Formability and Failure Evaluation of AA3003-H18 Sheets in Single-Point Incremental Forming Process through the Design of Experiments

The single-point incremental forming process (SPIF) is one of the emerging manufacturing methods because of its flexibility in producing the desired complex shapes with higher formability at low-cost compared to traditional sheet forming methods. In this research work, we experimentally investigate the forming process to determine the influence of process parameters and their contribution to enhancing the formability without causing a fracture by combining the design of experiments (DOE), grey relational analysis (GRA), and statistical analysis of variance (ANOVA). The surface morphology and the energy dispersive X-ray spectroscopy (EDS) method are used to perform elemental analysis and examine the formed parts during three forming stages. The DOE procedure, a central composite design with a face-centered option, is devised for AA3003-H18 Al alloy sheet for modeling the real-time experiments. The response surface methodology (RSM) approach is adopted to optimize the forming parameters and recognize the optimal test conditions. The statistically developed model is found to have agree with the test measurements. The prediction model’s capability in R2 is computed as 0.8931, indicating that the fitted regression model adequately aligns with the estimated grey relational grade (GRG) data. Other statistical parameters, such as root mean square error (RMSE) and average absolute relative error (AARE), are estimated as 0.0196 and 2.78%, respectively, proving the proposed regression model’s overall closeness to the measured data. In addition, the prediction error range is identified as −0.05 to 0.05, which is significantly lower and the residual data are distributed normally in the design space with variance and mean of 3.3748 and −0.1232, respectively. ANOVA is performed to understand the adequacy of the proposed model and the influence of the input factors on the response variable. The model parameters, including step size, feed rate, interaction effect of tool radius and step size, favorably influence the response variable. The model terms X₂ (0.020 and 11.30), X₃ (0.018 and 12.16), and X₁X₂ (0.026 and 9.72) are significant in terms of p-value and F-value, respectively. The microstructural inspection shows that the thinning behavior tends to be higher as forming depth advances to its maximum; the deformation is uniform and homogeneous under the predefined test conditions.     

Design of immunogens to elicit broadly neutralizing antibodies against HIV targeting the CD4 binding site

A vaccine which is effective against the HIV virus is considered to be the best solution to the ongoing global HIV/AIDS epidemic. In the past thirty years, numerous attempts to develop an effective vaccine have been made with little or no success, due, in large part, to the high mutability of the virus. More recent studies showed that a vaccine able to elicit broadly neutralizing antibodies (bnAbs), that is, antibodies that can neutralize a high fraction of global virus variants, has promise to protect against HIV. Such a vaccine has been proposed to involve at least three separate stages: First, activate the appropriate precursor B cells; second, shepherd affinity maturation along pathways toward bnAbs; and, third, polish the Ab response to bind with high affinity to diverse HIV envelopes (Env). This final stage may require immunization with a mixture of Envs. In this paper, we set up a framework based on theory and modeling to design optimal panels of antigens to use in such a mixture. The designed antigens are characterized experimentally and are shown to be stable and to be recognized by known HIV antibodies.

Vaccines are the most important medical countermeasure for protecting entire populations against viruses, of which smallpox and measles vaccines are successful examples. In fact, a safe and effective HIV vaccine is considered to be the best way to end the global AIDS epidemic (1). However, how to produce a universal vaccine for highly antigenically variable viruses like HIV is a daunting and yet unsolved problem. The high variability of this virus allows it to elude the immune system, making the produced antibodies ineffective; that is, they are generally specific for a given strain of the virus but not for other strains resulting from mutation. In some cases, HIV-infected patients can elicit antibodies that can recognize and neutralize a broad range of different viral strains (2, 3). These broadly neutralizing antibodies (bnAbs) usually take a long time to appear naturally in infected patients and then only in a subset of such individuals.The reason that bnAbs can arise is that even highly variable pathogens have regions with a well-defined, relatively conserved structure, which is required for their function. In HIV, entry depends on the trimeric spike exposed on the external lipid membrane of the virion, a heterotrimer formed by the gp120 and gp41 glycoproteins produced by posttranslational cleavage of a gp160 precursor. This protein binds to the CD4 coreceptor on CD4 T lymphocytes during HIV infection, and it has some relatively conserved regions that can be used as a target for bnAbs. Indeed, many bnAbs target the CD4 binding site (CD4bs) (4–8). If naive B cells that can bind to one of these relatively conserved regions can be expanded upon exposure to different variants of the virus, antibodies could evolve to better recognize the conserved portions, while avoiding the variable ones. The resulting antibodies can acquire breadth in this way, thereby becoming bnAbs. A successful vaccine would contain immunogens that can guide the immune system to produce bnAbs, rather than strain-specific antibodies.In the past, numerous approaches for the development of an effective HIV vaccine have been tried. They include the use of cleverly chosen natural HIV proteins, the design of a consensus (9) or “center-of-tree” (10) antigens, and the creation of a mosaic protein from different HIV strains (11). All these methods used a single optimized antigen in the vaccine and were shown to be ineffective at eliciting bnAbs (12, 13). One possible reason for this is that, when exposed to a single antigen, the immune system will produce antibodies specific for that particular antigen, and neutralization escape variants can easily develop. A possible solution is to use more than one antigen in a vaccination protocol. This raises a number of questions: How many antigens are necessary? How different should they be from each other? And in what temporal order should they be administered? Answering such questions is far from trivial, in particular due to the limited mechanistic understanding of affinity maturation (AM) in vivo. Another problem is that bnAbs have an unusually high number of somatic mutations, not only in the complementarity-determining regions (CDRs) but also in the immunoglobulin framework regions (7, 14). Recent computational data on the flexibility of the antibody and the need for framework mutations in the simulated AM showed how important it is for a vaccination protocol to have a specific antigen that can prime a good antibody precursor B cell receptor (BCR) (15). Moreover, it has been shown that putative precursors of known classes of bnAbs are generally not able to neutralize HIV or recognize envelope (Env), often due to clashes of the antibody with the glycosylation shield that protects the HIV Env protein (8, 16–18). For example, VRC01-class bnAbs are known to introduce a deletion or a mutation to a flexible glycine in the CDRL1 loop to avoid the glycan at N276 (19, 20).The above discussion led to the proposal of a vaccination strategy consisting of three steps. First, a special purpose antigen is used to activate the correct naïve or precursor B cell (17, 21). Since this precursor will generally not bind to native HIV, as a second step, one or more antigens are used as intermediates to induce somatic mutations and to allow recognition of the native virus. In the third step, one or more antigens are used in a mixture or in sequence to increase the breadth of the antibody population (19, 22, 23). Implementations of the first and second steps have already been shown to be promising in experiments (16, 21, 24–27). However, much less is known about the third step. Some insights into this question can be obtained by in silico simulations of AM. Using coarse-grained models, it has been shown that, while administering a single mixture containing multiple antigens may induce too much frustration to lead to bnAbs formation, a sequential approach, in which antigens are administered one after another, seems to be more effective (23). It was also observed that the number of antigens required in a mixture is correlated with their sequence dissimilarity, and optimal breadth is obtained at an optimal number of antigens and dissimilarity (28). Given the coarse-grained nature of these studies, the actual antigen sequences to use in experiments cannot be obtained from them.In this work, we focus on the third step of the proposed vaccination protocol. In particular, we derive a set of empirical rules and protocols to select an optimal panel of antigens to maximize the breadth of the produced antibodies upon AM. To be able to do so, it is essential to understand, at an atomistic level of detail, the role of each antigen amino acid in the antibody/antigen interaction. This aspect will be presented in the next section based on an analysis of the available crystallographic structures of bnAbs bound to the gp160 Env glycoprotein. However, the structures do not provide information concerning HIV stability and function. For example, generating antigen sequences by introducing purely random mutations will likely lead to sequences that are lethal for the virus and/or are not representative of HIV in vivo. To overcome this problem, it is useful to consider the structural data together with a model of the gp160 fitness landscape (29), which is a measure of the ability of HIV to tolerate mutations in its gp160 sequence to escape immune pressure. Structural and fitness information together provide a classification of the antibody/antigen interface and indicate the residues to mutate and the amino acids that are more probable at those positions.While this analysis helps to reduce the number of antigen sequences to consider by highlighting the “hot spots” of antibody/antigen binding, it leaves open the question of how to select a combination of antigen sequences for use in a vaccine. Given rules of optimal sequence dissimilarity and optimal fitness according to the HIV landscape, a Pareto frontier approach will be described. It is able to select, from all possible panels of antigen sequences, the few that are predicted to best elicit antibodies with a broad activity spectrum. Experimental evidence of the viability of the designed antigens and of their immunogenic properties is presented in the final section.     

Use of naloxone during cardiac arrest and CPR: potential adjunct for postcountershock electrical-mechanical dissociation

Naloxone has been shown to increase arterial pressure in hemorrhagic and septic shock. To determine if naloxone has salutary effects during cardiac arrest with conventional closed-chest cardiopulmonary resuscitation (CPR), ten dogs were studied during 20 minutes of ventricular fibrillation (VF) and CPR and during a 30-minute postcountershock period. Central aortic (Ao) and right atrial (RA) systolic and end-diastolic (EDP) pressures, instantaneous Ao-RA pressure difference (coronary perfusion pressure), and electromagnetic Ao flow were measured. Ao and RA samples were analyzed during a control period and at five-minute intervals during CPR for PO2, PCO2, and pH. During VF, a piston-cylinder device was used to perform anteroposterior sternal depressions and positive pressure ventilations (100% O2) at standard rates and ratios. After 15 minutes of CPR, animals were randomized and given either naloxone (5 mg/kg) or epinephrine (1 mg). Defibrillation was attempted five minutes later using 1 J/kg and then, if necessary, 2, 4, 8, 12, and 16 J/kg until VF was terminated or the maximum energy dose was reached. If VF persisted or if countershock resulted in asystole or a nonperfusing rhythm (electrical-mechanical dissociation [EMD]), the alternate drug (naloxone or epinephrine) was then given. Measured systolic pressures, coronary perfusion pressures, aortic flow, and blood gases were not significantly different during the control period or at five, ten, and 15 minutes of VF and CPR between animal groups prior to drug administration. When compared to hemodynamic values measured at 15 minutes, naloxone had no significant effect on pressures or aortic flow measured five minutes after administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal insulin-like growth factor I and growth hormone receptor binding in experimental diabetes and after unilateral nephrectomy in the rat

Summary We have measured specific binding of insulin-like growth factor I and growth hormone to renal plasma membranes from control, streptozotocin-diabetic, insulin-treated diabetic, uninephrectomised and combined diabetic-uninephrectomised male Wistar rats. Control, insulin-treated and uninephrectomised rats had similar body weights after 7 days (243±2 g), whereas diabetic and diabetic-uninephrectomised animals were significantly lighter (219±4 and 203±4 g, p<0.05). Blood glucose concentrations were similar in the diabetic and diabetic-uninephrectomised animals (around 26 mmol/l) but significantly lower in the insulin-treated group. Right kidney weight increased by 14% in the control, insulin-treated and sham-nephrectomised animals, by 33% in the diabetic group, 38% in the nephrectomised animals and 60% in the diabetic-nephrectomised group. The renal content of insulin-like growth factor I was similar and stable in the control, insulin-treated and sham-nephrectomised animals (208±14 ng/g wet weight) but rose to a peak of 669±35 ng/g in the diabetic group (p<0.001), 871±34 ng/g in the nephrectomised animals (p<0.001) and 1012±43 ng/g in the diabetic-uninephrectomised group (p<0.001). Maximum binding of insulin-like growth factor I fell on day 1 in the diabetic group (8.3±1.4 vs 5.2±0.71× 10^– mol/l; p<0.01) but thereafter was identical to control animals. In the insulin-treated animals, maximum binding rose to 11.0±1.1×10^–11 mol/l, significantly different from control and diabetic animals (p<0.01). Growth hormone binding fell acutely in both the diabetic and diabetic-nephrectomised animals (3.13±0.58 and 2.83±0.21 vs 7.77±0.68×10^–12 mol/l; p<0.001 for both). Following uninephrectomy, maximum binding of insulin-like growth factor I and growth hormone was unchanged from control values. We conclude that the rise in renal content of insulin-like growth factor I which precedes the compensatory growth seen after induction of diabetes and uninephrectomy is not due to alterations in insulin-like growth factor I receptor binding and is independent of growth hormone binding.     

Severe hyperglycemia: a determinant factor for hypofiltration in alloxan diabetic rats

Abstract. The relationships among glomerular filtration rate, renal plasma flow and extracellular fluid volume were investigated in control and severely hyperglycemic (442±33 mg/dl) untreated, alloxan diabetc rats. Most of diabetic animals showed significant lower values of inulin clearance (diabetics, 0.55±0.07 ml/min·100 g; controls, 0.97±0.04) and p-aminohippurate clearance (diabetics, 2.11±0.39 ml/min·100 g; controls, 3.93±0.25). Diabetic rats exhibited reduced efficiency in tubular Na⁺ reabsorption, increased urinary Na⁺ excretion (diabetics, 3.12±0.27 mEq/day; controls, 1.25±0.14) and diminished values of plasma renin activity (diabetics, 3.34±0.44 ng/ml·h; controls, 8.64±0.79). Significant negative correlations were found between glycemia and renal hemodynamic variables. Acute overload with glucose further decreased these variables in both groups: inulin clearance in diabetics vs. controls, 0.26±0.04 vs. 0.44±0.05 ml/min·100 g; p-aminohippuric acid clearance in diabetics vs. controls, 1.09±0.20 vs. 1.55±0.21 ml/min·100 g. We conclude that chronically hyperglycemic alloxan diabetic rats showed diminished glomerular filtration rates (inulin clearance), renal plasma flow (p-aminohippurate clearance) and extracellular fluid volume associated with urinary Na⁺ losses and alterations in the renin-angiotensin system. Decreased reninangiotensin system activity might reduce aldosterone secretion, which in turn could result in (succesively) urinary sodium loss, extracellular fluid volume contraction and reductions in glomerular filtration and renal plasma flow.     

Hydraulic Bench Testing of the TruCATHTM/TruCCOMTM Continuous Cardiac Output Monitor

The aim of this study was to test the truCATH^TM/ truCOMMS^TM continuous cardiac output catheter/monitor in a computer-controlled pulsatile mock loop system. The pulmonary artery catheter is equipped with two thermistors and a heating coil which maintains a 2°C temperature difference between the thermistors. The required electrical power is assumed to be an indicator of cardiac output. The catheter was tested under a variety of loading conditions including changes in heart rate (60, 75, 90, 120 beats/mm), filling pressures (0–15 mmHg), ventricular driving pressures (22–135 mmHg), and pulmonary resistance (0.08–1.47 mmHgs/mL) in random combinations, generating flows of 1.5–10 L/min. Fluid temperature was varied between 32 and 42°C. Our data demonstrate a good linear relation between the electrical power output of the TruCATH^TM/TruCOMMS^TM catheter and the actual flow as measured volumetrically. The system appeared to be sensitive to fluid temperature changes, but dimensionless analysis with Womersley and Reynolds numbers revealed that it is a direct consequence of the temperature-dependent water viscosity. We conclude that the TruCATH^TM/TruCOMMS^TM is a potentially useful clinical tool but the absolute correspondence between the catheter output and the patient's actual cardiac output remains to be assessed.     

Current treatment strategies of the German Hodgkin Study Group (GHSG)

Abstract:  Hodgkin's Lymphoma (HL) has developed to one of the best curable human cancers and overall about 80% of patients experience long-term disease free survival. Therefore, current treatment strategies aim at further improving treatment outcome, thereby trying to by minimize therapy-induced complications, such as infertility, cardiopulmonary toxicity, and secondary malignancies. Ongoing trials investigate a reduction of chemotherapy in terms of dose or cycles given, and the application of lower radiation doses and smaller radiation fields. For patients with a specific high-risk profile, new approaches with more intense drug combinations are currently being investigated. Moreover, the advent of effective salvage high-dose therapy for relapsed disease and a better understanding of prognostic factors have further improved the management of HL. Here, we summarize current strategies of the German Hodgkin Study Group (GHSG) in diagnostics and treatment of primary and relapsed HL, together with recent approaches for specific subgroups of HL patients.     

实验性氟中毒兔甲状腺的形态学观察

54只大耳白幼兔随机分为三组,每组18只;一组为对照,其余两组分别按10mg/kg/日和20mg/kg/日氟化钠喂养。在实验90、150、250天时,将动物分批处死,摘出甲状腺,用显微镜观察甲状腺的形态学变化。 结果表明,在实验90天时,各组动物甲状腺形态学表现无明显区别。实验150天时,10mg/kg/日和20mgF~-/kg/日组各检出1例广泛重度退变的甲状腺,并发现20mgF~-/kg/日滤泡直径增大。在实验250天时,10mgF~-/kg/日组检出两例弥漫增生性甲状腺肿,并发现滤泡直径增大。20mgF~-/kg/日组除检出2例弥漫增生性甲状腺肿外,还检出2例广泛重度退变的甲状腺,并发现滤泡直径明显增大及上皮细胞核直径明显变小。结果表明一定程度的氟中毒对甲状腺的形态学改变是有影响的。     

流行病学研究中“率”的标化和“率”的校正:方法探讨及SAS宏实现

目的 简述“率”的标化和“率”的校正的概念、区别以及计算方法,并用SAS宏程序实现直接标化率、间接标化率以及校正的率的计算,并以统计表格形式直接输出到rtf文件中.方法 对直接标化率、间接标化率以及校正的率的计算过程编写通用的SAS宏程序.结果 整理好相应的原始数据,设定好相应的宏参数,运行宏程序便可快速获得直接标化率、间接标化率以及校正的率的计算结果.结论 笔者编写的直接标化率、间接标化率以及校正的率的SAS宏程序具有通用、简便、实用的特点,在流行病学研究中具有一定的实用价值.