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The Wiskott--Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp) expression and function resulting in thrombocytopenia, eczema, recurrent infections, and autoimmunity. In T cells, WASp is required for immune synapse formation. Patients with WAS show reduced numbers of peripheral blood T lymphocytes and an altered T-cell receptor repertoire. In vitro, their peripheral T cells show decreased proliferation and cytokine production upon aCD3/aCD28 stimulation. It is unclear whether these T-cell defects are acquired during peripheral activation or are, in part, generated during thymic development. Here, we assessed the role of WASp during T-cell differentiation using artificial thymic organoid cultures and in the thymus of humanized mice. Although CRISPR/Cas9 WAS knockout hematopoietic stem and progenitor cells (HSPCs) rearranged the T-cell receptor and differentiated to T-cell receptor (TCR)+ CD4+ CD8+ double-positive (DP) cells similar to wild-type HSPCs, a partial defect in the generation of CD8 single-positive (SP) cells was observed, suggesting that WASp is involved in their positive selection. TCR repertoire analysis of the DP and CD8+ SP population, however, showed a polyclonal repertoire with no bias toward autoreactivity. To our knowledge, this is the first study of the role of WASp in human T-cell differentiation and on TCR repertoire generation. [ABSTRACT FROM AUTHOR]

Changes in the dynamic architecture of podocytes, the glomerular epithelial cells, lead to kidney dysfunction. Previous studies on protein kinase C and casein kinase 2 substrates in neurons 2 (PACSIN2), a known regulator of endocytosis and cytoskeletal organization, reveal a connection between PACSIN2 and kidney pathogenesis. Here, we show that the phosphorylation of PACSIN2 at serine 313 (S313) is increased in the glomeruli of rats with diabetic kidney disease. We found that phosphorylation at S313 is associated with kidney dysfunction and increased free fatty acids rather than with high glucose and diabetes alone. Phosphorylation of PACSIN2 emerged as a dynamic process that fine-tunes cell morphology and cytoskeletal arrangement, in cooperation with the regulator of the actin cytoskeleton, Neural Wiskott–Aldrich syndrome protein (N-WASP). PACSIN2 phosphorylation decreased N-WASP degradation while N-WASP inhibition triggered PACSIN2 phosphorylation at S313. Functionally, pS313-PACSIN2 regulated actin cytoskeleton rearrangement depending on the type of cell injury and the signaling pathways involved. Collectively, this study indicates that N-WASP induces phosphorylation of PACSIN2 at S313, which serves as a mechanism whereby cells regulate active actin-related processes. The dynamic phosphorylation of S313 is needed to regulate cytoskeletal reorganization. [ABSTRACT FROM AUTHOR]

Abstract Background Wiskott–Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder caused by abnormal expression of the WAS protein (WASp) due to mutations in the WAS gene, and is generally characterized by microthrombocytopenia, eczema, recurrent infections, and high susceptibility to autoimmune complications and hematological malignancies. Results Herein, we identified a novel WAS mutation (c.158 T > C) using next-generation sequencing in a Chinese pedigree with WAS. The expression of WASp in the patients and their families was detected by flow cytometry and western blot analysis. To explore the exon-splicing effect of intron mutations and the correlation between the genotype and clinical phenotype, four groups of wild-type (WT), exon mutant, intron mutant, and combined mutant recombinant plasmids were transfected into COS-7 cells in vitro. The proband showed dramatically decreased WASp expression, while the female carriers showed a slightly lower level of WASp. The expression of products in the mutant and WT recombinant plasmids was detected by real-time fluorescence quantitative polymerase chain reaction (PCR), which showed a significant reduction in the combined mutant group than in the WT, exon mutant, and intron mutant groups. The length of the expression products in the four groups showed no differences, each containing 360 base pairs. Sequence analysis confirmed that the c.158 T > C mutation appeared in the exon mutant and combined mutant groups, whereas the intron variant c.273 + 14C > T caused no other sequence changes. Conclusion This study confirmed that the intron mutation did not affect the splicing of exons and excluded the influence of the double mutations at the transcription level on the severe clinical manifestations in the cousin. This in vitro study provided new insights into the pathogenesis of intronic mutations in WAS.

Forces generated by actin assembly assist membrane invagination during clathrin-mediated endocytosis (CME). The sequential recruitment of core endocytic proteins and regulatory proteins, and assembly of the actin network, are well documented in live cells and are highly conserved from yeasts to humans. However, understanding of CME protein self-organization, as well as the biochemical and mechanical principles that underlie actin's role in CME, is lacking. Here, we show that supported lipid bilayers coated with purified yeast Wiskott Aldrich Syndrome Protein (WASP), an endocytic actin assembly regulator, and incubated in cytoplasmic yeast extracts, recruit downstream endocytic proteins and assemble actin networks. Time-lapse imaging of WASP-coated bilayers revealed sequential recruitment of proteins from different endocytic modules, faithfully replicating in vivo behavior. Reconstituted actin networks assemble in a WASP-dependent manner and deform lipid bilayers, as seen by electron microscopy. Time-lapse imaging revealed that vesicles are released from the lipid bilayers with a burst of actin assembly. Actin networks pushing on membranes have previously been reconstituted; here, we have reconstituted a biologically important variation of these actin networks that self-organize on bilayers and produce pulling forces sufficient to bud off membrane vesicles. We propose that actin-driven vesicle generation may represent an ancient evolutionary precursor to diverse vesicle forming processes adapted for a wide array of cellular environments and applications. [ABSTRACT FROM AUTHOR]

Primary immune deficiencies (PIDs) are genetic disorders impacting the appropriate development or functioning of any portion of the immune system. The broad adoption of high-throughput sequencing has driven discovery of new genes as well as expanded phenotypes associated with known genes. Beginning with the identification of WAS mutations in patients with severe Wiskott-Aldrich Syndrome, recognition of WAS mutations in additional patients has revealed phenotypes including isolated thrombocytopenia and X-linked neutropenia. Likewise RAC2 patients present with vastly different phenotypes depending on the mutation–ranging from reticular dysgenesis or severe neutrophil dysfunction with neonatal presentation to later onset common variable immune deficiency. This review examines genotype-phenotype correlations in patients with WAS (Wiskott-Aldrich Syndrome) and RAC2 mutations, highlighting functional protein domains, how mutations alter protein interactions, and how specific mutations can affect isolated functions of the protein leading to disparate phenotypes. Both gain- and loss-of-function mutations in Wiskott-Aldrich syndrome (WAS) and RAC2 are found throughout the genes and cause immunodeficiencies involving leukocyte actin remodeling. Patient phenotypes differ based on gain or loss of protein function or loss of protein. Identified RAC2 mutations include dominant loss-of-function resulting in severe infantile onset disease similar to leukocyte adhesion deficiency (LAD-like LOF) in which RAC2 cannot activate downstream effectors (black), dominant gain-of-function causing severe combined immune deficiency (SCID GOF) with constitutively activate RAC2 (bold red), and prolonged activated RAC2 causing common variable immune deficiency (CVID GOF) in which RAC2 fails to rapidly hydrolyze GTP but maintains intrinsic hydrolysis (salmon). Both gain- and loss-of-function mutations in Wiskott-Aldrich syndrome (WAS) and RAC2 are found throughout the genes, causing immunodeficiencies involving leukocyte actin remodeling. Patient phenotypes differ based on gain or loss of protein function or loss of protein. This review highlights the correlation between WAS and RAC2 mutations and patient presentations and explores the expanding cellular roles recognized for the two proteins. [ABSTRACT FROM AUTHOR]

Regardless of ethnicity or geographical distribution, Wiskott-Aldrich syndrome affects 1 in every 100,000 live male births. It has been established that Wiskott-Aldrich syndrome may potentially be a source of autoimmune illnesses and reticuloendothelial malignancies, even though most patients present with the traditional triad of thrombocytopenia, eczema, and recurrent bacterial infections. This case report introduces a 4-year-old boy born with hematemesis, thrombocytopenia, eczema, recurring infections, and, most surprisingly, normal platelet size. Genetic testing confirmed the diagnosis, primarily based on clinical suspicion. Thus the case study attempts to increase awareness among doctors in Bahrain and globally in considering the diagnosis of Wiskott-Aldrich syndrome in any patient with eczema, recurrent infections and thrombocytopenia regardless of having a normal mean platelet volume. [ABSTRACT FROM AUTHOR]

Introduction: The abnormal expression of the Wiskott-Aldrich syndrome protein (WASP) encoded by the Wiskott-Aldrich syndrome (WAS) gene has been implicated in tumor invasion and immune regulation. However, prognostic implications of WAS and its correlation tumor infiltrating in renal clear cell carcinoma (ccRCC) is not clear cut. Methods: The correlation between WAS expression, clinicopathological variables and clinical outcomes were evaluated using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Tumor Immune Estimation Resource (TIMER), UALCAN, Gene Expression Profiling Interaction Analysis (GEPIA), Kaplan-Meier (KM) plotter and other databases. Furthermore, we assessed the transcription expression of WAS in renal cancer tissues, various renal carcinoma cell lines and human renal tubular cells (HK2) using quantitative polymerase chain reaction (qPCR). A comprehensive analysis of multiple databases including TIMER, GEPIA, TISIDB, ESTIMATE algorithm, and CIBERSORT algorithm were performed to determine the correlation between WAS and tumor infiltrating immune cells in ccRCC. Results: The results displayed an increase in WAS mRNA level in ccRCC compared to normal tissue. WAS protein level was found highly expressed in cancer tissues, particularly within renal tumor cells via the human protein atlas (HPA). Interestingly, we found that elevated WAS expression was significantly positively correlated with the infiltration of CD8+ T cells, B cells, Monocytes, Neutrophils, Macrophages, T cell regulation, NK cells, and Dendritic cells in ccRCC. Bioinformatics demonstrated a strong correlation between WAS expression and 42 immune checkpoints, including the T cell exhaustion gene PD-1, which is critical for exploring immunotherapy for ccRCC. We revealed that patients with high WAS expression were less sensitive to immunotherapy medications. Conclusion: In conclusion, our study identified that WAS was a prognostic biomarker and correlated with immune infiltrates in ccRCC. [ABSTRACT FROM AUTHOR]

Immunoactinopathies caused by mutations in actin‐related proteins are a growing group of inborn errors of immunity (IEI). Immunoactinopathies are caused by a dysregulated actin cytoskeleton and affect hematopoietic cells especially because of their unique capacity to survey the body for invading pathogens and altered self, such as cancer cells. These cell motility and cell‐to‐cell interaction properties depend on the dynamic nature of the actin cytoskeleton. Wiskott‐Aldrich syndrome (WAS) is the archetypical immunoactinopathy and the first described. WAS is caused by loss‐of‐function and gain‐of‐function mutations in the actin regulator WASp, uniquely expressed in hematopoietic cells. Mutations in WAS cause a profound disturbance of actin cytoskeleton regulation of hematopoietic cells. Studies during the last 10 years have shed light on the specific effects on different hematopoietic cells, revealing that they are not affected equally by mutations in the WAS gene. Moreover, the mechanistic understanding of how WASp controls nuclear and cytoplasmatic activities may help to find therapeutic alternatives according to the site of the mutation and clinical phenotypes. In this review, we summarize recent findings that have added to the complexity and increased our understanding of WAS‐related diseases and immunoactinopathies. [ABSTRACT FROM AUTHOR]

Rho family GTPases regulate both linear and branched actin dynamics by activating downstream effectors to facilitate the assembly and function of complex cellular structures such as lamellipodia and contractile actomyosin rings. Wiskott-Aldrich Syndrome (WAS) family proteins are downstream effectors of Rho family GTPases that usually function in a one-to-one correspondence to regulate branched actin nucleation. In particular, the WAS protein Scar/WAVE has been shown to exhibit one-to-one correspondence with Rac GTPase. Here we show that Rac and SCAR are recruited to cell wounds in the Drosophila repair model and are required for the proper formation and maintenance of the dynamic actomyosin ring formed at the wound periphery. Interestingly, we find that SCAR is recruited to wounds earlier than Rac and is still recruited to the wound periphery in the presence of a potent Rac inhibitor. We also show that while Rac is important for actin recruitment to the actomyosin ring, SCAR serves to organize the actomyosin ring and facilitate its anchoring to the overlying plasma membrane. These differing spatiotemporal recruitment patterns and wound repair phenotypes highlight the Rac-independent functions of SCAR and provide an exciting new context in which to investigate these newly uncovered SCAR functions. [ABSTRACT FROM AUTHOR]

Members of the Wiskott–Aldrich Syndrome protein (WASp) family activate Arp2/3 complex (actin‐related proteins 2 and 3 complex) to form actin filament branches. The proline‐rich domain (PRD) of WASp contributes to branching nucleation, and the PRD of budding yeast Las17 binds actin filaments [Urbanek AN et al. (2013) Curr Biol 23, 196–203]. Biochemical assays showed the recombinant PRD of fission yeast Schizosaccharomyces pombe Wsp1p binds actin filaments with micromolar affinity. Recombinant PRDs of both Wsp1p and Las17p slowed the elongation of actin filaments by Mg‐ATP‐actin monomers by half and slowed the spontaneous polymerization of Mg‐ATP‐actin monomers modestly. The affinity of PRDs of WASp‐family proteins for actin filaments is high enough to contribute to the reported stimulation of actin filament branching by Arp2/3 complex. [ABSTRACT FROM AUTHOR]

Type B insulin resistance (TBIR) is a rare, often fulminant form of insulin resistance caused by autoantibodies against the insulin receptor. If left untreated, its mortality is high. Various immunosuppressive regimens have shown efficacy, but treatment effects are variable and time-delayed, and drug-induced complications may arise. We report a patient with TBIR arising as a complication of Wiskott–Aldrich syndrome. Stable remission of TBIR was achieved through allogeneic peripheral blood stem cell transplantation (PBSCT) over a follow-up period of more than 1.5 years. We thus demonstrate that PBSCT can be considered a treatment option in TBIR where conventional immunosuppressive therapy is ineffective or contraindicated.

Similar to the adult WAS patient, and despite the pathology report supporting atopic dermatitis, the unusual severe skin involvement of plantar and palmar surfaces in our case still raised concern for possible concurrent skin GVHD. To the Editor, Dupilumab has shown efficacy in the treatment of moderate to severe atopic dermatitis [[1]]. While hematopoietic cell transplantation (HCT) provides a curative treatment [[4]], autoimmune manifestations can still develop even after immune reconstitution, with 14% of transplanted patients developing autoimmune manifestations within the first year after HCT [[4]]. [Extracted from the article]

BACKGROUND: We undertook a study to determine the impact of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT) and their therapies upon the health-related quality of life (HRQOL) of patients and their families. MATERIALS AND METHODS: We undertook a survey of patients and their families, who self-identified as having either WAS or XLT. We assessed the PedsQL™ 4.0, the parent proxy form, and the family impact module. These results were compared with normative data from previously published reports. RESULTS: Sixty-eight patients (29 patients completed both the PedsQL™ 4.0 and the parent proxy form; 21 completed only the PedsQL™ 4.0; and 18 completed only the parent proxy form) were included. In contrast to patient-reported outcomes, parents of patients who had a bone marrow transplant (BMT) reported that their children had better QOL scores compared with those who did not (82.6 vs. 73.3, p = 0.023). The QOL of patients vs. previously published normative data showed decreases in patient scores for psychosocial health (72.62 vs. 86.58, p =

Wiskott-Aldrich syndrome (WAS)/X-linked thrombocytopenia (XLT) is a rare X-linked disease characterized by thrombocytopenia, eczema, and recurrent infection. In addition, WAS/XLT increases incidence of autoimmune diseases and malignancies. We reported 7 male patients, 2 with WAS and 5 with XLT, from 6 different families. Two novel mutations, p.Gly387GlufsTer58 and p.Ala134Asp, were identified in patients with WAS. Both patients had severe clinical phenotypes compatible with classic WAS and developed lethal outcomes with intracranial hemorrhage. Other than that, one patient with XLT developed pineoblastoma.

Abstract Introduction Wiskott–Aldrich syndrome is a rare X-linked primary immunodeficiency that mostly presents with a classic triad of eczema, microthrombocytopenia, recurrent infections, and increased risk of autoimmunity/malignancies. Case presentation We present an 8-month-old African male, born from nonconsanguineous parents and who presented with a history of eczematous skin rash since day 9 of life, with recurrent sinus infections, otitis media, and skin abscesses. An elder male sibling who had similar symptoms passed away during infancy. Investigations were consistent with microthrombocytopenia and significantly raised immunoglobulin E, while immunoglobulin A and immunoglobulin G were moderately elevated with normal immunoglobulin M. Genetic testing revealed the patient to be hemizygous for a pathogenic Wiskott–Aldrich syndrome gene variant (NM_000377.2:c.403C>T). He was managed conservatively with supportive treatment until he died a year later. Conclusion Despite Wiskott–Aldrich syndrome being a rare disease, it should be considered as a differential in any male child who presents with microthrombocytopenia and recurrent infections, especially in low-resource settings where genetic testing is not routinely available.

Objective: To investigate the clinical features, endoscopic manifestations, and genetic characteristics of a child with Wiskott-Aldrich syndrome(WAS) and Crohn′s disease, so as to provide reference for clinical diagnosis. Methods: The clinical manifestations, biological indicators, endoscopic characters, therapy, and follow-up of a child with Crohn′s disease combined with WAS were analyzed retrospectively. And literature was searched from PubMed, Wanfang Data, and CNKI. Results: A 6-year-old boy had recurrent abdominal pain, hematochezia for one month, and had perianal abscess for about half a month. He also had thrombocytopenia since infancy. Complete blood cell count showed moderate anemia (Hb 70 g/L) and decreased platelets (77×109/L). The boy had elevated erythrocyte sedimentation rate (71 mm/h) and fecal calprotectin (>1 800 μg/g). Colonoscopy showed multiple ulcers in colon and the pathological examination revealed chronic inflammation in mucosa of the terminal ileum and colon, some of which were accompanied by microabscess and crypt abscesses. The child was diagnosed with Crohn's disease. A splicing mutation (c.777+3_777+6 del GAGT) was identified in the exon 8 of WAS gene by next-generation sequencing. Consequently, the child was definitely diagnosed as WAS combined with Crohn′s disease. There were 9 relevant articles, showing that all 16 patients had childhood-onset inflammatory bowel disease (IBD) (1 day to 14.9 years old), and 10 of them were accompanied by thrombocytopenia. Various treatments, including drugs, surgery, and bone marrow transplantation were required. Seven patients were followed up, and three of them died. Conclusions: For children with IBD, particularly those with very early-onset inflammatory bowel disease, the possibility of monogenic diseases should be taken into account. If a male child with IBD have thrombocytopenia since childhood, the WAS gene should be detected.

Brugia malayi, a parasitic roundworm of humans, is colonized by the obligate intracellular bacterium, Wolbachia pipientis. The symbiosis between this nematode and bacterium is essential for nematode reproduction and long-term survival in a human host. Therefore, identifying molecular mechanisms required by Wolbachia to persist in and colonize B. malayi tissues will provide new essential information regarding the basic biology of this endosymbiosis. Wolbachia utilize a Type IV secretion system to translocate so-called "effector" proteins into the cytosol of B. malayi cells to promote colonization of the eukaryotic host. However, the characterization of these Wolbachia secreted proteins has remained elusive due to the genetic intractability of both organisms. Strikingly, expression of the candidate Wolbachia Type IV-secreted effector protein, Wbm0076, in the surrogate eukaryotic cell model, Saccharomyces cerevisiae, resulted in the disruption of the yeast actin cytoskeleton and inhibition of endocytosis. Genetic analyses show that Wbm0076 is a member of the family of Wiskott-Aldrich syndrome proteins (WAS [p]), a well-conserved eukaryotic protein family required for the organization of actin skeletal structures. Thus, Wbm0076 likely plays a central role in the active cell-to-cell movement of Wolbachia throughout B. malayi tissues during nematode development. As most Wolbachia isolates sequenced to date encode at least partial orthologs of wBm0076, we find it likely that the ability of Wolbachia to directly manipulate host actin dynamics is an essential requirement of all Wolbachia endosymbioses, independent of host cell species. Author summary: Filarial nematodes of the family Onchocercidae cause several debilitating human diseases such as lymphatic filariasis and onchocerciasis; more than 50 million people are infected by these arthropod-borne roundworms in mostly tropical and sub-tropical regions. Many of these nematodes, including Brugia malayi, are obligately colonized by an intracellular bacterium of the genus Wolbachia, which is absolutely required for the proper development and reproduction of these worms in a mammalian host. Clearance of Wolbachia from these nematodes leads to a loss of both worm viability and its ability to cause disease in humans. Efforts to understand the molecular interactions required to maintain this important bacterium: nematode endosymbiosis, however, have been hampered due to the genetic intractability of these organisms. In this work, we utilize yeast as a surrogate eukaryotic cell to show that a candidate secreted effector protein from Wolbachia, Wbm0076, disrupts eukaryotic actin dynamics and endocytosis. We also observe interactions of Wbm0076 with a highly-conserved eukaryotic actin regulatory protein. As some intracellular bacteria manipulate host actin dynamics to promote mobility within or into host cells, our study provides evidence of an important Wolbachia protein activity that may be essential for its proper localization during the development of B. malayi. [ABSTRACT FROM AUTHOR]

Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency disease with a predisposition towards autoimmunity and lymphoproliferative diseases. Non-Hodgkin lymphoma (NHL) is reported to be the predominant form of malignant tumor in WAS sufferers. Diffuse large B-cell lymphoma (DLBCL) is one of the most common types of NHL while it is uncommon to occur in paranasal sinuses and especially when associated with WAS. In this article, we report a unique case of WAS associated with DLBCL in paranasal sinuses and review the major publications of WAS-related lymphomas that occurred in the head and neck area. This study extends the available therapies for WAS-related lymphomas and emphasizes the significance of recognition for sinonasal lymphomas in WAS patients presenting with sinusitis. [ABSTRACT FROM AUTHOR]

Patients with Wiskott-Aldrich syndrome (WAS) harbor mutations in the WAS gene and suffer from immunodeficiency, microthrombocytopenia, and eczema. T-cells play an important role in immune response in the skin and the γδT-cells have an important role in skin homeostasis. Since WAS patients often present with eczema, we wanted to examine whether the T-cell receptor gamma (TRG) repertoire of the γδT-cells is affected in these patients. In addition, the immunoglobulin heavy chain (IGH) repertoire from genomic DNA of WAS patients was not yet studied. Thus, we sought to determine the effects that specific WAS mutations from our patients have in shaping the TRG and IGH immune repertoires. We collected clinical and genetic data on four WAS patients, each harboring a different mutation in the WAS gene. Using next-generation sequencing (NGS), we analyzed their TRG and IGH repertoires using genomic DNA isolated from their peripheral blood. We analyzed the TRG and IGH repertoire sequences to show repertoire restriction, clonal expansions, preferential utilization of specific V genes, and unique characteristics of the antigen binding region in WAS patients with eczema compared to healthy controls. Both the TRG and IGH repertoire showed diverse repertoire comparable to healthy controls on one the hand, and on the other hand, the IGH repertoire showed increased diversity, more evenly distributed repertoire and immaturity of the antigen binding region. Thus, we demonstrate by analyzing the repertoire based on genomic DNA, the various effect that WAS mutations have in shaping the TRG and IGH adaptive immune repertoires. [ABSTRACT FROM AUTHOR]

Purpose: Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease whose optimal curative treatment is hematopoietic stem cell transplantation (HSCT). Patients with WAS may suffer from cytomegalovirus retinitis (CMVR) which can cause vision loss. This study is to report the progression and prognosis of patients with WAS and CMVR. Methods: A retrospective case series of ten patients with WAS and CMVR before and after HSCT who were referred to the Ophthalmology Department of Xinhua Hospital from June 2018 to February 2021. Progression and prognosis were recorded. Results: Five patients were diagnosed with CMVR before receiving HSCT at a median age of 10.5 months (range: 4–23 months). Eight patients developed CMVR post-transplantation with a median interval from HSCT of 3.5 months (range: 1–9 months). Conclusion: Regular fundus examinations and prompt treatments in patients with WAS are therefore crucial before they receiving HSCT or approximately 3.5 months after HSCT until complete reconstitution of immune function. [ABSTRACT FROM AUTHOR]

Background: Wiskott–Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder caused by abnormal expression of the WAS protein (WASp) due to mutations in the WAS gene, and is generally characterized by microthrombocytopenia, eczema, recurrent infections, and high susceptibility to autoimmune complications and hematological malignancies. Results: Herein, we identified a novel WAS mutation (c.158 T > C) using next-generation sequencing in a Chinese pedigree with WAS. The expression of WASp in the patients and their families was detected by flow cytometry and western blot analysis. To explore the exon-splicing effect of intron mutations and the correlation between the genotype and clinical phenotype, four groups of wild-type (WT), exon mutant, intron mutant, and combined mutant recombinant plasmids were transfected into COS-7 cells in vitro. The proband showed dramatically decreased WASp expression, while the female carriers showed a slightly lower level of WASp. The expression of products in the mutant and WT recombinant plasmids was detected by real-time fluorescence quantitative polymerase chain reaction (PCR), which showed a significant reduction in the combined mutant group than in the WT, exon mutant, and intron mutant groups. The length of the expression products in the four groups showed no differences, each containing 360 base pairs. Sequence analysis confirmed that the c.158 T > C mutation appeared in the exon mutant and combined mutant groups, whereas the intron variant c.273 + 14C > T caused no other sequence changes. Conclusion: This study confirmed that the intron mutation did not affect the splicing of exons and excluded the influence of the double mutations at the transcription level on the severe clinical manifestations in the cousin. This in vitro study provided new insights into the pathogenesis of intronic mutations in WAS. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a heterogeneous cancer, and many risk factors for colorectal cancer have been established. For CRC metastasis, tumor cell migration, adhesion as well as invasion are important processes. Wiskott- Aldrich syndrome protein family member 3 (WASF3) is necessary for metastasis of various types of cancers. However, its role in CRC progression has not been fully elucidated. This study examined the in vitro functional roles of WASF3 in the CRC and explored the underlying molecular mechanisms. We used siRNA-WASF3 to gene silence WASF3 in colon cancer cell (HCT116) in vitro. The effects of WASF3 silencing on HCT116 cell apoptosis, proliferation, migration, as well as invasion were assessed by flow cytometry, CCK-8, and transwell assays. ZNF471 protein expressions were detected by immunofluorescence staining and RT-PCR. Moreover, the effects of ZNF471 were studied on a series of in vitro antitumor-promoting assays using HCT116. WASF3 knockdown expression using small interfering RNA (siRNA) ameliorated CRC cell proliferation, anchorage-independent growth, invasion, and metastasis. Furthermore, we observed that WASF3 contributed to upregulating the metastasis signaling pathway through inhibiting the expression of ZNF471. Our study suggests that targeting WASF3 signaling might be a novel therapeutic strategy for treating CRC. [ABSTRACT FROM AUTHOR]

Human Tnk1 (thirty-eight negative kinase 1) is a member of the Ack family of nonreceptor tyrosine kinases. Tnk1 contains a sterile alpha motif, a tyrosine kinase catalytic domain, an SH3 (Src homology 3) domain, and a large C-terminal region that contains a ubiquitin association domain. However, specific physiological roles for Tnk1 have not been characterized in depth. Here, we expressed and purified Tnk1 from Sf9 insect cells and established an in vitro assay system using a peptide substrate derived from the Wiskott-Aldrich Syndrome Protein (WASP). By Tnk1 expression in mammalian cells, we found that the N-terminal SAM domain is important for self-association and kinase activity. We also studied a fusion protein, originally discovered in a Hodgkin's Lymphoma cell line, that contains an unrelated sequence from the C17ORF61 gene fused to the C-terminus of Tnk1. Cells expressing the fusion protein showed increased tyrosine phosphorylation of cellular substrates relative to cells expressing WT Tnk1. A truncated Tnk1 construct (residues 1-465) also showed enhanced phosphorylation, indicating that the C17ORF61 sequence was dispensable for the effect. Additionally, in vitro kinase assays with the WASP peptide substrate showed no increase in intrinsic Tnk1 activity in C-terminally truncated constructs, suggesting that the truncations did not simply remove an autoinhibitory element. Fluorescence microscopy experiments demonstrated that the C-terminus of Tnk1 plays an important role in the subcellular localization of the kinase. Taken together, our data suggest that the noncatalytic regions of Tnk1 play important roles in governing activity and substrate phosphorylation. [ABSTRACT FROM AUTHOR]

Wiskott-Aldrich syndrome (WAS) is characterized by eczema, recurrent infections and microthrombocytopenia, with the latter being the most consistent finding in the course of the disease. The present case report describes a pediatric patient with WAS and severe bleeding phenotype resulting from a very low platelet count. In order to limit platelet transfusions and related risk of allo-immunization, use of recombinant activated factor VII (rFVIIa) for treatment of bleeding was decided. In addition, prophylactic treatment with eltrombopag was attempted, in order to increase platelet count and limit bleeding episodes. Management of the patient with the above mentioned agents led to a significant improvement in his clinical course and overall quality of life. This is the first report on off-label use of rFVIIa in a WAS patient. With regards to the off-label use of thrombopoietic agents in pediatric WAS patients, limited data is available and is reviewed in the report.

The article titled "Correction to 'LncRNA MYLK antisense RNA 1 activates cell division cycle 42/Neutal Wiskott–Aldrich syndrome protein pathway via microRNA‐101‐5p to accelerate epithelial‐to‐mesenchymal transition of colon cancer cells'" has two errors that need to be corrected. The first error is the incorrect affiliation of the First Affiliated Hospital of China Medical University, which should be corrected to the Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China. The second error is the incorrect name of the PV6000 product, which should be corrected to PV6000 (ZSGB‐BIO, Beijing, China). The authors apologize for these errors and confirm that all the results and conclusions of the article remain unchanged. [Extracted from the article]

Abstract Objective Wiskott–Aldrich syndrome (WAS) is a rare X‐linked primary immunodeficiency, characterized by micro‐thrombocytopenia, recurrent infections, and eczema. This study aims to describe common oral manifestations and evaluate oral microbioma of WAS patients. Material and methods In this cohort study, 11 male WAS patients and 16 male healthy controls were evaluated in our Center between 2010 and 2018. Data about clinical history, oral examination, Gingival Index (GI) and Plaque Index (PI) were collected from both groups. Periodontal microbiological flora was evaluated on samples of the gingival sulcus. Results WAS subjects presented with premature loss of deciduous and permanent teeth, inclusions, eruption disturbance, and significantly worse GI and PI. They also showed a trend toward a higher total bacterial load. Fusobacterium nucleatum, reported to contribute to periodontitis onset, was the most prevalent bacteria, together with Porphyromonas gingivalis and Tannerella forsythia. Conclusions Our data suggest that WAS patients are at greater risk of alterations in the oral cavity. The statistically higher incidence of periodontitis and the trend to higher prevalence of potentially pathological bacterial species in our small cohort, that should be confirmed in future in a larger population, underline the importance of dentistry monitoring as part of the multidisciplinary management of WAS patients.

BACKGROUND:Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, infections, and susceptibility to autoimmunity and malignancies. Thrombocytopenia is a constant finding, but its pathogenesis remains elusive. OBJECTIVE:To dissect the basis of the WAS platelet defect, we used a novel conditional mouse model (CoWas) lacking Wiskott-Aldrich syndrome protein (WASp) only in the megakaryocytic lineage in the presence of a normal immunologic environment, and in parallel we analyzed samples obtained from patients with WAS. METHODS:Phenotypic and functional characterization of megakaryocytes and platelets in mutant CoWas mice and patients with WAS with and without autoantibodies was performed. Platelet antigen expression was examined through a protein expression profile and cluster proteomic interaction network. Platelet immunogenicity was tested by using ELISAs and B-cell and platelet cocultures. RESULTS:CoWas mice showed increased megakaryocyte numbers and normal thrombopoiesis in vitro, but WASp-deficient platelets had short lifespan and high expression of activation markers. Proteomic analysis identified signatures compatible with defects in cytoskeletal reorganization and metabolism yet surprisingly increased antigen-processing capabilities. In addition, WASp-deficient platelets expressed high levels of surface and soluble CD40 ligand and were capable of inducing B-cell activation in vitro. WASp-deficient platelets were highly immunostimulatory in mice and triggered the generation of antibodies specific for WASp-deficient platelets, even in the context of a normal immune system. Patients with WAS also showed platelet hyperactivation and increased plasma soluble CD40 ligand levels correlating with the presence of autoantibodies. CONCLUSION:Overall, these findings suggest that intrinsic defects in WASp-deficient platelets decrease their lifespan and dysregulate immune responses, corroborating the role of platelets as modulators of inflammation and immunity.

UNLABELLED: ABSTRACTObjective:Pediatric bone marrow transplants represent a medically stressful, potentially traumatic experience for children and caregivers, and psychological support for parental caregivers is paramount to their long-term well-being. However, many medical centers do not have protocols in place to sustain caregiver well-being during these distressing experiences. METHOD: We report on a case of a 10-month-old infant with Wiskott Aldrich Syndrome who was hospitalized for bone marrow transplantation. RESULT: We describe the significant burden that fell upon caregivers during and after a bone marrow transplantation. SIGNIFICANCE OF RESULTS: This case helped guide our suggestions to improve care for caregivers. Several logistical hurdles could be overcome to alleviate some of these burdens. We suggest that a child psychologist or psychiatrist should be on patient care teams and be attentive to parental stress, impairments, or impediments to self-care, and signs of emergency of mental illness in this setting of medical trauma. Additionally, promotion of sleep hygiene and linkage to support systems can maximize resiliency. Finally, we believe that hospital administrators should partner with clinicians to facilitate routine support during highly stressful transitions of care.

ABSTRACTObjective:Pediatric bone marrow transplants represent a medically stressful, potentially traumatic experience for children and caregivers, and psychological support for parental caregivers is paramount to their long-term well-being. However, many medical centers do not have protocols in place to sustain caregiver well-being during these distressing experiences.MethodWe report on a case of a 10-month-old infant with Wiskott Aldrich Syndrome who was hospitalized for bone marrow transplantation.ResultWe describe the significant burden that fell upon caregivers during and after a bone marrow transplantation.Significance of resultsThis case helped guide our suggestions to improve care for caregivers. Several logistical hurdles could be overcome to alleviate some of these burdens. We suggest that a child psychologist or psychiatrist should be on patient care teams and be attentive to parental stress, impairments, or impediments to self-care, and signs of emergency of mental illness in this setting of medical trauma. Additionally, promotion of sleep hygiene and linkage to support systems can maximize resiliency. Finally, we believe that hospital administrators should partner with clinicians to facilitate routine support during highly stressful transitions of care.

Smitha Hosahalli Vasanna, Maria A Pereda, Jignesh Dalal Department of Pediatrics, Division of Pediatric Hematology Oncology, Rainbow Babies and Children’s Hospital, University Hospitals, Cleveland, OH, USACorrespondence: Jignesh DalalDepartment of Pediatrics, Division of Pediatric Hematology Oncology, Rainbow Babies and Children’s Hospital, University Hospitals, 11100 Euclid Ave, Cleveland, OH, 44106, USATel +1 2169831027Fax +1 2168445431Email jignesh.dalal@uhhospitals.orgAbstract: Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive inborn error of immunity (IEI) first described in 1937. Classic WAS is characterized by the triad of thrombocytopenia with small platelets, recurrent infections due to combined immunodeficiency, and eczema. Hematopoietic stem cell transplantation (HSCT) was the only curative option available for five decades, with excellent outcomes reported for matched sibling donors (MSD) and matched unrelated donors (MUD). More recently, alternative donor transplants such as umbilical cord blood (UCB) and haploidentical transplant have emerged as viable options due to improvements in better graft selection, cell dosing, and effective allograft manipulation measures. Gene therapy is another potential curative option with promising results, yet currently is offered only as part of a clinical trial.Keywords: Wiskott–Aldrich syndrome, X-linked thrombocytopenia, supportive care, hematopoietic stem cell transplantation, gene therapy

Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia, and X-linked congenital neutropenia collectively are designated WAS-related disorders. All are attributable to pathogenic variants of the WAS protein (WASp) and present a broad spectrum of hematopoietic cellular defects that chiefly involve platelets and lymphocytes. Pathogenic mutations in the WAS gene (located at Xp11.22-23) are implicated, affecting 12 exons. Herein, we describe a neonate with congenital thrombocytopenia and platelet dysfunction due to a novel c.1500_1504dup (p.Asp502Gly) variant of the WAS gene. This mutation produces a frameshift, with substitution of aspartic acid for glycine at position 502 of the protein, and causes a downstream stop-loss codon. Clinically, the infant displayed severe thrombocytopenia and thrombasthenia, in the absence of other WAS-related traits (i.e., immune deficiency, eczema). Once a multigene panel analysis was complete, conditioning and then successful hematopoietic stem-cell transplantation took place at the age of 8 months. This case highlights the importance of genetic testing in instances where other diagnostics prove inconclusive.

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Tumor‐derived extracellular vesicles (EVs) function as critical mediators in selective modulation of the microenvironment of distant organs to generate a pre‐metastatic niche that facilitates organotropic metastasis. Identifying the organ‐specific molecular determinants of EVs can develop potential anti‐metastatic therapeutic targets. In the current study, large oncosomes (LOs), atypically large cancer‐derived EVs, are found to play a crucial role in facilitating bone‐tropic metastasis of hepatocellular carcinoma (HCC) cells by engineering an osteoclastic pre‐metastatic niche and establishing a vicious cycle between the osteoclasts and HCC cells. Transmembrane protein, VAMP‐associated protein A (VAPA), is significantly enriched on LOs surface via direct interaction with LOs marker αV‐integrin. VAPA‐enriched LOs‐induced pre‐metastatic education transforms the bone into a fertile milieu, which supports the growth of metastatic HCC cells. Mechanically, LOs‐delivered VAPA integrates to plasma membrane of osteoclasts and directly interacts with and activates neural Wiskott–Aldrich syndrome protein (N‐WASP) via dual mechanisms, consequently resulting in ARP2/3 complex‐mediated reorganization of actin cytoskeleton in osteoclasts and osteoclastogenesis. Importantly, treatment with N‐WASP inhibitor 187‐1‐packaged LOs (LOs/187‐1) dramatically abolishes the inductive effect of VAPA‐enriched LOs on pre‐metastatic niche formation and precludes HCC bone metastasis. These findings reveal a plausible mechanism for bone‐tropism of HCC and can represent a potential strategy to prevent HCC bone metastasis. [ABSTRACT FROM AUTHOR]

Background: Esophageal carcinoma is the highly lethal cancer in the world, predominantly in some areas of East Asia. We previously reported that overexpression of cytoskeleton regulator Wiskott-Aldrich syndrome protein and SCAR Homolog (WASH) associates with poor prognosis of patients with esophageal squamous cell carcinoma (ESCC). However, the molecular mechanism and clinical significance involved in WASH overexpression have not been fully elucidated. Methods: Bioinformatics analysis and luciferase reporter assay were used to predict and validate miR-637 as a regulator of WASH in ESCC cell lines. qRT-PCR, Western blotting and ELISA assays were performed to examine RNA expression and protein levels, respectively. Next, the biological functions of miR-637 were explored by tumor sphere formation assay in vitro and nude mouse tumor xenograft in vivo. Finally, we evaluated the association of miR-637 levels with clinical features in ESCC patients. Results: We identified miR-637 as a WASH-targeting miRNA. miR-637 mimic strongly attenuated the downstream IL-8 production and tumor sphere formation in esophageal cancer cells, whereas miR-637 inhibitor displayed an opposite effect. IL-8 could facilitate stem-like properties and partially rescue the phenotypes induced by miR-637 mimic. Furthermore, miR-637 inhibitor dramatically promoted IL-8 expression and cancer stemness properties in a WASH-dependent manner. Ectopic expression of miR-637 also inhibited tumor growth in a mouse model. Clinically, low expression of miR-637 was observed in tumor tissues and the low expression levels of miR-637 were correlated with poor survival of ESCC patients. In particular, plasma miR-637 could be used as a noninvasive biomarker for ESCC patients. Conclusions: These results implicate the potential application of miR-637 for diagnosis and prognosis of esophageal cancer. [ABSTRACT FROM AUTHOR]

Introduction : Inborn errors of immunity (IEI) represent a heterogeneous large group of genetic disorders characterized by susceptibility of affected individuals to recurrent infections, autoimmune/inflammatory diseases, allergy, and malignancy. We aimed to report for the first time the Algerian registry for IEI in children. Methods: We described the characteristics of IEI in Algerian children from the data collected in the Algerian registry for IEI between 1985 and 2021. Results: Over a period of 37 years, we included 887 children (530 male, 59.6%) with a mean age at diagnosis of 3.23 years and a mean diagnosis delay of 2 years. The prevalence rate was estimated at 1.97/100,000 inhabitants or 5.91/100,000 children. The parental consanguinity was found in 52.6%. The most prevalent category was combined immunodeficiencies (CID) (35.5%), followed by predominantly antibody deficiencies (24.5%) and CID with syndromic features (18.3%). The most predominant diseases were severe CID (134 cases), MHC II deficiency (99 cases), agammaglobulinemia (82 cases), common variable immunodeficiency (78 cases), hyper IgE syndromes (61 patients), ataxia-telangiectasia (46 patients), Wiskott-Aldrich syndrome (40 patients) and chronic granulomatous disease (39 cases). The clinical presentation was dominated by lower respiratory tract infections (69%), failure to thrive (38.3%), and chronic diarrhea (35.2%). Genetic analysis was performed in 156 patients (17.6%). The global mortality rate was 28.4% mainly caused by CID. Conclusion: This is the first report of the Algerian registry for IEI in children. Data is globally similar to that of the Middle East and North African (MENA) registries with high consanguinity, predominance of CID, and significant mortality. This registry highlights the weak points that should be improved in order to provide better patient care. [ABSTRACT FROM AUTHOR]

Background: Wiskott-Aldrich syndrome is an Inborn Error of Immunity characterized by thrombocytopenia, small platelets, severe eczema, recurrent infections, tendency to autoimmune diseases and neoplasms. The diagnosis of the syndrome can be difficult, especially when platelets are of normal size. Case report: A three-year-old male patient was referred to a specialized sector of university hospital for presenting acute otitis media that progressed to sepsis by Haemophilus influenzae. At one month of age, he had been diagnosed with autoimmune thrombocytopenia, and splenectomy was performed at two years of age. During follow-up, three hospitalizations were necessary: an infection by Streptococcus pneumoniae, which progressed to sepsis; one due to exacerbation of eczema, isolating S. epidermidis; another due to fever of undetermined origin. The tests showed normal number of platelets after splenectomy, platelets always with normal size. At age four, tests were performed: IgE 3128 Ku/L; IgA, IgG, and normal anti-polysaccharide antibodies; decreased IgM; decrease CD19, TCD4, naïve T and B; increased TCD8; normal NK. A diagnostic hypothesis of "probable" WAS was made. Genetic research has identified the c.295C>T mutation in the WAS gene. Conclusions: The case reported expressed a new mutation in the SWA gene, characterized by clinical manifestations of the mild phenotype of Wiskott-Aldrich syndrome, with thrombocytopenia, platelets of normal size, and X-linked inheritance. It is important to establish the early diagnosis and treatment to offer a better quality of life in these patients. [ABSTRACT FROM AUTHOR]

Severe congenital neutropenia (SCN) is characterized by severe neutropenia and recurrent critical infections. X-linked neutropenia (XLN) is caused by a gain-of-function mutation in the Wiskott-Aldrich syndrome gene (WAS), the product of which (WASp) is expressed only in blood cells, especially during neutrophil maturation. To investigate the mechanism of neutropenia, we established a novel knock-in mouse line expressing WASp-I292T. WASp-I292T neutrophils exhibited activated (dysregulated) actin polymerization. Although WASp-I292T mice did not recapitulate neutropenia, neutrophil levels were increased in the bone marrow, and extramedullary hematopoiesis was observed. Bone marrow neutrophils from WASp-I292T mice exhibited attenuated transmigration. These abnormalities were associated with downregulation of NFκB and TP53 and faulty activation of their downstream pathways. [Display omitted] • WASp-I292T mutation constitutively activates the WASp. • WASp-I292T knock-in enhances neutrophil production in the bone marrow and extramedullary hematopoiesis in the spleen. • WASp-I292T neutrophils evidenced defects in chemotaxis and neutrophil supply from the bone marrow. • F-actin dysregulation downregulates NFκB and TP53 via multiple mechanisms. [ABSTRACT FROM AUTHOR]

To cope with continuous physiological and environmental stresses, cells of all sizes require an effective wound repair process to seal breaches to their cortex. Once a wound is recognized, the cell must rapidly plug the injury site, reorganize the cytoskeleton and the membrane to pull the wound closed, and finally remodel the cortex to return to homeostasis. Complementary studies using various model organisms have demonstrated the importance and complexity behind the formation and translocation of an actin ring at the wound periphery during the repair process. Proteins such as actin nucleators, actin bundling factors, actin-plasma membrane anchors, and disassembly factors are needed to regulate actin ring dynamics spatially and temporally. Notably, Rho family GTPases have been implicated throughout the repair process, whereas other proteins are required during specific phases. Interestingly, although different models share a similar set of recruited proteins, the way in which they use them to pull the wound closed can differ. Here, we describe what is currently known about the formation, translocation, and remodeling of the actin ring during the cell wound repair process in model organisms, as well as the overall impact of cell wound repair on daily events and its importance to our understanding of certain diseases and the development of therapeutic delivery modalities. [ABSTRACT FROM AUTHOR]

Inborn errors of immunity (IEI) are characterized by diverse clinical manifestations that are dominated by atypical, recurrent, chronic, or severe infectious or noninfectious features, including autoimmunity, lymphoproliferative disease, granulomas, and/or malignancy, which contribute substantially to morbidity and mortality. Some data suggest a correlation between clinical manifestations of IEI and altered gut microbiota. Many IEI display microbial dysbiosis resulting from the proliferation of pro-inflammatory bacteria or a decrease in anti-inflammatory bacteria with variations in the composition and function of numerous microbiota. Dysbiosis is considered more established, mainly within common variable immunodeficiency, selective immunoglobulin A deficiency, severe combined immunodeficiency diseases, Wiskott-Aldrich syndrome, Hyper-IgE syndrome, autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED), immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome, IL-10 receptor deficiency, chronic granulomatous disease, and Kostmann disease. For certain IEIs, the specific predominance of gastrointestinal, respiratory, and cutaneous involvement, which is frequently associated with dysbiosis, justifies the interest for microbiome identification. With the better understanding of the relationship between gut microbiota, host immunity, and infectious diseases, the integration of microbiota modulation as a therapeutic approach or a preventive measure of infection becomes increasingly relevant. Thus, a promising strategy is to develop optimized prebiotics, probiotics, postbiotics, and fecal microbial transplantation to rebalance the intestinal microbiota and thereby attenuate the disease activity of many IEIs. [ABSTRACT FROM AUTHOR]

Takayasu arteritis (TAK) has been rarely reported in patients with immunodeficiency. In this review, we present two cases with childhood-onset TAK (c-TAK) and primary immunodeficiency while reviewing similar cases in the literature. We reviewed the data for our two pediatric patients with c-TAK and primary immunodeficiency. We also reviewed the literature for patients with c-TAK and immunodeficiency from the inceptions of the databases up to November 2021. A 14-year-old patient had lipopolysaccharide-sensitive beige-like anchor (LRBA) deficiency, and a 16-year-old had X-linked severe combined immunodeficiency (X-linked SCID). During the follow-up, they developed findings suggestive of vasculitides such as hypertension, elevation in acute phase reactants, weakness, and weight loss. Thoracoabdominal computed tomography angiography revealed findings consistent with vasculitis involving the aorta and its major branches. Patients were diagnosed with c-TAK, and corticosteroids were given to both patients in the treatment. We identified 11 articles describing 17 TAK patients with immunodeficiency in our literature search. Two of the patients with c-TAK were infected with human immunodeficiency virus (HIV), another patient had Wiskott-Aldrich syndrome, and the other had idiopathic CD4 + T lymphocytopenia. Nine adult patients with TAK were infected with HIV, three patients had common variable immunodeficiency disorder (CVID), and the other had STAT1 gain-of-function mutation. Clinicians should consider that immunodeficiencies may be accompanied by vasculitic conditions such as TAK. Hypertension, increased inflammatory markers, and constitutional symptoms may be red flags for the development of TAK. [ABSTRACT FROM AUTHOR]