A case report on deficiency of adenosine deaminase 2 with relapse-remission course and analysis of genotype-phenotype correlation.

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic disease caused by biallelic mutations in adenosine deaminase 2 (ADA2). The varying phenotypes of the disease often lead to delayed diagnosis or misdiagnosis. We report an 11-year-old boy with DADA2 and provide a preliminary analysis of genotype-phenotype correlation. The age of onset of the disease was 8 years old. The disease successively involved the brainstem, muscles, joints, and cerebrum. After three relapse-remission episodes over 3 years, the patient was finally diagnosed with DADA2 by whole-exome sequencing. Compound heterozygous variants in the ADA2 gene (NM_001282225.2: c.1072G>A, p.Gly358Arg; c.419dupC, p.Arg141Lysfs*37) were found in the patient. He did not receive anti-TNF therapy and had no relapse after a 8-month follow-up. We identified a novel variant of the ADA2 gene, and the associated disease course may follow a relapse-remission pattern. Homozygous mutations of p.Gly358Arg can cause pure red cell aplasia, whereas compound heterozygous variations may lead to different phenotypes. Variants in the catalytic domain and frameshift mutations may also cause relatively benign phenotypes besides causing hematological disorders. Further studies are needed to clarify the genotypic-phenotypic relationship of this disease.

Particle-Polymer Union with Changeable Wettability for Constructing Bijels Using a Simple Mixing Method.

Bicontinuous emulsion gels (bijels) are nonequilibrium dispersed systems with particle-stabilized continuous fluid domains, and the internal connectivity of channels brings the possibility of efficient mass transport, endowing bijels great potential in diverse applications. Different from the common method to produce bijels, the spinodal decomposition, which needs precise temperature control and is restricted by the selection of liquid pairs, in this work, a direct mixing method was performed to construct bijels, simplifying the fabrication process. The hydrophilic rod-shaped cellulose nanocrystalline (CNC) particles were in situ combined with the hydrophobic polymer, aminopropyl-terminated polydimethylsiloxane (PDMS-NH2), to acquire a controllable interfacial wettability of CNC. The CNC@mPDMS-NH2 complexes were adsorbed at the water-toluene interface and achieved a change of Pickering emulsion types, oil-in-water, bijel, and water-in-oil, through tuning the interfacial performance of CNC@mPDMS-NH2 complexes. A three-dimensional scanning image and curvature calculation were applied to verify the obtained bijel, further demonstrating the successful preparation of the bicontinuous structure. This work enriched the members of particles for stabilizing bijels and was considered to be scalable in manufacturing for applications on a large scale.

The impact of healthcare reform on the dynamic changes in health service utilization and equity: a 10-year follow-up study.

In the past decade, the government of China has implemented healthcare reforms to provide universal access to healthcare by 2020. We aimed to systematically analyse the dynamic changes in health services and equity during the past 10 years to understand the correlation between health services and social-economic status. We performed a longitudinal study in which we extracted aggregated data mainly from a project (2009, 2011, 2012, 2015, 2019). A multi-stage stratified cluster randomized design was used to obtain a representative sample in each county. Concentration indexes were used to analyse the equity of the changes in utilization. We built multivariate random-effects generalized least squares regression models with the panel data to test whether the rate of receiving a medical consultation in the last 2 weeks or the rate of hospital admission or the prevalence of chronic illness was associated with social-economic status including education level and rural disposable income per capita. We found declines in both the rate of not receiving a medical consultation during the last 2 weeks (P < 0.05 intervention group) and the rate of hospital avoidance (P < 0.05) from 2009 to 2019. The equity in residents' health service utilization has improved constantly. We additionally found that rural disposable income per capita is a protective factor for the rate of a receiving a medical consultation during the last 2 weeks and the rate of hospital admission. China's 2009 healthcare reform have positively influenced utilization rates and equity in health service utilization in the past decade, a range of health service-targeted strategies are needed including strengthen the prevention and treatment of chronic diseases, focus attention on the health status of elderly residents and improve social-economic status, especially the level of education.

Public Key Encryption with Keyword Search in Cloud: A Survey.

With the popularization of cloud computing, many business and individuals prefer to outsource their data to cloud in encrypted form to protect data confidentiality. However, how to search over encrypted data becomes a concern for users. To address this issue, searchable encryption is a novel cryptographic primitive that enables user to search queries over encrypted data stored on an untrusted server while guaranteeing the privacy of the data. Public key encryption with keyword search (PEKS) has received a lot of attention as an important branch. In this paper, we focus on the development of PEKS in cloud by providing a comprehensive research survey. From a technological viewpoint, the existing PEKS schemes can be classified into several variants: PEKS based on public key infrastructure, PEKS based on identity-based encryption, PEKS based on attribute-based encryption, PEKS based on predicate encryption, PEKS based on certificateless encryption, and PEKS supporting proxy re-encryption. Moreover, we propose some potential applications and valuable future research directions in PEKS.

Molecular evolution of the deuterolysin (M35) family genes in Coccidioides.

Coccidioides is a primary fungal pathogen of humans, causing life-threatening respiratory disease known as coccidioidomycosis (Valley fever) in immunocompromised individuals. Recently, Sharpton et al (2009) found that the deuterolysin (M35) family genes were significantly expanded in both the Coccidioides genus and in U. reesii, and that Coccidioides has acquired three more M35 family genes than U. reesii. In the present work, phylogenetic analyses based on a total of 28 M35 family genes using different alignments and tree-building methods consistently revealed five clades with high nodal supports. Interestingly, likelihood ratio tests suggested significant differences in selective pressure on the ancestral lineage of three additional duplicated M35 family genes from Coccidioides species compared to the other lineages in the phylogeny, which may be associated with novel functional adaptations of M35 family genes in the Coccidioides species, e.g., recent pathogenesis acquisition. Our study adds to the expanding view of M35 family gene evolution and functions as well as establishes a theoretical foundation for future experimental investigations.

A key role for Pak4 in proliferation and differentiation of neural progenitor cells.

The Pak4 serine/threonine kinase regulates cytoskeletal organization, and controls cell growth, proliferation, and survival. Deletion of Pak4 in mice results in embryonic lethality prior to embryonic day 11.5. Pak4 knockout embryos exhibit abnormalities in the nervous system, the heart, and other tissues. In this study a conditional deletion of Pak4 was generated in order to study the function of Pak4 in the development of the brain. Nervous system-specific conditional deletion of Pak4 was accomplished by crossing mice with a floxed allele of Pak4 with transgenic mice expressing Cre recombinase under the control of the nestin promoter. The conditional Pak4 knockout mice were born normally, but displayed growth retardation and died prematurely. The brains showed a dramatic decrease in proliferation of cortical and striatal neuronal progenitor cells. In vitro analyses revealed a reduced proliferation and self-renewing capacity of neural progenitor cells isolated from Pak4 knockout brains. The mice also exhibited cortical thinning, impaired neurogenesis and loss of neuroepithelial adherens junctions. By the time the mice died, by 4weeks after birth, severe hydrocephalus could also be seen. These results suggest that Pak4 plays a critical role in the regulation of neural progenitor cell proliferation and in establishing the foundation for development of the adult brain.

Essential role for the Pak4 protein kinase in extraembryonic tissue development and vessel formation.

Pak4 is a member of the group B family of Pak serine/threonine kinases, originally identified as an effector protein for the Rho GTPase Cdc42. Pak4 knockout mice are embryonic lethal and do not survive past embryonic day 11.5. Previous work on Pak4 knockout mice has focused on studying the phenotype of the embryo. Abnormalities in the extraembryonic tissue, however, are common causes of early embryonic death in knockout mice. Extraembryonic tissue associated with the Pak4-null embryos was therefore examined. Abnormalities in both yolk sacs and placentas resulted when Pak4 was deleted. These included a lack of vasculature throughout the extraembryonic tissue, as well as an abnormally formed labyrinthine layer of the placenta. Interestingly, epiblast-specific deletion of Pak4 using a conditional knockout system, did not rescue the embryonic lethality. In fact, it did not even rescue the extraembryonic tissue defects. Our results suggest that the extraembryonic tissue abnormalities are secondary to defects that occur in response to epiblast abnormalities. More detailed analysis suggests that abnormalities in vasculature throughout the extraembryonic tissue and the epiblast may contribute to the death of the Pak4-null embryos.

The pak4 protein kinase plays a key role in cell survival and tumorigenesis in athymic mice.

Pak4 is a member of the B group of p21-activated (Pak) kinases, originally identified as an effector protein for Cdc42. Although Pak4 is expressed at low levels in most adult tissues, it is highly overexpressed in tumor cell lines. Here, we show that Pak4 is also overexpressed in primary tumors, including colon, esophageal, and mammary tumors. Overexpression of Pak4 also leads to tumor formation in athymic mice, whereas deletion of Pak4 inhibits tumorigenesis. Although a constitutively active Pak4 mutant was previously shown to promote oncogenic transformation in cultured cells, our results are the first to show that Pak4 also promotes tumorigenesis in experimental animals. Furthermore, these results show for the first time that not only constitutively active Pak4, but also wild-type Pak4, is transforming, when experimental animals are used. These results are highly significant because wild-type Pak4, rather than activated Pak4, is overexpressed in tumor cells. Our results suggest that overexpression or activation of Pak4 is a key step in oncogenic transformation, due to its ability to promote cell survival and subsequent uncontrolled proliferation. The finding that Pak4 is up-regulated in so many types of cancers indicates that Pak4 may play a vital role in a wide range of different types of cancer. This makes it an attractive candidate for drug therapy for different types of cancer.

Effects of Ginkgo biloba extract (EGb 761) on hydroxyl radical-induced thymocyte apoptosis and on age-related thymic atrophy and peripheral immune dysfunctions in mice.

In this study, the effect of EGb 761, a standard extract of Ginkgo biloba leaf, on thymocyte apoptosis and age-related thymic atrophy and on peripheral immune dysfunctions was investigated in mice. When primary culture of thymocytes was preincubated with 100 microg/ml EGb 761 before their exposure to hydroxyl radicals (*OH) generated by Fe(2+)-mediated Fenton reaction, apoptotic cell death induced by *OH was distinctly prevented as determined by DNA laddering, the TUNEL assay and flow cytometric analysis. Furthermore, oral EGb 761 administration (about 1.5 mg/day/mouse) for 60 consecutive days led to a significant thymic regrowth in 22-month-old mice as revealed by the increment of thymus weight and total numbers of thymocytes. Partial recovery of peripheral immune capacities such as mitogen responsiveness and NK cell activity were also found in the old mice after 60 days of EGb 761 supplementation. Taken together, our study indicates that in addition to its protective and rescuing abilities on neurodegenerative disorders and cardiovascular diseases, EGb 761 was also found active in the rejuvenation of degenerated thymus and accordingly the strengthening of the immune system. These beneficial effects of EGb 761 on immune system are based on its antioxidant properties as well as the cell proliferation-stimulating effect.

Melatonin rejuvenates degenerated thymus and redresses peripheral immune functions in aged mice.

The effect of melatonin on age-related thymic involution and peripheral immune dysfunctions was investigated. Exogenous melatonin was administered through the drinking water (15 microg/ml) of 22-month-old female C57BL mice for 60 consecutive days. Our results show that melatonin distinctly reversed the age-related thymic involution as revealed by the notable increase of thymus weight, total number of thymocytes and percentage of thymocytes at G2+S phases. More strikingly, spleen weight, total number of splenocytes and some peripheral immune capacity such as mitogen responsiveness and NK cell activity were also significantly recovered by 60 days of melatonin application in aged mice. Our findings demonstrate that even when the melatonin supplementation begins late in life, the age-related thymic involution and peripheral immune dysfunctions can be restored at least partially in old mice.