Mechanical force determines chimeric antigen receptor microclustering and signaling.

Chimeric antigen receptor (CAR) T cells are activated to trigger the lytic machinery after antigen engagement, and this has been successfully applied clinically as therapy. The mechanism by which antigen binding leads to the initiation of CAR signaling remains poorly understood. Here, we used a set of short double-stranded DNA (dsDNA) tethers with mechanical forces ranging from ∼12 to ∼51 pN to manipulate the mechanical force of antigen tether and decouple the microclustering and signaling events. Our results revealed that antigen-binding-induced CAR microclustering and signaling are mechanical force dependent. Additionally, the mechanical force delivered to the antigen tether by the CAR for microclustering is generated by autonomous cell contractility. Mechanistically, the mechanical-force-induced strong adhesion and CAR diffusion confinement led to CAR microclustering. Moreover, cytotoxicity may have a lower mechanical force threshold than cytokine generation. Collectively, these results support a model of mechanical-force-induced CAR microclustering for signaling.

A Review of Laser Ultrasonic Lamb Wave Damage Detection Methods for Thin-Walled Structures.

Thin-walled structures, like aircraft skins and ship shells, are often several meters in size but only a few millimeters thick. By utilizing the laser ultrasonic Lamb wave detection method (LU-LDM), signals can be detected over long distances without physical contact. Additionally, this technology offers excellent flexibility in designing the measurement point distribution. The characteristics of LU-LDM are first analyzed in this review, specifically in terms of laser ultrasound and hardware configuration. Next, the methods are categorized based on three criteria: the quantity of collected wavefield data, the spectral domain, and the distribution of measurement points. The advantages and disadvantages of multiple methods are compared, and the suitable conditions for each method are summarized. Thirdly, we summarize four combined methods that balance detection efficiency and accuracy. Finally, several future development trends are suggested, and the current gaps and shortcomings in LU-LDM are highlighted. This review builds a comprehensive framework for LU-LDM for the first time, which is expected to serve as a technical reference for applying this technology in large, thin-walled structures.

A PI(4,5)P2-derived "gasoline engine model" for the sustained B cell receptor activation.

To efficiently initiate activation responses against rare ligands in the microenvironment, lymphocytes employ sophisticated mechanisms involving signaling amplification. Recently, a signaling amplification mechanism initiated from phosphatidylinositol (PI) 4, 5-biphosphate [PI(4,5)P2] hydrolysis and synthesis for sustained B cell activation has been reported. Antigen and B cell receptor (BCR) recognition triggered the prompt reduction of PI(4,5)P2 density within the BCR microclusters, which led to the positive feedback for the synthesis of PI(4,5)P2 outside of the BCR microclusters. At single molecule level, the diffusion of PI(4,5)P2 was slow, allowing for the maintenance of a PI(4,5)P2 density gradient between the inside and outside of the BCR microclusters and the persistent supply of PI(4,5)P2 from outside to inside of the BCR microclusters. Here, we review studies that have contributed to uncovering the molecular mechanisms of PI(4,5)P2-derived signaling amplification model. Based on these studies, we proposed a "gasoline engine model" in which the activation of B cell signaling inside the microclusters is similar to the working principle of burning gasoline within the engine chamber of a gasoline engine. We also discuss the evidences showing the potential universality of this model and future prospects.

Regulation of feather follicle development and Msx2 gene SNP degradation in Hungarian white goose.

BACKGROUND: Hungarian white goose has excellent down production performance and was introduced to China in 2010. The growth and development of feather follicles has an important impact on down production. Goose feather follicles can be divided into primary and secondary feather follicles, both of which originate in the embryonic stage. Msx2 (Msh Homeobox 2) plays a regulatory role in tissues and organs such as eyes, teeth, bones and skin. However, its regulatory mechanism on goose feather follicles development remains unclear. RESULTS: Msx2 gene first increased, then decreased and increased at the end (E13, E18, E23, E28) during embryonic feather follicle development, and the expression level was the highest at E18. The pEGFP-N1-Msx2 overexpression vector and si-Msx2 siRNA vector were constructed to transfect goose embryo dermal fibroblasts. The results showed that the cell viability of ov-Msx2 group was significantly increased, and the gene expression levels of FGF5 and TGF-ß1 genes were significantly down-regulated (P < 0.05), the expressions of PCNA, Bcl2, CDK1, FOXN1 and KGF genes were significantly up-regulated (P < 0.05). After transfection of siRNA vector, the cell viability of the si-Msx2 group was significantly decreased (P < 0.01) compared with the si-NC group. TGF-ß1 expression was significantly up-regulated (P < 0.05), FGF5 expression was extremely significantly up-regulated (P < 0.01), while PCNA, Bcl2, CDK1, FOXN1 and KGF gene expression was significantly down-regulated (P < 0.05). High-throughput sequencing technology was used to mine the exon SNPs of Msx2. A total of 11 SNP loci were screened, four of the SNPs located in exon 1 were missense mutations. The feather follicle diameter of the GC genotype at the G78C site is significantly larger than that of the other two genotypes. CONCLUSIONS: Msx2 maybe inhibit the apoptosis of goose dermal fibroblasts and promotes their proliferation. G78C can be used as a potential molecular marker for downy Variety.

Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism.

CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

Rictor positively regulates B cell receptor signaling by modulating actin reorganization via ezrin.

As the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2) has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell development, especially the peripheral development. However, the role of Rictor on B cell receptor (BCR) signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell-specfic Rictor knockout (KO) mice to investigate how Rictor regulates BCR signaling. We found that the key positive and negative BCR signaling molecules, phosphorylated Brutons tyrosine kinase (pBtk) and phosphorylated SH2-containing inositol phosphatase (pSHIP), are reduced and enhanced, respectively, in Rictor KO B cells. This suggests that Rictor positively regulates the early events of BCR signaling. We found that the cellular filamentous actin (F-actin) is drastically increased in Rictor KO B cells after BCR stimulation through dysregulating the dephosphorylation of ezrin. The high actin-ezrin intensity area restricts the lateral movement of BCRs upon stimulation, consequently reducing BCR clustering and BCR signaling. The reduction in the initiation of BCR signaling caused by actin alteration is associated with a decreased humoral immune response in Rictor KO mice. The inhibition of actin polymerization with latrunculin in Rictor KO B cells rescues the defects of BCR signaling and B cell differentiation. Overall, our study provides a new pathway linking cell metablism to BCR activation, in which Rictor regulates BCR signaling via actin reorganization.

Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility.

Germinal centres support antibody affinity maturation and memory formation. Follicular T-helper cells promote proliferation and differentiation of antigen-specific B cells inside the follicle. A genetic deficiency in the inducible co-stimulator (ICOS), a classic CD28 family co-stimulatory molecule highly expressed by follicular T-helper cells, causes profound germinal centre defects, leading to the view that ICOS specifically co-stimulates the follicular T-helper cell differentiation program. Here we show that ICOS directly controls follicular recruitment of activated T-helper cells in mice. This effect is independent from ICOS ligand (ICOSL)-mediated co-stimulation provided by antigen-presenting dendritic cells or cognate B cells, and does not rely on Bcl6-mediated programming as an intermediate step. Instead, it requires ICOSL expression by follicular bystander B cells, which do not present cognate antigen to T-helper cells but collectively form an ICOS-engaging field. Dynamic imaging reveals ICOS engagement drives coordinated pseudopod formation and promotes persistent T-cell migration at the border between the T-cell zone and the B-cell follicle in vivo. When follicular bystander B cells cannot express ICOSL, otherwise competent T-helper cells fail to develop into follicular T-helper cells normally, and fail to promote optimal germinal centre responses. These results demonstrate a co-stimulation-independent function of ICOS, uncover a key role for bystander B cells in promoting the development of follicular T-helper cells, and reveal unsuspected sophistication in dynamic T-cell positioning in vivo.

De Novo Transcriptome Sequencing Analysis of Goose (Anser anser) Embryonic Skin and the Identification of Genes Related to Feather Follicle Morphogenesis at Three Stages of Development.

The objective of this study was to evaluate the changes in the goose embryo transcriptome during feather development. RNA-Sequencing (RNA-Seq) was used to find the transcriptome profiles of feather follicles from three stages of embryonic dorsal skin at embryonic day 13, 18, and 28 (E13, E18, E28). The results showed that 3001, 6634, and 13,780 genes were differently expressed in three stages. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that differentially expressed genes (DEGs) in E13 vs. E18 were significantly mapped into the GO term of extracellular structure organization and the pathway of extracellular matrix (ECM)-receptor interaction. In E18 vs. E28, the top significantly mapped into GO term was the single-organism developmental process; the pathway was also the ECM-receptor interaction. DEGs in E13 vs. E28 were significantly mapped into the GO term of the multicellular organismal process and the pathway of cell adhesion molecules. Subsequently, the union of DEGs was categorized by succession cluster into eight profiles, which were then grouped into four ideal profiles. Lastly, the seven genes spatio-temporal expression pattern was confirmed by real-time PCR. Our findings advocate that interleukin 20 receptor subunit alpha (IL20RA), interleukin 6 receptor (IL6R), interleukin 1 receptor type 1 (IL-1R1), Wnt family member 3A (WNT3A), insulin-like growth factor binding protein 3 (IGFBP3), bone morphogenetic protein 7 (BMP7), and secreted-frizzled related protein 2 (SFRP2) might possibly play vital roles in skin and feather follicle development and growth processes.

[Differentially expressed circular RNAs in human gastric cancer cells].

The purpose of this study was to investigate the expression profile of circular RNA (circRNA) in gastric cancer cells MGC-803, SGC-7901 and NCI-N87 with different degrees of differentiation and normal gastric epithelial cells GES-1. High throughput circRNA microarray technique was used to detect the differential expression of circRNA between three kinds of differentiated gastric cancer cells and normal gastric epithelial cells. The interaction of microRNAs (miRNAs) with circRNAs was predicted by bioinformatics software, and circRNA, which might have great significance in gastric cancer, was identified by literature search. The results showed that there were 79 up-regulated circRNAs and 229 down-regulated circRNAs in gastric cancer cells with different degrees of differentiation compared with those in normal gastric epithelial cells. Through bioinformatics software analysis and literature retrieval, it was found that hsa_circ_0001897 was related to the staging and metastasis of gastric cancer, while the miR-150-5p, which combined with it, was closely related to many kinds of digestive tract tumors, such as colon cancer, liver cancer, and cholangiocarcinoma. The miR-16-5p, which has binding sites with hsa_circ_0008106 and hsa_circ_0060456, has been confirmed to be involved in the development of gastric cancer. The above results suggest that hsa_circ_0001897, hsa_circ_0008106 and hsa_circ_0060456 may be closely related to the occurrence and development of gastric cancer by interacting with miRNA.

Revealing underlying regulatory mechanisms of LINC00313 in Osimertinib-resistant LUAD cells by ceRNA network analysis.

BACKGROUND: Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is the preferred treatment for EGFR-mutated lung cancer. However, acquired resistance inevitably develops. While non-coding RNAs have been implicated in lung cancer through various functions, the molecular mechanisms responsible for osimertinib resistance remain incompletely elucidated. METHODS: RNA-sequencing technology was employed to determine differentially expressed lncRNAs (DE-lncRNAs) and mRNAs (DE-mRNAs) between H1975 and H1975OR cell lines. Starbase 2.0 was utilized to predict DE-lncRNA and DE-mRNA interactions, constructing ceRNA networks. Subsequently, functional and pathway enrichment analysis were performed on target DE-mRNAs to identify pathways associated with osimertinib resistance. Key target DE-mRNAs were then selected as potential risk signatures for lung adenocarcinoma (LUAD) prognostic modeling using multivariate Cox regression analyses. The Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and immunohistochemistry staining were used for result validation. RESULTS: Functional analysis revealed that the identified DE-mRNAs primarily enriched in EGFR-TKI resistance pathways, especially in the PI3K/Akt signaling pathway, where their concerted actions may lead to osimertinib resistance. Specifically, upregulation of LINC00313 enhanced COL1A1 expression by acting as a miR-218-5p sponge, triggering an upstream response that activates the PI3K/Akt pathway, potentially contributing to osimertinib resistance. Furthermore, the expressions of LINC00313 and COL1A1 were validated by qRT-PCR, and the activation of the PI3K/Akt pathway was confirmed by immunohistochemistry staining. CONCLUSIONS: Our results suggest that the LINC00313/miR-218-5p/COL1A1 axis potentially contributes to osimertinib resistance through the PI3K/Akt signaling pathway, providing novel insights into the molecular mechanisms underlying acquired osimertinib resistance in LUAD. Additionally, our study may aid in the identification of potential therapeutic targets for overcoming resistance to osimertinib.

Uncovering small RNA-mediated responses to cold stress in a wheat thermosensitive genic male-sterile line by deep sequencing.

The male sterility of thermosensitive genic male sterile (TGMS) lines of wheat (Triticum aestivum) is strictly controlled by temperature. The early phase of anther development is especially susceptible to cold stress. MicroRNAs (miRNAs) play an important role in plant development and in responses to environmental stress. In this study, deep sequencing of small RNA (smRNA) libraries obtained from spike tissues of the TGMS line under cold and control conditions identified a total of 78 unique miRNA sequences from 30 families and trans-acting small interfering RNAs (tasiRNAs) derived from two TAS3 genes. To identify smRNA targets in the wheat TGMS line, we applied the degradome sequencing method, which globally and directly identifies the remnants of smRNA-directed target cleavage. We identified 26 targets of 16 miRNA families and three targets of tasiRNAs. Comparing smRNA sequencing data sets and TaqMan quantitative polymerase chain reaction results, we identified six miRNAs and one tasiRNA (tasiRNA-ARF [for Auxin-Responsive Factor]) as cold stress-responsive smRNAs in spike tissues of the TGMS line. We also determined the expression profiles of target genes that encode transcription factors in response to cold stress. Interestingly, the expression of cold stress-responsive smRNAs integrated in the auxin-signaling pathway and their target genes was largely noncorrelated. We investigated the tissue-specific expression of smRNAs using a tissue microarray approach. Our data indicated that miR167 and tasiRNA-ARF play roles in regulating the auxin-signaling pathway and possibly in the developmental response to cold stress. These data provide evidence that smRNA regulatory pathways are linked with male sterility in the TGMS line during cold stress.

Efficient coupling between dielectric waveguide modes and exterior plasmon whispering gallery modes.

Inefficient coupling between dielectric guided mode and plasmon mode has been overlooked in the past. The coupling mechanism is essentially different from the conventional coupling between dielectric modes. Based on qualitative theoretical analysis, we proposed two methods to strengthen the coupling between dielectric waveguide modes and exterior plasmon whispering gallery modes. One is using a U-shaped bent waveguide to break the adiabatic mode conversion process, and the other is to utilize higher-order dielectric mode to reach phase matching with plasmon mode. Both the transmission spectrum of waveguide and the energy spectrum of cavity demonstrate that the coupling efficiency can be greatly improved. These simple configurations are potential for wide applications, for example, tunable integrated optical devices and sensors.

Imaging PIP2 and BCR microclusters in B cell immunological synapse.

The humoral immune response is dependent on B cell activation and differentiation, which is typically triggered by the formation of immunological synapses at the interface between B cells and the antigen presenting surfaces. However, due to the highly dynamic and transient feature of immunological synapses, it has been difficult to capture and investigate the molecular events that occur within them. The planar lipids bilayer (PLB) supported antigen presenting surface combined with high-resolution high-speed total internal reflection fluorescence microscope (TIRFM) live cell imaging system has been proved to be a powerful tool that allows us to visualize the dynamic events in immunological synapse. In addition, the phospholipid phosphatidylinositol-(4,5)-biphosphate (PIP2) plays a unique role in B cell activation, and it is difficult to investigate the synaptic dynamics of PIP2 molecules. Hence, we describe here the general procedures for the utilization of a PLB based antigen presenting system combining TIRFM based imaging methods to visualize the spatial-temporal co-distribution of PIP2 and BCR microcluster within the B cell immunological synapse.

Improved neonatal outcomes by multidisciplinary simulation-a contemporary practice in the demonstration area of China.

Background: Simulation-based training improves neonatal resuscitation and decreases perinatal mortality in low- and middle-income countries. Interdisciplinary in-situ simulation may promote quality care in neonatal resuscitation. However, there is limited information regarding the effect of multidisciplinary in-situ simulation training (MIST) on neonatal outcomes. We aimed to investigate the impact of MIST on neonatal resuscitation in reducing the incidence of neonatal asphyxia and related morbidities. Methods: Weekly MIST on neonatal resuscitation has been conducted through neonatal and obstetrical collaboration at the University of Hong Kong-Shenzhen Hospital, China, since 2019. Each simulation was facilitated by two instructors and performed by three health care providers from obstetric and neonatal intensive care units, followed by a debriefing of the participants and several designated observers. The incidence of neonatal asphyxia, severe asphyxia, hypoxic-ischemic encephalopathy (HIE), and meconium aspiration syndrome (MAS) before (2017-2018) and after (2019-2020) the commencement of weekly MIST were analyzed. Results: There were 81 simulation cases including the resuscitation of preterm neonates of different gestational ages, perinatal distress, meconium-stained amniotic fluid, and congenital heart disease with 1,503 participant counts (225 active participants). The respective incidence of neonatal asphyxia, severe asphyxia, HIE, and MAS decreased significantly after MIST (0.64%, 0.06%, 0.01%, and 0.09% vs. 0.84%, 0.14%, 0.10%, and 0.19%, respectively, all P < 0.05). Conclusions: Weekly MIST on neonatal resuscitation decreased the incidence of neonatal asphyxia, severe asphyxia, HIE, and MAS. Implementation of regular resuscitation simulation training is feasible and may improve the quality of neonatal resuscitation with better neonatal outcomes in low- and middle-income countries.

Neonatal resuscitation workshop for trainees in standardized medical residency training-a pilot practice in Shenzhen, China.

Background: Neonatal resuscitation is an important skillset for clinicians attending deliveries. Accredited neonatal resuscitation training is not obligatory in most training centers of standardized medical residency programs before 2022 in China. We investigated the feasibility and effectiveness of neonatal resuscitation simulation training (neo-RST) in residents in Shenzhen, China. Methods: Four two-day neo-RST workshops were conducted in the University of Hong Kong-Shenzhen Hospital and Shenzhen Health Capacity Building and Continuing Education Center in 2020-2021. The workshops had Neonatal Resuscitation Program (NRP)® update, skill stations and simulation practice with debriefing. Each participant had the integrated skill station assessment (ISSA) at the end of workshop. Participants of workshops included residents of different disciplines and health care providers (HCPs) of neonatal and obstetrical departments. We compared demographic characteristics, neonatal resuscitation knowledge before training, ISSA overall and categorical scores on skill sets between residents and HCPs. Results: In 2020-2021, 4 neo-RST workshops were conducted with 48 residents and 48 HCPs. The residents group had less working experience, less prior experience in neo-RST and lower neonatal resuscitation knowledge scores than those of HCPs group. After the workshop, residents had higher overall ISSA score than that of HCPs group (90.2 ± 5.9 vs. 86.3 ± 6.6%, P = 0.003, respectively). There was no significant difference in the numbers of participants scored <80% in residents and HCPs group (3 [6.3%] vs. 7 [14.6%], respectively). Regarding the categorical scores, residents scored significantly higher in preparation, ventilation, crisis resource management and behavioral skills but lower in appropriate oxygen use, when compared with the HCPs. Conclusion: Neo-RST for residents is feasible with promising short-term educational outcomes. Neo-RST could be implemented in standardized medical residency programs in China.

GPR35-mediated kynurenic acid sensing contributes to maintenance of gut microbiota homeostasis in ulcerative colitis.

Ulcerative colitis (UC) is a recurrent inflammatory disease related to gut microbiota disorder. Metabolites and their sensors play an important role in the communication between gut microbes and their host. Our previous study revealed that G protein-coupled receptor 35 (GPR35) is a key guardian of kynurenic acid (KA) and a core element of the defense responses against gut damage. However, the mechanism remains unknown. In this study, a DSS-induced rat colitis model was established and 16S rRNA sequencing was applied to explore the influence of GPR35-mediated KA sensing on gut microbiota homeostasis. Our results demonstrated that GPR35-mediated KA sensing is a necessary component in maintaining gut barrier integrity against DSS-induced damage. Furthermore, we provide compelling evidence suggesting that GPR35-mediated KA sensing plays a crucial role in maintaining gut microbiota homeostasis, which contributes to alleviation of DSS-induced colitis. In addition, five classes (Actinobacteria, Beta-/Gamma-proteobacteria, Erysipelotrichi, and Coriobacteriia) and six genera (Corynebacterium, Allobaculum, Parabacteroides, Sutterella, Shigella, and Xenorhabdus) were identified as the marked bacterial taxa that characterized the progression and outcome of colitis and are regulated by GPR35-mediated KA sensing. Our findings highlight that GPR35-mediated KA sensing is an essential defense mechanism against disorder of gut microbiota in UC. The results provide insights into the key role of specific metabolites and their monitor in maintaining gut homeostasis.

New Strategy for Promoting Vascularization in Tumor Spheroids in a Microfluidic Assay.

Previous studies have developed vascularized tumor spheroid models to demonstrate the impact of intravascular flow on tumor progression and treatment. However, these models have not been widely adopted so the vascularization of tumor spheroids in vitro is generally lower than vascularized tumor tissues in vivo. To improve the tumor vascularization level, a new strategy is introduced to form tumor spheroids by adding fibroblasts (FBs) sequentially to a pre-formed tumor spheroid and demonstrate this method with tumor cell lines from kidney, lung, and ovary cancer. Tumor spheroids made with the new strategy have higher FB densities on the periphery of the tumor spheroid, which tend to enhance vascularization. The vessels close to the tumor spheroid made with this new strategy are more perfusable than the ones made with other methods. Finally, chimeric antigen receptor (CAR) T cells are perfused under continuous flow into vascularized tumor spheroids to demonstrate immunotherapy evaluation using vascularized tumor-on-a-chip model. This new strategy for establishing tumor spheroids leads to increased vascularization in vitro, allowing for the examination of immune, endothelial, stromal, and tumor cell responses under static or flow conditions.

Molecular diagnosis of severe combined immunodeficiency--identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 mutations in a cohort of Chinese and Southeast Asian children.

Severe combined immunodeficiencies (SCID) are a group of rare inherited disorders with profound defects in T cell and B cell immunity. From 2005 to 2010, our unit performed testing for IL2RG, JAK3, IL7R, RAG1, RAG2, DCLRE1C, LIG4, AK2, and ZAP70 mutations in 42 Chinese and Southeast Asian infants with SCID adopting a candidate gene approach, based on patient's gender, immune phenotype, and inheritance pattern. Mutations were identified in 26 patients, including IL2RG (n = 19), IL7R (n = 2), JAK3 (n = 2), RAG1 (n = 1), RAG2 (n = 1), and DCLRE1C (n = 1). Among 12 patients who underwent hematopoietic stem cell transplantation, eight patients survived. Complications and morbidities during transplant period were significant, especially disseminated bacillus Calmette-Guérin disease which was often difficult to control. This is the first cohort study on SCID in the Chinese and Southeast Asian population, based on a multi-centered collaborative research network. The foremost issue is service provision for early detection, diagnosis, management, and definitive treatment for patients with SCID. National management guidelines for SCID should be established, and research into an efficient platform for genetic diagnosis is needed.

ER-Phagy and Microbial Infection.

The endoplasmic reticulum (ER) is an essential organelle in cells that synthesizes, folds and modifies membrane and secretory proteins. It has a crucial role in cell survival and growth, thus requiring strict control of its quality and homeostasis. Autophagy of the ER fragments, termed ER-phagy or reticulophagy, is an essential mechanism responsible for ER quality control. It transports stress-damaged ER fragments as cargo into the lysosome for degradation to eliminate unfolded or misfolded protein aggregates and membrane lipids. ER-phagy can also function as a host defense mechanism when pathogens infect cells, and its deficiency facilitates viral infection. This review briefly describes the process and regulatory mechanisms of ER-phagy, and its function in host anti-microbial defense during infection.

MicroRNA expression profiling and target gene analysis in gastric cancer.

This study aims to identify differentially expressed microRNAs (miRNAs) in gastric cancer by comparing gastric cancerous tissues with normal tissues, explore the potential roles.The miRNA expression microarray was employed on gastric cancer tissues, and apparently normal para-cancerous tissues from 3 patients undergoing radical surgery were matched. Quantitative RT-PCR was performed on the other 7 patients to validate the findings of the microarray. Furthermore, Gene Ontology (GO) analysis and enrichment analysis of KEGG Pathway were performed for 5 dysregulated candidate miRNAs, including 3 upregulated (miR-31-3p, miR-6736-3p, and miR-147b) and 2 downregulated (miR-3065-5p and miR-3921) miRNAs, in order to determine the role of miRNAs in tumorigenesis and development.Among these miRNAs, 17 miRNAs were found to be upregulated, and 19 miRNAs were found to be downregulated. The dysregulated expression of 5 candidate miRNAs, including miR-31-3p, miR-147b, miR-6736-3p, miR-3065-5p, and miR-3921, were verified by quantitative RT-PCR in the validation set. Among these miRNAs, miR-31-3p, miR-6736-3p, miR-3065-5p, and miR-3921 had 551 target gene intersections. The GO and KEGG Pathway analyses Revealed that miR-31-3p, miR-6736-3p, miR-3065-5p, and miR-3921 may participate in multiple pathophysiological processes, such as foreign substance metabolism and chemical carcinogenesis.The profile of differentially expressed miRNAs was successfully screened, and 4 miRNAs (i.e., miR-31-3p, miR-6736-3p, miR-3065-5p, and miR-3921) appeared to be involved in gastric carcinogenesis. These might serve as promising biomarkers for gastric cancer.