bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large multicenter randomized trials in autism: key insights gained from the balovaptan clinical development program
Authors: Jacob Suma , Anagnostou Evdokia , Hollander Eric , Jou Roger , McNamara Nora , Sikich Linmarie , Tobe Russell , Murphy Declan , McCracken James , Ashford Elizabeth , Chatham Christopher , Clinch Susanne , Smith Janice , Sanders Kevin , Murtagh Lorraine , Noeldeke Jana , Veenstra-VanderWeele Jeremy 
Published: June 2022

Abstract
Background
Autism spectrum disorder (ASD) is a common and heterogeneous neurodevelopmental condition that is characterized by the core symptoms of social communication difficulties and restricted and repetitive behaviors. At present, there is an unmet medical need for therapies to ameliorate these core symptoms in order to improve quality of life of autistic individuals. However, several challenges are currently faced by the ASD community relating to the development of pharmacotherapies, namely in the conduct of clinical trials. Balovaptan is a V1a receptor antagonist that has been investigated to improve social communication difficulties in individuals with ASD. In this viewpoint, we draw upon our recent first-hand experiences of the balovaptan clinical development program to describe current challenges of ASD trials.

Discussion points
The balovaptan trials were conducted in a wide age range of individuals with ASD with the added complexities associated with international trials. When summarizing all three randomized trials of balovaptan, a placebo response was observed across several outcome measures. Placebo response was predicted by greater baseline symptom severity, online recruitment of participants, and less experienced or non-academic trial sites. We also highlight challenges relating to selection of outcome measures in ASD, the impact of baseline characteristics, and the role of expectation bias in influencing trial results.

Conclusion
Taken together, the balovaptan clinical development program has advanced our understanding of the key challenges facing ASD treatment research. The insights gained can be used to inform and improve the design of future clinical trials with the collective aim of developing efficacious therapies to support individuals with ASD.
Predictors of cord blood unit cell content in a volume unrestricted large series collections: a chance for a fast and cheap multiparameter selection model
Authors: Fumarola Stefania , Lucarini Alessandra , Lucchetti Giovanna , Piroli Luana , Pierelli Luca 
Published: June 2022

Abstract
Background
Cord blood plays a very important role in stem cell transplantation and therapy with an emerging implication also in regenerative medicine. The number of cells available in a single cord blood unit (CBU), in particular, the CD34+ and total nucleated cell (TNC) content influences the transplantation clinical outcome. We analysed a very large series of CBUs, collected for private banking without any specific volume restriction, to deeply investigate the best predictors of cord blood stem cells content.

Methods
Maternal and neonatal clinic laboratory data of a total 2583 UCBs were obtained from the InScientiaFides cord blood bank based in Republic of San Marino. Univariate and multivariate analysis were conducted to better interpret the data and to build a predictive model to select, the CBU with high CD34+ content.

Results
Our univariate analysis shows that seasonality and the geographical area affects the quality of umbilical cord blood. Gestational age, babie’s gender and birth weight have a positive correlation with CB TNC content. The babie’s birth weight affects positively also CD34+ content and CBU volume while the cesarean delivery affect the CB volume only. Our predictive model, based on multivariate analysis, shows that male babie’s, gestational age lower to 39 weeks, cesarean delivery and CBUs with a content of TNC higher than 3.44 × 108 (group A) have a significant higher CD34+ content than group B (female babie’s, gestational age higher than 39 weeks and vaginal delivery). The group A have a 37.5% of CBUs with a concentration of CD34+  > 2 × 106, while no CBUs with high concentration of CD34+ were detect in group B.

Conclusion
This study, conducted on a very large series of CBUs without any specific volume constraint, highlighted the prenatal and maternal factors that significantly influence the quality of the CBU collected. Specifically, it highlights that volume is not the best predictor of CD34+ CBU content; for this reason it cannot be taken into consideration alone for the analysis of the collected samples. Our final aim is to identify relevant factors, immediately available, that help to choice UCB with high CD34+ cell content, especially in simultaneous deliveries.
Activin B-activated Cdc42 signaling plays a key role in regulating adipose-derived mesenchymal stem cells-mediated skin wound healing
Authors: Huang Simin , Wang Xueer , Zhang Min , Huang Mianbo , Yan Yuan , Chen Yinghua , Zhang Yijia , Xu Jinfu , Bu Lingwei , Fan Ruyi , Tang Huiyi , Zeng Canjun , Zhang Lu , Zhang Lin 
Published: June 2022

Abstract
Background
In our previous study, activin B in combination with ADSCs enhances skin wound healing. However, the underlying molecular mechanisms are not well studied. Cdc42 is recognized to play a critical role in the regulation of stem cells.

Methods
Pull-down assay was performed to investigate the activity of Cdc42. The dominant-negative mutant of Cdc42 (Cdc42N17) was used to explore the role of Cdc42 in activin B-induced ADSCs migration, proliferation, and secretion in vitro. Cdc42N17-transfected ADSCs were injected into a full-thickness excisional wound model to explore their efficiency in wound healing in vivo. The wound healing efficacy was evaluated by the wound closure rates and histological examination. The neovascularization and wound contraction were detected by immunohistochemistry staining of CD31 and α-SMA. Finally, the underlying mechanisms were explored by RNA sequencing.

Results
Cdc42N17 inhibited ADSCs migration, proliferation, and secretion induced by activin B. Furthermore, Cdc42N17-transfected ADSCs inhibited the wound closure rate and suppressed the expression of CD31 and α-SMA induced by activin B in vivo. The RNA sequencing showed that the differentially expressed genes in Cdc42N17-transfected ADSCs versus ADSCs were associated with cell migration, proliferation, and adhesion. Further study revealed that the Cdc42-Erk-Srf pathway was required for activin B-induced proliferation in ADSCs.

Conclusions
Our study indicates that Cdc42 plays a crucial role in ADSCs-mediated skin wound healing induced by activin B.

Graphical Abstract
Preclinical study of human umbilical cord mesenchymal stem cell sheets for the recovery of ischemic heart tissue
Authors: Gao Shuang , Jin Yongqiang , Ma Jianlin , Wang Juan , Wang Jing , Shao Zehua , Fan Taibing , Zhang Mingkui , Chang Dehua 
Published: June 2022

Abstract
Background
Human umbilical cord mesenchymal stem cells (hUC-MSCs) have been widely used due to their multipotency, a broad range of sources, painless collection, and compliance with standard amplification. Cell sheet technology is a tissue engineering methodology requiring scaffolds free, and it provides an effective method for cell transplantation. To improve the therapeutic efficacy, we combined hUC-MSCs with cell sheet technology to evaluate the safety and efficacy of hUC-MSC sheets in preclinical studies using appropriate animal models.

Methods
hUC-MSC sheets were fabricated by hUC-MSCs from a cell bank established by a standard operation process and quality control. Cytokine secretion, immunoregulation, and angiopoiesis were evaluated in vitro. Oncogenicity and cell diffusion assays of hUC-MSC sheets were conducted to verify the safety of hUC-MSCs sheet transplantation in mice. To provide more meaningful animal experimental data for clinical trials, porcine myocardial infarction (MI) models were established by constriction of the left circumflex, and hUC-MSC sheets were transplanted onto the ischemic area of the heart tissue. Cardiac function was evaluated and compared between the experimental and MI groups.

Results
The in vitro results showed that hUC-MSC sheets could secrete multiple cellular factors, including VEGF, HGF, IL-6, and IL-8. Peripheral blood mononuclear cells had a lower proliferation rate and lower TNF-α secretion when co-cultured with hUC-MSC sheets. TH1 cells had a smaller proportion after activation. In vivo safety results showed that the hUC-MSCs sheet had no oncogenicity and was mainly distributed on the surface of the ischemic myocardial tissue. Echocardiography showed that hUC-MSC sheets effectively improved the left ventricular ejection fraction (LVEF), and the LVEF significantly changed (42.25 ± 1.23% vs. 66.9 ± 1.10%) in the hUC-MSC transplantation group compared with the MI group (42.52 ± 0.65% vs. 39.55 ± 1.97%) at 9 weeks. The infarct ratio of the hUC-MSCs sheet transplantation groups was also significantly reduced (14.2 ± 4.53% vs. 4.00 ± 2.00%) compared with that of the MI group.

Conclusion
Allogeneic source and cell bank established by the standard operation process and quality control make hUC-MSCs sheet possible to treat MI by off-the-shelf drug with universal quality instead of individualized medical technology.
High-efficient serum-free differentiation of endothelial cells from human iPS cells
Authors: Hamad Sarkawt , Derichsweiler Daniel , Gaspar John Antonydas , Brockmeier Konrad , Hescheler Jürgen , Sachinidis Agapios , Pfannkuche Kurt Paul 
Published: June 2022

Abstract
Introduction
Endothelial cells (ECs) form the inner lining of all blood vessels of the body play important roles in vascular tone regulation, hormone secretion, anticoagulation, regulation of blood cell adhesion and immune cell extravasation. Limitless ECs sources are required to further in vitro investigations of ECs’ physiology and pathophysiology as well as for tissue engineering approaches. Ideally, the differentiation protocol avoids animal-derived components such as fetal serum and yields ECs at efficiencies that make further sorting obsolete for most applications.

Method
Human induced pluripotent stem cells (hiPSCs) are cultured under serum-free conditions and induced into mesodermal progenitor cells via stimulation of Wnt signaling for 24 h. Mesodermal progenitor cells are further differentiated into ECs by utilizing a combination of human vascular endothelial growth factor A165 (VEGF), basic fibroblast growth factor (bFGF), 8-Bromoadenosine 3′,5′-cyclic monophosphate sodium salt monohydrate (8Bro) and melatonin (Mel) for 48 h.

Result
This combination generates hiPSC derived ECs (hiPSC-ECs) at a fraction of 90.9 ± 1.5% and is easily transferable from the two-dimensional (2D) monolayer into three-dimensional (3D) scalable bioreactor suspension cultures. hiPSC-ECs are positive for CD31, VE-Cadherin, von Willebrand factor and CD34. Furthermore, the majority of hiPSC-ECs express the vascular endothelial marker CD184 (CXCR4).

Conclusion
The differentiation method presented here generates hiPSC-ECs in only 6 days, without addition of animal sera and at high efficiency, hence providing a scalable source of hiPSC-ECs.
The influence of age, sex, and exercise on autophagy, mitophagy, and lysosome biogenesis in skeletal muscle
Authors: Triolo Matthew , Oliveira Ashley N. , Kumari Rita , Hood David A. 
Published: June 2022

Abstract
Background
Aging decreases skeletal muscle mass and quality. Maintenance of healthy muscle is regulated by a balance between protein and organellar synthesis and their degradation. The autophagy-lysosome system is responsible for the selective degradation of protein aggregates and organelles, such as mitochondria (i.e., mitophagy). Little data exist on the independent and combined influence of age, biological sex, and exercise on the autophagy system and lysosome biogenesis. The purpose of this study was to characterize sex differences in autophagy and lysosome biogenesis in young and aged muscle and to determine if acute exercise influences these processes.

Methods
Young (4–6 months) and aged (22–24 months) male and female mice were assigned to a sedentary or an acute exercise group. Mitochondrial content, the autophagy-lysosome system, and mitophagy were measured via protein analysis. A TFEB-promoter-construct was utilized to examine Tfeb transcription, and nuclear-cytosolic fractions allowed us to examine TFEB localization in sedentary and exercised muscle with age and sex.

Results
Our results indicate that female mice, both young and old, had more mitochondrial protein than age-matched males. However, mitochondria in the muscle of females had a reduced respiratory capacity. Mitochondrial content was only reduced with age in the male cohort. Young female mice had a greater abundance of autophagy, mitophagy, and lysosome proteins than young males; however, increases were evident with age irrespective of sex. Young sedentary female mice had indices of greater autophagosomal turnover than male counterparts. Exhaustive exercise was able to stimulate autophagic clearance solely in young male mice. Similarly, nuclear TFEB protein was enhanced to a greater extent in young male, compared to young female mice following exercise, but no changes were observed in aged mice. Finally, TFEB-promoter activity was upregulated following exercise in both young and aged muscle.

Conclusions
The present study demonstrates that biological sex influences mitochondrial homeostasis, the autophagy-lysosome system, and mitophagy in skeletal muscle with age. Furthermore, our data suggest that young male mice have a more profound ability to activate these processes with exercise than in the other groups. Ultimately, this may contribute to a greater remodeling of muscle in response to exercise training in males.
Development of a novel human CD147 knock-in NSG mouse model to test SARS-CoV-2 viral infection
Authors: Badeti Saiaditya , Jiang Qingkui , Naghizadeh Alireza , Tseng Hsiang-chi , Bushkin Yuri , Marras Salvatore A. E. , Nisa Annuurun , Tyagi Sanjay , Chen Fei , Romanienko Peter , Yehia Ghassan , Evans Deborah , Lopez-Gonzalez Moises , Alland David , Russo Riccardo , Gause William , Shi Lanbo , Liu Dongfang 
Published: June 2022

Abstract
Background
An animal model that can mimic the SARS-CoV-2 infection in humans is critical to understanding the rapidly evolving SARS-CoV-2 virus and for development of prophylactic and therapeutic strategies to combat emerging mutants. Studies show that the spike proteins of SARS-CoV and SARS-CoV-2 bind to human angiotensin-converting enzyme 2 (hACE2, a well-recognized, functional receptor for SARS-CoV and SARS-CoV-2) to mediate viral entry. Several hACE2 transgenic (hACE2Tg) mouse models are being widely used, which are clearly invaluable. However, the hACE2Tg mouse model cannot fully explain: (1) low expression of ACE2 observed in human lung and heart, but lung or heart failure occurs frequently in severe COVID-19 patients; (2) low expression of ACE2 on immune cells, but lymphocytopenia occurs frequently in COVID-19 patients; and (3) hACE2Tg mice do not mimic the natural course of SARS-CoV-2 infection in humans. Moreover, one of most outstanding features of coronavirus infection is the diversity of receptor usage, which includes the newly proposed human CD147 (hCD147) as a possible co-receptor for SARS-CoV-2 entry. It is still debatable whether CD147 can serve as a functional receptor for SARS-CoV-2 infection or entry.

Results
Here we successfully generated a hCD147 knock-in mouse model (hCD147KI) in the NOD-scid IL2Rgammanull (NSG) background. In this hCD147KI-NSG mouse model, the hCD147 genetic sequence was placed downstream of the endogenous mouse promoter for mouse CD147 (mCD147), which creates an in vivo model that may better recapitulate physiological expression of hCD147 proteins at the molecular level compared to the existing and well-studied K18-hACE2-B6 (JAX) model. In addition, the hCD147KI-NSG mouse model allows further study of SARS-CoV-2 in the immunodeficiency condition which may assist our understanding of this virus in the context of high-risk populations in immunosuppressed states. Our data show (1) the human CD147 protein is expressed in various organs (including bronchiolar epithelial cells) in hCD147KI-NSG mice by immunohistochemical staining and flow cytometry; (2) hCD147KI-NSG mice are marginally sensitive to SARS-CoV-2 infection compared to WT-NSG littermates characterized by increased viral copies by qRT-PCR and moderate body weight decline compared to baseline; (3) a significant increase in leukocytes in the lungs of hCD147KI-NSG mice, compared to infected WT-NSG mice.

Conclusions
hCD147KI-NSG mice are more sensitive to COVID-19 infection compared to WT-NSG mice. The hCD147KI-NSG mouse model can serve as an additional animal model for further interrogation whether CD147 serve as an independent functional receptor or accessory receptor for SARS-CoV-2 entry and immune responses.
Both prokaryotes and eukaryotes produce an immune response against plasmids with 5ʹ-GTTTGTT-3ʹ
Authors: Li Nan , Jiang Dongya , He Luqingqing , Yue Yunyun , Zhang Qinxin , Wang Shuang , Zhang Yunfeng , Wei Yuxuan , Zhao Qingshun 
Published: June 2022

AbstractIn the evolutionary “arms race” from prokaryotes to eukaryotes, some memories of foreign DNA have been conserved for defensive purposes. Shortly after invasion by the plasmid, pEGFP-N1, the conserved the defense gene, isg15, was activated in the zebrafish zygote and in mammalian cells. Based on the sequence similarity, we found three virus-derived sequences in pEGFP-N1 which share the 5ʹ-GTTTGTT-3ʹ core sequence, an epigenetic factor leading to increased expression of isg15. Mutation of the core sequence greatly reduces the degradation rate of the plasmid in E. coli cells or zebrafish embryos. We conclude that a conserved defense response, common to both eukaryotic and prokaryotic cells, allows identification and degradation of plasmids containing 5ʹ-GTTTGTT-3ʹ.
Necessary and sufficient conditions on the existence of solutions for the exterior Dirichlet problem of Hessian equations
Authors: Dai Limei , Li Hongfei 
Published: June 2022

AbstractIn this paper, we consider the exterior Dirichlet problem of Hessian equations $\sigma _{k}(\lambda (D^{2}u))=g(x)$

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Small-convection limit for two-dimensional chemotaxis-Navier–Stokes system with logarithmic sensitivity and logistic-type source
Authors: Wu Jie 
Published: June 2022

AbstractIn this paper, we consider the small-convection limit of chemotaxis-Navier–Stokes system with logarithmic sensitivity and logistic-type source $$ \textstyle\begin{cases} n^{\kappa}_{t}+\boldsymbol{u}^{\kappa}\cdot \nabla{n}^{\kappa}= \Delta{n}^{\kappa}-\chi \nabla \cdot ({n^{\kappa}}\nabla \log{c^{\kappa}})+f(n^{\kappa}), &x\in \Omega , t>0, \\ c^{\kappa}_{t}+\boldsymbol{u}^{\kappa}\cdot \nabla{c}^{\kappa}=\Delta{c}^{\kappa}-c^{\kappa}+n^{\kappa}, &x\in \Omega , t>0, \\ \boldsymbol{u}^{\kappa}_{t}+\kappa (\boldsymbol{u}^{\kappa}\cdot \nabla )\boldsymbol{u}^{\kappa}=\Delta \boldsymbol{u}^{\kappa}+\nabla{P}^{\kappa}+n^{\kappa}\nabla \phi , &x\in \Omega , t>0, \\ \nabla \cdot \boldsymbol{u}^{\kappa}=0, & x\in \Omega , t>0, \end{cases} $$

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Influencing factors of obesity in community patients with deficit schizophrenia: a cross-sectional study
Authors: Yong Na , Pan Jiyang , Li Xuehua , Yu Ling , Hou Xin 
Published: June 2022

Abstract
Background
Obesity is very common in patients with schizophrenia. We aimed to evaluate the influencing factors of obesity in community patients with deficit schizophrenia, to provide implication for schizophrenia management in community.

Methods
We selected patients with deficit schizophrenia who lived in 10 communities in our city from March 1 to June 30, 2021. The characteristics of included schizophrenia patients were evaluated and analyzed. Pearson correlation analysis was conducted to evaluate the obesity and related characteristics. Logistic regression analyses were conducted to assess the risk factors of obesity in patients with schizophrenia.

Results
A total of 284 patients with schizophrenia were included, the incidence of obesity in patients with schizophrenia was 56.70%. gender (r = 0.619), waist circumference (r = 0.644), BMI (r = 0.891), diabetes (r = 0.698), FG (r = 0.582), triglyceride (r = 0.618), HDL-C (r = −0.644), LDL-C (r = 0.583), apolipoprotein B (r = 0.595), and PANSS score (r = 0.813) were all correlated with the obesity in patients with schizophrenia (all p < 0.05). Logistic regression analysis indicated that female (OR 2.129, 95% CI 1.615–3.022), waist circumference ≥ 90 cm (OR 3.814, 95% CI 2.778 ~ 4.312), diabetes (OR 2.856, 95% CI 1.905 ~ 3.448), FG ≥ 88 mg/dL (OR 1.551, 95% CI 1.284 ~ 2.183), triglyceride ≥ 160 mg/dL (OR 1.804, 95% CI 1.236–2.845), HDL-C ≤ 0.8 mmol/L (OR 2.032, 95% CI 1.614–3.079), LDL-C ≥ 2.0 mmol/L (OR 1.926, 95% CI 1.442–2.041) and apolipoprotein B ≥ 0.70 g/L (OR 2.119, 95% CI 1.658–2.873) were the risk factors of obesity in patients with schizophrenia (all p < 0.05).

Conclusions
The obesity rate of patients with deficit schizophrenia in the community is high, and there are many associated risk factors. Early intervention targeted on those risk factors are warranted to reduce the obesity in schizophrenia patients.
An immersive micro-manipulation system using real-time 3D imaging microscope and 3D operation interface for high-speed and accurate micro-manipulation
Authors: Yokoe Kenta , Aoyama Tadayoshi , Fujishiro Toshiki , Takeuchi Masaru , Hasegawa Yasuhisa 
Published: June 2022

AbstractThe use of intracytoplasmic sperm injection (ICSI), an assisted reproductive technique (ART), is increasing widely. ICSI is currently performed by specially skilled embryologists. However, with the increasing demand for ART, the shortage of skilled embryologists has become a problem. Therefore, we propose an immersive micromanipulation system that requires no special skills for efficient and accurate micromanipulation. Our proposed system is composed of a real-time three-dimensional (3D) imaging microscope and 3D operation interfaces. The 3D operation interfaces are stationary pen-type or wearable glove-type interfaces. In this system, an operator wearing a head-mounted display (HMD) and using 3D operation interfaces is immersed in a virtual micromanipulation space. The operator can move the pipettes by 3D operation interface and freely change the viewpoint. We verified that the proposed system improves the speed and accuracy of operating a pipette through two types of experiments with subjects.