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In this study, austenitic stainless steel 316L and titanium alloy (ASTM grade 5) were welded together by micro-resistance spot welding at different combinations of welding parameters and by using specifically designed electrode geometry. The welded joints were subjected to tensile shear strength test in order to determine the strength of the welded zones. In addition, micro-hardness and microstructural examinations of the fracture mode (failure analysis) were carried out in order to examine the influence of welding parameters on the welded joints. The results showed that using a combination of 2.0 kN welding current, 100 ms welding time, and 241 N welding force yield the highest load value, 378.25 N by using full factorial design of experiment (DOE). Welding current is the most significant parameter which is obtained through analysis of variance (ANOVA). However, the increase in welding current should be controlled to avoid weld metal expulsion. The microstructure of these resistance-welded metals are detailed and investigated by using SEM and EDS mapping analysis. Based on the SEM observations, columnar dendritic structures can be seen at the fusion zone (FZ) of the welded nugget.

Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities 1 . Although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported, most cases of HIES are sporadic, and their pathogenesis has remained mysterious for a long time. Here we show that dominant-negative mutations in the human signal transducer and activator of transcription 3 ( STAT3 ) gene result in the classical multisystem HIES. We found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were found, all of which were located in the STAT3 DNA-binding domain. The patients’ peripheral blood cells showed defective responses to cytokines, including interleukin (IL)-6 and IL-10, and the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3 . These results highlight the multiple roles played by STAT3 in humans, and underline the critical involvement of multiple cytokine pathways in the pathogenesis of HIES. Hyper-immunoglobulin E syndrome (HIES) is a complex primary immunodeficiency associated with inflammation, high levels of serum IgE, multiple infections and skeletal abnormalities. In this paper, the disease is linked to germline, heterozygous in-frame mutations in the DNA binding domain of the transcription activator STAT3 in eight of fifteen unrelated patients.

In this study, the synergetic effect of multi-walled carbon nanotubes (MWCNTs) and porous Cu interlayer (PCI) on the intermetallic compound (IMC) formation and shear strength of Sn–3.0Ag–0.5Cu (SAC 305) solder system was investigated. The solder joints were prepared by subjecting two different series of MWCNTs-reinforced SAC 305 solder systems (i.e., SAC–0.01CNT and SAC–0.04CNT) sandwiched with porous Cu interlayer having pores per inch (PPI) of 15, 25 and 50 to reflow soldering on Cu substrate. Electron microscopy and spectroscopy techniques were used to view and detect the intermetallic compound phases, respectively. The scallop-shaped Cu 6 Sn 5 IMC phase was observed at the solder/PCI interface, while on the other hand, an additional layer-type Cu 3 Sn IMC phase formed alongside the Cu 6 Sn 5 IMC at the solder/Cu interface. Given the promising properties of PCI material, empirical findings showed that the presence of PCI in the solder joint inhibited the formation of interfacial IMC layer at the solder/Cu substrate with the SAC–0.01CNT–25PCI exhibiting the least IMC thickness. More so, the PCI material effectively enhanced the shear strength of the MWCNTs-reinforced composite solder joints. Generally, the strengthening capacity of the PCI material was greatly underscored in the SAC–0.01CNT– x PCI series with the sample prepared with PCI of 15 PPI demonstrating the superior shear strength of 21.1 MPa.

Approximately 80% of patients with Alport syndrome have X-linked Alport syndrome (XLAS), which is caused by mutations in the type IV collagen alpha 5 gene ( COL4A5 ). In patients with XLAS, approximately 10–15% of COL4A5 mutations occur as spontaneous events. Here, we describe maternal germline mosaicism in a family of XLAS patients. Since our patient’s parents showed normal urinary findings without COL4A5 mutation using genomic DNA isolated from peripheral leukocytes, the patient was initially diagnosed with “sporadic” XLAS. However, genetic analysis of the patient’s sister with microscopic hematuria identified the same COL4A5 heterozygous mutation. Therefore, we concluded that our patient and the sister had XLAS caused by maternal germline mosaicism, not “sporadic” XLAS. Our case suggests that “sporadic” XLAS may in some patients be caused by the transmission of an abnormal allele from either parent with germline mosaicism in COL4A5 . Germline mosaicism is thought to be rare, but we should consider that even asymptomatic parents of “sporadic” XLAS patients could carry a somatic and/or germline mosaicism. More cautious genetic counseling is advisable for all “sporadic” XLAS patients. Furthermore, urinalysis screening of “sporadic” XLAS patients’ siblings is also important to enable an earlier detection of parental germline mosaicism.

Evaluation of: Aiuti A, Biasco L, Scaramuzza S et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 341(6148), 1233151 (2013).Wiskott-Aldrich syndrome (WAS), an X-linked primary immunodeficiency disease (PID) with unique and characteristic features, had been considered to be a good candidate for gene therapy. In 2010, hematopoietic stem cell (HSC) gene therapy, using a retroviral vector, was performed for WAS patients; however, concerns remain regarding the long-term safety of this therapy as several patients with PID developed myeloproliferative diseases due to insertional mutagenesis related to HSC gene therapy using retroviral vectors. Aiuti et al. first reported HSC gene therapy for WAS using a lentiviral vector and compared the safety and efficacy of the two therapies in the context of the same disease background. They undertook a detailed study of the vector integration sites and concluded that lentiviral HSC gene therapy was safer than retroviral gene therapy.

BackgroundPatients with refractory nephrotic syndrome (NS) are at high risk of medication-induced glucose metabolism disorders, because of their long-term use of diabetogenic medications, particularly glucocorticoids and calcineurin inhibitors (CNIs). However, there have been no comprehensive evaluations of glucose metabolism disorders in pediatric patients with refractory NS. Moreover, glucocorticoids and CNIs could not be discontinued in these patients until the effectiveness of rituximab on refractory NS was shown, and therefore, there has been limited opportunity to evaluate glucose metabolism disorders after discontinuation of these medications.MethodsConsecutive pediatric patients who started rituximab treatment for refractory NS were enrolled. Their glucose metabolism conditions were evaluated using the oral glucose tolerance tests (OGTT) and HbA1c levels at the initiation of rituximab treatment. Patients with glucose metabolism disorders at the first evaluation were reevaluated after approximately 2 years.ResultsOverall, 57% (20/35) of study patients had glucose metabolism disorders, and 40% (8/20) of these patients were detected only by their 2-h OGTT blood glucose levels and not by their fasting blood glucose or HbA1c levels. Non-obese/non-overweight patients had significantly more glucose metabolism disorders than obese/overweight patients (p = 0.019). In addition, glucose metabolism disorders in 71% (10/14) of patients persisted after the discontinuation of glucocorticoids and CNIs.ConclusionsWhether the patient is obese/overweight or not, patients with refractory NS are at high risk of developing glucose metabolism disorders, even in childhood. Non-obese/non-overweight patients who are at high risk of diabetes need extra vigilance.

Introduction Adenosine deaminase (ADA) deficiency is an ultrarare inherited purine metabolism disorder characterized by severe combined immunodeficiency. Elapegademase‐lvlr is a new pegylated recombinant bovine ADA used in enzyme‐replacement therapy (ERT) for ADA deficiency. Therefore, replacement with the new drug may eliminate the infectious risks associated with the currently used bovine intestinal‐derived product, pegademase. Methods We conducted a multicenter, single‐arm, open‐label, phase 3, and postmarketing clinical study of elapegademase for patients with ADA deficiency. The following biochemical markers were monitored to determine an appropriate dose of elapegademase: the trough deoxyadenosine nucleotide (dAXP) level ≤0.02 μmol/mL in erythrocytes or whole blood and the trough serum ADA activity ≥1100 U/L (equivalent to plasma levels ≥15 μmol/h/mL) indicated sufficient enzyme activity and detoxification as efficacy endpoints and monitored adverse events during the study as safety endpoints. Results A total of four patients (aged 0–25 years) were enrolled. One infant patient died of pneumonia caused by cytomegalovirus infection whereas the other three completed the study and have been observed in the study period over 3 years. The infant patient had received elapegademase at 0.4 mg/kg/week until decease and the others received elapegademase at maximum doses of 0.3 mg/kg/week for 164–169 weeks. As a result, all four patients achieved undetectable levels of dAXPs together with sufficient enzyme activity, increased T and B cell numbers, and slightly elevated and maintained IgM and IgA immunoglobulin levels. Serious adverse events occurred in three patients, all of which were assessed as unrelated to elapegademase. Conclusions This study showed that elapegademase had comparable safety and efficacy to pegademase as ERT for ADA deficiency by demonstrating stable maintenance of sufficient ADA activity and lowering dAXP to undetectable levels, while no drug‐related adverse events were reported (Trial registration: JapicCTI‐163204). Time course changes in the trough dAXP concentrations of erythrocytes and whole blood.

Porous Copper (Cu) was brazed to Cu plates using Cu-9.7Sn-5.7Ni-7P amorphous filler metal. The effects of brazing parameters on the porous Cu and brazed joints were investigated. The furnace brazing temperatures employed were 660 °C and 680 °C, and the holding times were 10 and 15 min. After brazing, the microstructure was analyzed using Scanning Electron Microscope (SEM) equipped with Electron Dispersive X-ray Spectroscope (EDS). SEM results showed that the thickness of the brazed seam at the base joint decreased with increasing temperature and time. At low brazing temperature, microvoids and cracks were observed at the joint interface. The microvoids and cracks disappeared in the sample brazed at 680 °C for 15 min, and higher diffusion of the filler was noted in the overall bonded region. The formation of Cu-P, Cu-Ni, and Ni-Sn phases at the joint interface was validated using X-ray diffraction. The phases formed increased the hardness of the brazed joints and porous Copper. It was observed that the rigidity of porous Copper tends to increase due to surface hardening effects. The rigidity of porous Cu after brazing is important in ensuring minimal deformation during cooling device servicing, which is an integral feature of prospect product development.

This study compares the high-Ag-content Sn-3Ag-0.5Cu with the low- Ag-content Sn-1Ag-0.5Cu solder alloy and the three quaternary solder alloys Sn-1Ag-0.5Cu-0.1Fe, Sn-1Ag-0.5Cu-0.3Fe, and Sn-1Ag-0.5Cu-0.5Fe to understand the beneficial effects of Fe on the microstructural stability, mechanical properties, and thermal behavior of the low-Ag-content Sn-1Ag-0.5Cu solder alloy. The results indicate that the Sn-3Ag-0.5Cu solder alloy possesses small primary β-Sn dendrites and wide interdendritic regions consisting of a large number of fine Ag 3 Sn intermetallic compound (IMC) particles. However, the Sn-1Ag-0.5Cu solder alloy possesses large primary β-Sn dendrites and narrow interdendritic regions of sparsely distributed Ag 3 Sn IMC particles. The Fe-bearing SAC105 solder alloys possess large primary β-Sn dendrites and narrow interdendritic regions of sparsely distributed Ag 3 Sn IMC particles containing a small amount of Fe. Moreover, the addition of Fe leads to the formation of large circular FeSn 2 IMC particles located in the interdendritic regions. On the one hand, tensile tests indicate that the elastic modulus, yield strength, and ultimate tensile strength (UTS) increase with increasing Ag content. On the other hand, increasing the Ag content reduces the total elongation. The addition of Fe decreases the elastic modulus, yield strength, and UTS, while the total elongation is still maintained at the Sn-1Ag-0.5Cu level. The effect of aging on the mechanical behavior was studied. After 720 h and 24 h of aging at 100°C and 180°C, respectively, the Sn-1Ag-0.5Cu solder alloy experienced a large degradation in its mechanical properties after both of the aging conditions, whereas the mechanical properties of the Sn-3Ag-0.5Cu solder alloy degraded more dramatically after 24 h of aging at 180°C. However, the Fe-bearing SAC105 solder alloys exhibited only slight changes in their mechanical properties after both aging procedures. The inclusion of Fe in the Ag 3 Sn IMC particles suppresses their IMC coarsening, which stabilizes the mechanical properties of the Fe-bearing SAC105 solder alloys after aging. The results from differential scanning calorimetry (DSC) tests indicate that the addition of Fe has a negligible effect on the melting behavior. However, the addition of Fe significantly reduces the solidification onset temperature and consequently increases the degree of undercooling. In addition, fracture surface analysis indicates that the addition of Fe to the Sn-1Ag-0.5Cu alloy does not affect the mode of fracture, and all tested alloys exhibited large ductile dimples on the fracture surface.

Double-sided laser beam welding of skin-stringer joints is a proven method for many industrial applications such as in aircraft assemblies where riveted differential joints are being replaced with welded integral structures. In the present study, dissimilar aluminum alloys of AA2024-0 and AA7075-T6 were laser welded on both sides in a T-joint configuration using a low-power Yb-fiber laser with the addition of a BA4047 filler wire. The optimized parameters were determined by developing a Mamdani fuzzy smart model. The influence of BA4047 filler wires on weld morphology was investigated using optical microscopy (OM) and scanning electron microscope (SEM). The cross-section of the joints revealed that the fusion zone (FZ) and heat affected zones (HAZ) are wider when filler wire was added as compared to those without it. This result shows that the low-power fiber laser has sufficient energy to melt the tip of the filler wire and subsequently the base materials, forming a liquid bridge to facilitate the smooth flow of molten metal between the stringer and the skin. No obvious voids were observed in the cross-sections of the joint interface. The strengths of joints were evaluated using a pull test, and hardness values were measured at the base metal (BM), FZ, and HAZ using the Vickers hardness test. At lower welding speeds with constant low-laser power, it was shown that the addition of the aluminum-silicon base alloy has increased the overall hardness and welding strengths of the samples.