bluuebunny/crossref_metadata_2025_split huggingface dataset:
A somatic mutation in PIK3CD unravels a novel candidate gene for lymphatic malformation
Authors: Wang Shengcai , Wang Wei , Zhang Xuexi , Gui Jingang , Zhang Jie , Guo Yongli , Liu Yuanhu , Han Lin , Liu Qiaoyin , Li Yanzhen , Sun Nian , Liu Zhiyong , Du Jiangnan , Tai Jun , Ni Xin 
Published: May 2021

Abstract
Background
Lymphatic malformations (LMs) are benign congenital malformations that stem from the abnormal development of the lymphatic vessels during early embryogenesis. Somatic PIK3CA gene mutations are conventional cause leading to LMs. Both macrocystic and microcystic LMs arise due to lymphatic endothelial cell-autonomous defects, depending on the time in development at which PIK3CA gene mutation occurs. Recent study finds a PIK3CA mutation in 79% of LMs. However, discovering new genetic events in this disease is crucial to identify the molecular mechanism of the pathogenesis and further develop new targeted therapies.

Results
Here, we initially performed whole-exome sequencing in six children with LMs to find a new causal gene. Somatic mutations in PIK3CA (c.1633G > A [p. E545K] and PIK3CD (c.1997T > C [p.L666P]) were discovered in two different individuals. In vitro functional studies were conducted to demonstrate the pathogenicity of the novel mutation c.1997T > C in PIK3CD. We found that L666P promoted the cell proliferation and migration of human umbilical vein endothelial cells (HUVECs) and induced hyperactivation of the mTOR pathway. These findings indicate that the PIK3CD mutation affects downstream signalling in endothelial cells, which may impair normal lymphangiogenesis.

Conclusions
This study reveals a novel candidate gene associated with the development of LMs, which is consistent with previous researches. These findings in our study may offer a novel gene target for developing therapies, which acts in tight interaction with the previously known PIK3CA.
Engineering oleaginous yeast Rhodotorula toruloides for overproduction of fatty acid ethyl esters
Authors: Zhang Yang , Peng Jie , Zhao Huimin , Shi Shuobo 
Published: May 2021

Abstract
Background
Production of biofuels and green chemicals by microbes is currently of great interest due to the increasingly limited reserves of fossil fuels. Biodiesel, especially fatty acid ethyl esters (FAEEs), is considered as an attractive alternative because of its similarity with petrodiesel and compatibility with existing infrastructures. Cost-efficient bio-production of FAEEs requires a highly lipogenic production host that is suitable for large-scale fermentation. As a non-model oleaginous yeast that can be cultured to an extremely high cell density and accumulate over 70% cell mass as lipids, Rhodotorula toruloides represents an attractive host for FAEEs production.

Results
We first constructed the FAEE biosynthetic pathways in R. toruloides by introducing various wax ester synthase genes from different sources, and the bifunctional wax ester synthase/acyl-CoA-diacyglycerol acyltransferase (WS/DGAT) gene from Acinetobacter baylyi was successfully expressed, leading to a production of 826 mg/L FAEEs through shake-flask cultivation. We then mutated this bifunctional enzyme to abolish the DGAT activity, and further improved the titer to 1.02 g/L. Finally, to elevate the performance of Δku70-AbWS* in a bioreactor, both batch and fed-batch cultivation strategies were performed. The FAEEs titer, productivity and yield were 4.03 g/L, 69.5 mg/L/h and 57.9 mg/g (mg FAEEs/g glucose) under batch cultivation, and 9.97 g/L, 90.6 mg/L/h, and 86.1 mg/g under fed-batch cultivation. It is worth mentioning that most of the produced FAEEs were secreted out of the cell, which should greatly reduce the cost of downstream processing.

Conclusion
We achieved the highest FAEEs production in yeast with a final titer of 9.97 g/L and demonstrated that the engineered R. toruloides has the potential to serve as a platform strain for efficient production of fatty acid-derived molecules.
Clinical characteristics and prognosis of patients with isolated thrombotic vs. obstetric antiphospholipid syndrome: a prospective cohort study
Authors: Jiang Hui , Wang Chu-Han , Jiang Nan , Li Jing , Wu Chan-Yuan , Wang Qian , Li Meng-Tao , Tian Xin-Ping , Zhao Jiu-Liang , Zhao Yan , Zeng Xiao-Feng 
Published: May 2021

Abstract
Background
Several studies suggested that thrombotic and obstetric antiphospholipid syndromes could be independent identities, but few have systematically compared their clinical characteristics and prognosis.

Objective
The objective of this study is to identify key differences between thrombotic APS (tAPS) and obstetric APS (oAPS).

Methods
This single-center, prospective study included consecutive patients with primary antiphospholipid syndrome (APS) receiving treatment at the Peking Union Medical College Hospital during a period from 2013 to 2020.

Results
Screening of the database yielded a total of 244 women with positive antiphospholipid antibody (aPL). Among the 105 women with primary APS, 39 (37.14%) had isolated tAPS (ItAPS), 44 (41.90%) had isolated oAPS (IoAPS), and 9 (8.57%) had both tAPS and tAPS+oAPS. In comparison to those with IoAPS, patients with ItAPS had older age (41.92 ± 11.97 vs. 33.16 ± 4.22 years, P < 0.01), higher rate of cardiovascular risk (at least one positive of coronary heart disease, hypertension, obesity, diabetes, and hyperlipidemia) (41.03% vs. 6.82%, P < 0.01), and higher frequency of thrombocytopenia (43.59% vs. 20.45%, P < 0.05). Antibody profiles were generally similar among the groups, but isolated anti-β2GPI positivity was more common in patients with IoAPS (52.27% vs. 17.94% for ItAPS, P = 0.01). Triple aPL positivity was more common in patients with both tAPS and oAPS (66.67% vs. 46.15% for ItAPS vs. 25% for IoAPS, P = 0.022). Blood homocysteine was higher in patients with ItAPS (11.20 vs. 9.90 μmol/L for IoAPS, P < 0.05), but there were no differences in inflammatory markers or complements. Recurrence rate of thrombosis was higher in patients with ItAPS (33.33% vs. 2.27% for IoAPS, P ≤ 0.001) with a mean follow-up of 61 months.

Conclusion
Despite generally similar antibody and biochemical profiles, patients with ItAPS had much higher risk of recurrent thrombosis than IoAPS, supporting distinct mechanisms of pathogenesis.
Fli1 deficiency suppresses RALDH1 activity of dermal dendritic cells and related induction of regulatory T cells: a possible role in scleroderma
Authors: Miura Shunsuke , Watanabe Yusuke , Saigusa Ryosuke , Yamashita Takashi , Nakamura Kouki , Hirabayashi Megumi , Miyagawa Takuya , Yoshizaki Ayumi , Trojanowska Maria , Sato Shinichi , Asano Yoshihide 
Published: May 2021

Abstract
Background
Aldehyde dehydrogenase 1 family member A1 (RALDH1)-producing dermal dendritic cells (DCs), a conventional DC subset regulating skin fibrosis, are decreased in the involved skin of patients with systemic sclerosis (SSc). In this study, we investigated the contribution of Fli1 deficiency, a potential predisposing factor of SSc, to the phenotypical alteration of RALDH1-producing dermal DCs by using SSc model mice and SSc skin samples.

Methods
Bleomycin (BLM)-induced skin fibrosis was generated with Fli1+/− and wild-type mice. The proportions of DC and CD4+ T cell subsets were determined by flow cytometry in the dermis of BLM-treated mice. Fli1 expression in dermal DCs was evaluated by immunofluorescence with skin samples of SSc and healthy control subjects.

Results
RALDH activity of dermal DCs was significantly decreased in BLM-treated Fli1+/− mice compared with BLM-treated wild-type mice, whereas the proportion of CD103−CD11b− dermal DCs, a major DC subset producing RALDH1 in response to BLM injection, was comparable between groups. Relevant to this finding, the proportion of regulatory T cells (Tregs) in the dermis was decreased in BLM-treated Fli1+/− mice relative to BLM-treated wild-type mice, while the proportions of Th1, Th2 and Th17 cells were unaltered. In the involved skin of SSc patients, Fli1 was downregulated in CD11c+ cells, including dermal DCs.

Conclusions
Fli1 deficiency inhibits RALDH1 activity of CD103−CD11b− dermal DCs and related induction of Tregs in BLM-treated mice. Considering Fli1 reduction in SSc dermal DCs, Fli1deficiency may impair the dermal DC-Treg system, contributing to the development of skin fibrosis in SSc.
The effect of omega3 fatty acid supplementation on PPARγ and UCP2 expressions, resting energy expenditure, and appetite in athletes
Authors: Moradi Sara , Alivand Mohamadreza , KhajeBishak Yaser , AsghariJafarabadi Mohamad , Alipour Maedeh , Chilibeck Philip D. , Alipour Beitullah 
Published: May 2021

AbstractBackgroundOmega3 fatty acids as a ligand of energy-related genes, have a role in metabolism, and energy expenditure. These effects are due to changes in the expression of peroxisome proliferator-activated receptor-gamma (PPARγ) and uncoupling protein2 (UCP2). This study evaluated the effect of omega3 supplements on PPARγ mRNA expression and UCP2 mRNA expression and protein levels, as regulators of energy metabolism, resting energy expenditure (REE), and appetite in athletes.MethodsIn a 3-week double-blind RCT in Tabriz, Iran, in 2019, 36 male athletes, age 21.86 (±3.15) y with 16.17 (±5.96)% body fat were randomized to either an intervention (2000 mg/day omega3; EPA: 360, DHA: 240) or placebo (2000 mg/day edible paraffin) groups. Appetite and REE were assessed before and after the intervention. PPARγ and UCP2 mRNA expression and UCP2 protein levels in blood were evaluated by standard methods.ResultsResults showed PPARγ mRNA levels, and UCP2 mRNA and protein levels increased in omega3 group (p < 0.05), as did REE (p < 0.05). Also, differences in the sensation of hunger or satiety were significant (p < 0.05).ConclusionsOur findings showed that omega3 supplementation leads to the up-regulation of PPARγ and UCP2 expressions as the indicators of metabolism in healthy athletes.
Genomic characterization of bacteria from the ultra-oligotrophic Madison aquifer: insight into the archetypical LuxI/LuxR and identification of novel LuxR solos
Authors: Wengert Peter C. , Wong Narayan H. , Barton Hazel A. , Gan Han Ming , Hudson André O. , Savka Michael A. 
Published: May 2021

Abstract
Objectives
To characterize the bacterial community of Wind Cave’s Madison aquifer through whole-genome sequencing, and to better understand the bacterial ecology by identifying genes involved in acyl-homoserine lactone (AHL) based quorum-sensing (QS) systems.

Results
Genome-based taxonomic classification revealed the microbial richness present in the pristine Madison aquifer. The strains were found to span eleven genera and fourteen species, of which eight had uncertain taxonomic classifications. The genomes of strains SD129 and SD340 were found to contain the archetypical AHL QS system composed of two genes, luxI and luxR. Surprisingly, the genomes of strains SD115, SD129, SD274 and SD316 were found to contain one to three luxR orphans (solos). Strain SD129, besides possessing an archetypical AHL QS luxI-luxR pair, also contained two luxR solos, while strain SD316 contained three LuxR solos and no luxI-luxR pairs. The ligand-binding domain of two LuxR solos, one each from strains SD129 and SD316, were found to contain novel substitutions not previously reported, thus may represent two LuxR orphans that detection and response to unknown self-produced signal(s), or to signal(s) produced by other organisms.
Conscious rat PET imaging with soft immobilization for quantitation of brain functions: comprehensive assessment of anesthesia effects on cerebral blood flow and metabolism
Authors: Suzuki Chie , Kosugi Mutsumi , Magata Yasuhiro 
Published: May 2021

Abstract
Background
Animal brain functions evaluated by in vivo imaging under anesthesia can be affected by anesthetic agents, resulting in incorrect assessment of physiological brain function. We therefore performed dynamic positron emission tomography (PET) imaging of conscious rats using recently reported soft immobilization to validate the efficacy of the immobilization for brain function assessments. We also determined the effects of six anesthetic agents—a mixed anesthetic agent (MMB), ketamine + xylazine (KX), chloral hydrate (Chloral), pentobarbital (PTB), propofol (PF), and isoflurane (IFL)—on brain function by comparison with conscious rats.

Results
The immobilization enabled 45-min dynamic [18F]FDG-PET acquisition with arterial blood sampling using conscious rats without the use of special techniques or invasive surgery. The spatial resolution and quantitativity of [18F]FDG-PET were not significantly lower for conscious rats than for anesthetized rats. While MMB, Chloral, PTB, and PF showed ubiquitous reduction in the cerebral metabolic rates of glucose (CMRglu) in brain regions, KX and IFL showed higher reductions in cerebellum and interbrain, and cerebellum, respectively. Cerebral blood flow (CBF) was reduced by MMB, KX, PTB, and PF; increased by IFL; and unaltered by Chloral. The magnitude of decrease in CMRglu and CBF for MMB were not larger than for other five anesthetic agents, although blood glucose levels and body temperature can be easily affected by MMB.

Conclusion
The six anesthetic agents induced various effects on CMRglu and CBF. The immobilization technique presented here is a promising tool for noninvasive brain functional imaging using conscious rats to avoid the effects of anesthetic agents.
Exploring the oxygenase function of Form II Rubisco for production of glycolate from CO2
Authors: Yang Fan , Zhang Junli , Cai Zhen , Zhou Jie , Li Yin 
Published: May 2021

AbstractThe oxygenase activity of Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) converts ribulose-1,5-bisphosphate (RuBP) into 2-phosphoglycolate, which in turn channels into photorespiration, resulting in carbon and energy loss in higher plants. We observed that glycolate can be accumulated extracellularly when two genes encoding the glycolate dehydrogenase of cyanobacteria Synechocystis sp. PCC 6803 were inactivated. This inspired us to explore the oxygenase function of Rubisco for production of glycolate, an important industrial chemical, from CO2 by engineered cyanobacteria. Since the oxygenase activity of Rubisco is generally low in CO2-rich carboxysome of cyanobacteria, we introduced Form II Rubisco, which cannot be assembled in carboxysome, into the cytoplasm of cyanobacteria. Heterologous expression of a Form II Rubisco from endosymbiont of tubeworm Riftia pachyptila (RPE Rubisco) significantly increased glycolate production. We show that the RPE Rubisco is expressed in the cytoplasm. Glycolate production increased upon addition of NaHCO3 but decreased upon supplying CO2. The titer of glycolate reached 2.8 g/L in 18 days, a 14-fold increase compared with the initial strain with glycolate dehydrogenase inactivated. This is also the highest glycolate titer biotechnologically produced from CO2 ever reported. Photosynthetic production of glycolate demonstrated the oxygenase activity of Form II Rubisco can be explored for production of chemicals from CO2.
Programming adaptive laboratory evolution of 4-hydroxyisoleucine production driven by a lysine biosensor in Corynebacterium glutamicum
Authors: Yu Xinping , Shi Feng , Liu Haiyan , Tan Shuyu , Li Yongfu 
Published: May 2021

Abstract4-Hydroxyisoleucine (4-HIL) is a promising drug for treating diabetes. In our previous study, 4-HIL was synthesized from self-produced L-isoleucine (Ile) in Corynebacterium glutamicum by expressing an Ile dioxygenase gene. Although the 4-HIL production of recombinant strain SZ06 increased significantly, a by-product, L-lysine (Lys) was accumulated because of the share of the first several enzymes in Ile and Lys biosynthetic pathways. In this study, programming adaptive laboratory evolution (ALE) was designed and conducted in SZ06 to promote 4-HIL biosynthesis. At first, a programming evolutionary system pMK was constructed, which contains a Lys biosensor LysG-PlysE and an evolutionary actuator composed of a mutagenesis gene and a fluorescent protein gene. The evolutionary strain SZ06/pMK was then let to be evolved programmatically and spontaneously by sensing Lys concentration. After successive rounds of evolution, nine mutant strains K1 − K9 with significantly increased 4-HIL production and growth performance were obtained. The maximum 4-HIL titer was 152.19 ± 14.60 mM, 28.4% higher than that in SZ06. This titer was higher than those of all the metabolic engineered C. glutamicum strains ever constructed. The whole genome sequencing of the nine evolved strains revealed approximately 30 genetic mutations in each strain. Only one mutation was directly related to the Lys biosynthetic pathway. Therefore, programming ALE driven by Lys biosensor can be used as an effective strategy to increase 4-HIL production in C. glutamicum.
Role of sleep on respiratory failure after extubation in the ICU
Authors: Thille Arnaud W. , Barrau Stephanie , Beuvon Clément , Marie Damien , Reynaud Faustine , Bardin Justine , Pépin-Lehalleur Adrien , Bironneau Vanessa , Meurice Jean-Claude , Coudroy Rémi , Frat Jean-Pierre , Robert René , Rault Christophe , Drouot Xavier 
Published: May 2021

AbstractBackgroundSleep had never been assessed immediately after extubation in patients still in the ICU. However, sleep deprivation may alter respiratory function and may promote respiratory failure. We hypothesized that sleep alterations after extubation could be associated with an increased risk of post-extubation respiratory failure and reintubation. We conducted a prospective observational cohort study performed at the medical ICU of the university hospital of Poitiers in France. Patients at high-risk of extubation failure (> 65 years, with any underlying cardiac or lung disease, or intubated > 7 days) were included. Patients intubated less than 24 h, with central nervous or psychiatric disorders, continuous sedation, neuroleptic medication, or uncooperative were excluded. Sleep was assessed by complete polysomnography just following extubation including the night. The main objective was to compare sleep between patients who developed post-extubation respiratory failure or required reintubation and the others.ResultsOver a 3-year period, 52 patients had complete polysomnography among whom 12 (23%) developed post-extubation respiratory failure and 8 (15%) required reintubation. Among them, 10 (19%) had atypical sleep, 15 (29%) had no deep sleep, and 33 (63%) had no rapid eye movement (REM) sleep. Total sleep time was 3.2 h in median [interquartile range, 2.0–4.4] in patients who developed post-extubation respiratory failure vs. 2.0 [1.1–3.8] in those who were successfully extubated (p = 0.34). Total sleep time, and durations of deep and REM sleep stages did not differ between patients who required reintubation and the others. Reintubation rates were 21% (7/33) in patients with no REM sleep and 5% (1/19) in patients with REM sleep (difference, − 16% [95% CI − 33% to 6%];p = 0.23).ConclusionsSleep assessment by polysomnography after extubation showed a dramatically low total, deep and REM sleep time. Sleep did not differ between patients who were successfully extubated and those who developed post-extubation respiratory failure or required reintubation.
Hilfer fractional differential inclusions with Erdélyi–Kober fractional integral boundary condition
Authors: Lachouri Adel , Abdo Mohammed S. , Ardjouni Abdelouaheb , Abdalla Bahaaeldin , Abdeljawad Thabet 
Published: May 2021

AbstractIn this article, we debate the existence of solutions for a nonlinear Hilfer fractional differential inclusion with nonlocal Erdélyi–Kober fractional integral boundary conditions (FIBC). Both cases of convex- and nonconvex-valued right-hand side are considered. Our obtained results are new in the framework of Hilfer fractional derivative and Erdélyi–Kober fractional integral with FIBC via the fixed point theorems (FPTs) for a set-valued analysis. Some pertinent examples demonstrating the effectiveness of the theoretical results are presented.
On a pair of fuzzy mappings in modular-like metric spaces with applications
Authors: Rasham Tahair , Shoaib Abdullah , Park Choonkill , Agarwal Ravi P. , Aydi Hassen 
Published: May 2021

AbstractThe aim of this work is to establish results in fixed point theory for a pair of fuzzy dominated mappings which forms a rational fuzzy dominated V-contraction in modular-like metric spaces. Some results via a partial order and using the graph concept are also developed. We apply our results to ensure the existence of a solution of nonlinear Volterra-type integral equations.
Nonexistence results of Caputo-type fractional problem
Authors: Kassim Mohammed D. , Ali Saeed M. , Abdo Mohammed S. , Jarad Fahd 
Published: May 2021

AbstractIn this paper, we deal with Caputo-type fractional differential inequality where there is a low-order fractional derivative with the term polynomial source. We investigate the nonexistence of nontrivial global solutions in a suitable space via the test function technique and some properties of fractional integrals. Finally, we demonstrate three examples to illustrate our results. The presented results are more general than those in the literature, which can be obtained as particular cases.
Fixed point problems for generalized contractions with applications
Authors: Nazam Muhammad , Park Choonkil , Arshad Muhammad 
Published: May 2021

AbstractIn this paper, we investigate the conditions on the control mappings $\psi ,\varphi :(0,\infty )\rightarrow \mathbb{R}$
ψ
,
φ
:
(
0
,
∞
)
→
R
that guarantee the existence of the fixed points of the mapping $T:X\rightarrow P(X)$
T
:
X
→
P
(
X
)
satisfying the following inequalities: $$ \psi \bigl(H(Tx,Ty)\bigr)\leq \varphi \bigl(d(x,y)\bigr) \quad \forall x,y\in X, \text{provided that } H(Tx,Ty)>0, $$
ψ

(
H
(
T
x
,
T
y
)
)

≤
φ

(
d
(
x
,
y
)
)

∀
x
,
y
∈
X
,
provided that
H
(
T
x
,
T
y
)
>
0
,
and $$ \psi \bigl(H(Tx,Ty)\bigr)\leq \varphi \bigl(A(x,y)\bigr) \quad \forall x,y\in X, \text{provided that } H(Tx,Ty)>0, $$
ψ

(
H
(
T
x
,
T
y
)
)

≤
φ

(
A
(
x
,
y
)
)

∀
x
,
y
∈
X
,
provided that
H
(
T
x
,
T
y
)
>
0
,
where $A(x,y)=\max \{ d(x,y), d(x,Tx), d(y,Ty), (d(x,Ty) +d(Tx,y))/2 \} $
A
(
x
,
y
)
=
max
{
d
(
x
,
y
)
,
d
(
x
,
T
x
)
,
d
(
y
,
T
y
)
,
(
d
(
x
,
T
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)
+
d
(
T
x
,
y
)
)
/
2
}
, and $(X, d)$
(
X
,
d
)
is a metric space. The obtained fixed point results improve many earlier results on the set-valued contractions. As an application, we consider the existence of the solutions of an FDE.