Characterizing epochs of star formation across the Milky Way disc using age–metallicity distributions of GALAH stars
Authors: Sahlholdt Christian L , Feltzing Sofia , Feuillet Diane K 
Published: December 2021

ABSTRACT
We provide a detailed map of the ages and metallicities of turn-off stars in the Milky Way disc based on data from GALAH DR3 and Gaia EDR3. From this map, we identify previously undetected features in the age–metallicity distribution of disc stars and interpret these results as indicating a three-phase formation history of the Milky Way. In the first phase, inner disc stars form along a single age–metallicity sequence and are today kinematically hot. The end of this phase is marked by a local minimum in the inner disc age distribution 10 Gyr ago. At this time, we find the stellar populations to transition from high to low alpha-element abundances and from high to low vertical velocity dispersion. In the second phase, stars form across the disc with outwardly decreasing metallicity. In this phase, inner disc stars form at supersolar metallicities in a continuation of the early age–metallicity relation, while outer disc stars begin forming at metallicities at least 0.5 dex lower. Finally, the third phase is associated with a recent burst of star formation across the local disc marked by a local minimum in the age–metallicity distribution 4–6 Gyr ago. Future quantitative comparisons between the observed age–metallicity distribution and those of simulated galaxies could help constrain the processes driving each of the star formation phases.
Role of the radiative stage for cosmic ray acceleration in SNRs
Authors: Zirakashvili V N , Ptuskin V S 
Published: December 2021

ABSTRACT
We consider diffusive shock acceleration in supernova remnants throughout their evolution including a radiative stage. It is found that a more efficient acceleration and fast exit of particles at the radiative stage results in the hardening of the source cosmic ray proton and electron spectra at energies ∼100–500 GeV. The effect is stronger for cosmic ray electrons.
Role of PemI in the Staphylococcus aureus PemIK toxin–antitoxin complex: PemI controls PemK by acting as a PemK loop mimic
Authors: Kim Do-Hee , Kang Sung-Min , Baek Sung-Min , Yoon Hye-Jin , Jang Dong Man , Kim Hyoun Sook , Lee Sang Jae , Lee Bong-Jin 
Published: December 2021

Abstract
Staphylococcus aureus is a notorious and globally distributed pathogenic bacterium. New strategies to develop novel antibiotics based on intrinsic bacterial toxin–antitoxin (TA) systems have been recently reported. Because TA systems are present only in bacteria and not in humans, these distinctive systems are attractive targets for developing antibiotics with new modes of action. S. aureus PemIK is a type II TA system, comprising the toxin protein PemK and the labile antitoxin protein PemI. Here, we determined the crystal structures of both PemK and the PemIK complex, in which PemK is neutralized by PemI. Our biochemical approaches, including fluorescence quenching and polarization assays, identified Glu20, Arg25, Thr48, Thr49, and Arg84 of PemK as being important for RNase function. Our study indicates that the active site and RNA-binding residues of PemK are covered by PemI, leading to unique conformational changes in PemK accompanied by repositioning of the loop between β1 and β2. These changes can interfere with RNA binding by PemK. Overall, PemK adopts particular open and closed forms for precise neutralization by PemI. This structural and functional information on PemIK will contribute to the discovery and development of novel antibiotics in the form of peptides or small molecules inhibiting direct binding between PemI and PemK.
Diverse DNA modification in marine prokaryotic and viral communities
Authors: Hiraoka Satoshi , Sumida Tomomi , Hirai Miho , Toyoda Atsushi , Kawagucci Shinsuke , Yokokawa Taichi , Nunoura Takuro 
Published: December 2021

Abstract
DNA chemical modifications, including methylation, are widespread and play important roles in prokaryotes and viruses. However, current knowledge of these modification systems is severely biased towards a limited number of culturable prokaryotes, despite the fact that a vast majority of microorganisms have not yet been cultured. Here, using single-molecule real-time sequencing, we conducted culture-independent ‘metaepigenomic’ analyses (an integrated analysis of metagenomics and epigenomics) of marine microbial communities. A total of 233 and 163 metagenomic-assembled genomes (MAGs) were constructed from diverse prokaryotes and viruses, respectively, and 220 modified motifs and 276 DNA methyltransferases (MTases) were identified. Most of the MTase genes were not genetically linked with the endonuclease genes predicted to be involved in defense mechanisms against extracellular DNA. The MTase-motif correspondence found in the MAGs revealed 10 novel pairs, 5 of which showed novel specificities and experimentally confirmed the catalytic specificities of the MTases. We revealed novel alternative specificities in MTases that are highly conserved in Alphaproteobacteria, which may enhance our understanding of the co-evolutionary history of the methylation systems and the genomes. Our findings highlight diverse unexplored DNA modifications that potentially affect the ecology and evolution of prokaryotes and viruses in nature.
Neuronal exposure induces neurotransmitter signaling and synaptic mediators in tumors early in brain metastasis
Authors: Deshpande Krutika , Martirosian Vahan , Nakamura Brooke Naomi , Iyer Mukund , Julian Alex , Eisenbarth Rachel , Shao Ling , Attenello Frank , Neman Josh 
Published: December 2021

Abstract

Background
Brain metastases (BM) are responsible for neurological decline and poor overall survival. Although the pro-metastatic roles of glial cells, and the acquisition of neuronal attributes in established BM tumors have been described, there are no studies that investigate the initial interplay between neurons and brain-seeking tumor cells. The aim of this study was to characterize early tumor-neuron interactions and the induced CNS-adaptive changes in tumor cells prior to macro-colonization

Methods
Utilizing pure neuronal cultures and brain-naïve and patient-derived BM tumor cells, we surveyed the early induction of mediators of neurotransmitter (NT) and synaptic signaling in breast and lung tumor cells. Reliance on microenvironmental GABA in breast-to-brain metastatic cells (BBMs) was assessed in vitro and in vivo.

Results
Coculture with neurons induces early expression of classical NT receptor genes (HTR4, GRIA2, GRIN2B, GRM4, GRM8, DRD1) and neuronal synaptic mediators (CNR1, EGR2, ARC, NGFR, NRXN1) in breast and lung cancer cells. NT-dependent classification of tumor cells within the neuronal niche shows breast cancer cells become GABAergic responsive brain metastases (GRBMs) and transition from relying on autocrine GABA, to paracrine GABA from adjacent neurons; while autocrine Dopaminergic breast and lung tumor cells persist. In vivo studies confirm reliance on paracrine GABA is an early CNS-acclimation strategy in breast cancer. Moreover, neuronal contact induces early resurgence in Reelin expression in tumor cells through epigenetic activation, facilitating CNS adaptation.

Conclusion
Tumor-neuron interactions allow for CNS adaptation early in the course of brain metastasis.
Intravenous immunoglobulin for interstitial lung diseases of anti-melanoma differentiation-associated gene 5-positive dermatomyositis
Authors: Wang Li-Mei , Yang Qi-Hua , Zhang Lei , Liu Sheng-Yun , Zhang Pan-Pan , Zhang Xin , Liu Xiao-Jun , Han Li-Shuai , Li Tian-Fang 
Published: December 2021

Abstract

Objective
Rapidly progressive interstitial lung disease (RP-ILD) in DM patients positive for anti-melanoma differentiation-associated gene 5 (anti-MDA5) autoantibody (MDA5-DM) often have a poor prognosis, frequently fatal. As there is a scarcity of data regarding the effect of intravenous immunoglobulin (IVIG) on RP-ILD in MDA5-DM patients (MDA5-RPILD), we conducted this study to determine the efficacy of a IVIG add-on initial treatment.

Methods
Patients with newly-onset MDA5-RPILD from September 2018 to June 2020 were retrospectively reviewed for 6 months in the First Affiliated Hospital of Zhengzhou University. They were divided into two groups: IVIG and non-IVIG groups. The major measurement of treatment outcome was the difference in the mortality in 3-month and 6-month between two group patients. Other relevant indicators were also recorded, including the incidence of infection, the dosages of GCs, the remission rate and the variables in laboratory data.

Results
The IVIG group (n = 31) showed significantly lower 6-month mortality rate than the non-IVIG group (n = 17) (22.6% vs 52.9%; P =0.033). The IVIG group patients had a higher remission rate at 3 months (71.0% vs 41.2%; P =0.044). Gradual reduction was observed in the first 3 months with regard to the titre of anti-MDA5 autoantibody, the serum level of ferritin and the ground glass opacification GGO scores.

Conclusion
IVIG adjunct therapy is a very effective first-line treatment for patients with MDA5-RPILD. IVIG may increase the survival and remission rate by lowering ferritin concentration, anti-MDA5 titre and GGO score.