*Millennial Oscillations of Solar Irradiance and Magnetic Field in 600–2600 DOI: http://dx.doi.org/10.5772/intechopen.96450*

#### **Figure 11.**

Hence, the solar irradiance *S* can vary either because of the variations of intensity *I* of solar radiation at the Sun itself or because of the variations of a distance *d* between the Sun and Earth. The variations of the solar intensity *I* is caused by the variations of solar activity induced by the electro-magnetic dynamo action in the

If the intensity *I*⊙ of radiation on the Sun is considered to be constant at a given time (*I*⊙=const), then the solar irradiance *S* can also change because of a variation of the Sun-Earth distance caused by the Earth orbital motion itself leading to the terrestrial seasons and by solar inertial motion whose effects are not yet fully investigated. In any case, by knowing the ephemeris of the S-E distances and using Eq. (2) above for calculating solar irradiance at two different distances *d*1 and *d*2, one can find the relationship between the solar irradiance, *S*1 and *S*2 at these

1 ¼ *S*2 � *d*2

Therefore, if at a distance *d*1 the average solar irradiance is 1366 *W=m*2 [22, 31]

2*:* (3)

*S*1 � *d*2

then if the distance is changed to *d*2, the solar irradiance *S* should also change following the Eq. (3). For example, if the distance *d*2 between the Earth and Sun was to be decreased by 0.016 au (as shown in section 3 for two millennia 600–2600)

so that the initial irradiance of 1366 *W=m*2 divided by the square of the new distance results in the irradiance of 1411 *W=m*2. The difference in the irradiance is 1411–1366 = 45 *W=m*2, that is 3.3% that is exactly the magnitude mentioned in the

**4.2 Orbital variations of solar irradiance in the millennia 600–2600**

In section below the solar irradiance is explored in more details for the two millennia from 600 to 2600 AD for the S-E distances presented in section 3.

As established in section 3, the Sun-Earth distances are changing accordingly to the ellipse curve as Kepler's 3rd law assigns. Instead, these distances are defined by the two motions: the Earth and Sun about the barycentre of the solar system with the latter caused by the gravitational effects of large planets of the solar system, or solar inertial motion (SIM). Therefore, the daily variations of solar irradiance over a year will be affected by the combination of the Earth revolution on its orbit and the

By using Eq. (3) let us calculate the solar irradiance at any day of a year during the two millennia M1 and M2. For the TSI normalisation the magnitude of *S*1 = 1366 *W=m*2 [31] can be used for the longest distance in June 1700. Then the daily TSI magnitudes for every month of a year for three years for each millennium: M1 (600, 1100, 1600) and M2 (1700, 2020, 2600) are presented in **Figure 11** (for January– June), and 12 (for July–December) with their annual variations compared in **Figure 13**. The small differences ( ≤ 0.001 au) between the S-E distances of 1600 and 1700 are considered when calculating the total solar irradiance for M2. The overall variations of the sum of the TSI deposited to Earth in each year are presented in **Figure 14** calculated for: (a) the mean TSI magnitudes averaged for every month, e.g. by adding the TSI magnitudes for 12 months (left plot) and (b) the daily TSI magnitudes, e.g. by adding the TSI magnitudes for all days in each year considered. In M1 the increase of solar irradiance during the months January–June is nearly balanced by its decrease from July to December (**Figures 11** and **12**, left column) while in M2 the solar irradiance is noticeably higher in February–July when the

distances, which follows the inverse square law [53]:

first paragraph of the last section of paper [19].

Sun's revolution about the barycentre.

**42**

solar interior.

*Solar System Planets and Exoplanets*

*Variations of the daily solar irradiance in (W=m*2*) in January–June for three sample years selected in the millennia M1 (600–1600) (left) and M2 (1600–2600) (right). Left column: Blue - year 600, red 1100 and green 1600; right column: Blue - 1700, red - 2020 and grey - 2600. X-axis shows days of the months.*


*4.1.3 Radiation degradation*

Several studies on this issue were performed due to the employment of Kapton® and other commercial PIs in aircraft and aerospace applications. Kapton® in particular is renowned for its outstanding resilience to ionizing irradiation, as compared to other widely used PIs.

The photodegradation of PIs results in macro- and micro-cracks coming from the scission of macromolecular backbones and low molecular mass volatiles such as CO and CO2 (and CHF3 in the case of 6FDA-containing PIs). The resulting oligomeric or polymeric chains display phenol, amine, isocyanate, and carboxylic acid terminal groups [157, 158]. Most UV irradiation experiments showed biexponential degradation kinetics [159].

In the case of beam-induced degradation processes, CO and CO2 are the major volatile fragments, with an additional significant contribution of short hydrocarbons like CxHy [160–162]. The degradation requires heavy energetic conditions and can be inhibited by the addition of various fillers [157]. Additionally, the process is accelerated by air exposure, which quickly determines a significant loss of radicals.

When the aging experiments mimicked low earth orbit, space-flight conditions (temperatures between 10 and 300 K, ultra-high vacuum [10–11 Torr], and high concentration of electronically excited atoms [108 atoms•cm3 of atomic O]), the degradation proceeded through chain scission and generated H2, CO, and CO2 [163, 164]. Similar experiments mimicking geostationary orbit conditions (involving high energy [90 keV] electrons) showed a board range of radiation-induced damage (breakage of chemical bonds and formation of new ones) and a strong effect on optical (lower transmittance) and charge transport (higher conductivity) features [165].

Most ion- or radiation-induced degradation studies have been performed at room temperature, and very little is known about degradation effects determined by irradiation experiments performed at extreme (very low [cryogenic] or high) temperatures [160].

### *4.1.4 Biodegradation*

PIs are generally known to be biostable and bioinert, a very useful trait when it comes to biomedical applications (implantable devices, especially) [8]. However, the biodegradation of some PI-based materials would prove an advantageous feature in terms of recyclability and environmental impact. However, this requires specially designed building blocks and very strict control of the overall synthetic procedure.

One successful example in this regard is the two-stage synthesis of a biodegradable PI starting from an aliphatic amine derived from poly(propylene fumarate) and two commercial aromatic dianhydrides [166].

Both the PAA precursor and the cyclized PI proved biodegradable in a buffer solution, with a weight loss between 20 and 40% after 60 days of exposure, depending on the amount of amine used.

This represents a good starting point for a new research topic in the field of bioPIs. Similar studies are currently considering some of the partially or completely bio-based PIs described in the second section of this chapter.


**Author details**

Longbiao Li\* and Dmytro Tiniakov College of Civil Aviation, Nanjing University of Aeronautics and Astronautics, Nanjing, PR China

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


**Light-Assisted Catalysis in Water and Indoor Air Cleaning: Challenges and Perspectives**

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**3. Diagnostic utility of autoantibody biomarkers**

### **3.1. Early detection of disease**

affected in inflammatory bowel disease, while myelin - a fatty substance that protects nerve fibres in the brain and spinal cord - is destroyed in Multiple Sclerosis. In RA, connective tissues are affected and in SLE, auto-reactivity usually occurs in skin, heart and lung tissues. Sjogren's syndrome occurs when autoantibodies target secretory glands that produce tears

**Figure 2.** Gender-dependent susceptibility to autoimmune diseases, infectious diseases, inflammatory diseases and

In other diseases, however, the functional role of autoantibodies is less clear. For example, in neurodegenerative diseases such as Parkinson's and Alzheimer's Diseases, increased cellular toxicity is caused by the accumulation and aggregation of misfolded proteins, which might also result in the generation of protective autoantibodies in some patients. For example, in Parkinson's Disease (PD), the protein alpha-synuclein misfolds and aggregates to form Lewy bodies; these bodies form in the brain tissues of PD patients and infiltrate the neurons, disrupting signalling process in the brain. A recent study reported that a defined set of epitopes derived from alpha-synuclein drive cytotoxic T-cell responses in people with PD [23], whilst another recent study reported a decline in anti-alpha-synuclein autoantibodies in PD patients compared to controls, suggesting that in some patients anti-alpha-synuclein autoantibodies

Similarly, in Alzheimer's Disease (AD), the microtubule-associated protein Tau accumulates and aggregates in neurons causing neuronal degeneration. Tau also accumulates and

and saliva, causing extreme dryness and other complications [22].

might play a protective role [24].

cancers.

164 Autoantibodies and Cytokines

Autoantibody production is a key indicator of many diseases and has emerged as an important tool in predicting onset of a number of diseases. Autoantibodies are in principle detectable many years before manifestation of disease or symptoms and have been observed in an ever-widening range of disease areas, which makes novel autoantibodies attractive plausible biomarkers for early diagnosis of a broader spectrum of diseases now. Known autoantibody biomarkers have been reported to predate symptoms in Sjogren's syndrome, rheumatoid arthritis, Alzheimer's disease and cancers, as discussed below:

Sjogren's syndrome is an autoimmune disease that affects parts of the body which produce secretions such as tears and saliva. The symptoms overlap with other autoimmune conditions and can range from mild to severe, causing nausea, fatigue, joint pain as well as excessive dryness of the eyes and mouth. Autoantibodies attack cells in mucous membranes and moisture-secreting glands of the eyes and mouth, causing dryness, irritation and pain. A study published in 2015 concluded that autoantibodies are present up to 18–20 years before the diagnosis of primary Sjogren's syndrome [27]. A total of five autoantibodies were analysed, namely antinuclear antibodies, rheumatoid factor and autoantibodies against Ro 60/SSA, Ro 52/SSA, and La/SSB, with 81% of the patients who became seropositive after diagnosis having autoantibodies in pre-diagnostic serum samples. More importantly, these autoantibodies were present in the earliest available serum sample of 95% of the patients who expressed autoantibodies before diagnosis and before the onset of first symptoms [27].

detection of six autoantibodies directed against prostate cancer with PSA levels, increasing the accuracy of detection from 65% using PSA alone to 81% with both methods [37]. A similar outcome was achieved in breast cancer diagnosis using a panel of six autoantigens to detect ductal carcinoma *in situ* and lung cancer with specificity of 85 and 92%, respectively [38]. It is thus evident that having an increased level of specific circulating autoantibodies may reflect the overall state of the immune response of an individual, whilst the presence of such autoantibodies in otherwise healthy individuals might be an indicator of future autoimmune or

Autoantibody-Based Diagnostic Biomarkers: Technological Approaches to Discovery and Validation

http://dx.doi.org/10.5772/intechopen.75200

167

An accurate pathology diagnosis is of central importance in precision medicine, since it should guide choice of the most effective treatment and management regimens. Reliable biomarkers for monitoring and prediction of disease course, stage and progression will be therefore invaluable, particularly in therapeutic decision-making to treat disease at an early stage. Current research has not only established the presence of autoantibodies in several diseases but has also shown that they have the potential to be used as biomarkers capable of diagnosis and staging various degrees of pathology. One such example is Type 1 insulindependent diabetes - a chronic autoimmune disease that impairs the insulin-producing beta cells in the pancreas, preventing the body from producing enough insulin to regulate blood glucose levels. This disease can be characterised into well-defined stages, and the rate of progression to symptomatic disease can be predicted with appreciable accuracy [39]. Stage 1 is defined by the presence of two or more islet autoantibodies and progressing at a variable rate to a second stage of glucose intolerance or dysglycaemia, before becoming clinically

In another example, Cai et al. reported that anti-p53 antibodies develop several years before the clinical diagnosis of certain cancers and suggested that monitoring the change of serum p53 antibodies before and after treatment of patients diagnosed with oesophageal carcinoma with radiotherapy would be useful for evaluating the prognosis and response to the treatment. This study showed that the positive rate of p53-antibodies in patients with oesophageal carcinoma was related to histological grade, stage of the disease and lymph node metastasis but not to age, gender, or site of tumour formation. The study also reported a significant difference in the level of serum p53 antibodies before and after radiotherapy treatment, with the positive rate of p53 antibodies in patients who responded to radiotherapy being much lower than the patients who did not respond to radiotherapy [40]. A separate study by Shimada et al. showed that seropositive oesophageal squamous cell carcinoma patients, whose serum anti-p53 titre did not decrease after surgery, exhibited worse prognosis than patients who showed seroconversion. Thus, a correlative study between the level of tumour autoantibodies and the overall survival outcome of cancer patients (reflected in the change in tumour status or tumour burden related to the therapy) could be extremely informative for evaluating therapeutic interventions [41]. Stage-specific autoantibody biomarkers screening is thus in principle useful in predicting onset of disease, thereby providing an opportunity to intervene

other disorders.

symptomatic (stage 3).

**3.2. Disease staging and treatment monitoring**

and delay or prevent the onset of clinical symptoms.

RA is a chronic autoimmune disease characterised by inflammation of synovial joints, leading to joint erosion and deterioration. Rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) are detected in the blood of 80% and 60–70% of RA-affected individuals, respectively. Anti-CCP autoantibodies were detected in some patient sera samples 12–14 years prior to the development of RA and 34–40% of the RA patients were anti-CCP positive prior to disease onset [28].

The presence of autoantibodies has also been implicated in AD. Aβ-autoantibodies were reported to show promise as an effective blood biomarker for AD and a positive association between Aβ-autoantibody titres and cognitive status have been reported [29]. Glial autoantibody markers to glutamate were detected in the plasma of AD patients and, interestingly, the level of that autoantibody in patients with moderate and severe dementia was 2-fold higher than that in patients with mild dementia [30]. In addition, autoantibodies to ATP synthase were reported to be found frequently in the sera of AD patients but not in age-matched healthy subjects or in patients with Parkinson's disease or atherosclerosis, suggesting anti-ATP synthase autoantibodies could be a specific biomarker for AD [29].

In addition to autoimmune diseases, multiple studies have described autoantibody production prior to cancer diagnosis, including in lung cancer [31], prostate cancer [32] and ovarian cancer [33]. Autoantibody production in cancer is thought to be a product of immunosurveillance - a process in which the body's own systems recognise and eliminate abnormal cells during early tumorigenesis [34] - suggesting that detection of disease-associated autoantibodies may be feasible in the asymptomatic stages of cancer and may predate the clinical signs of tumour progression by months or years, thus enabling their use in early diagnosis [35].

By way of example, in healthy mammalian cells, cAMP-dependent protein kinase A (PKA) is an intracellular enzyme, while in most cancers it is secreted into the circulatory system as ECPKA. The level of ECPKA was found to be elevated in various stages of a wide range of cancers including bladder, breast, cervical, colon, esophageal, gastric, liver, lung, ovarian, prostate, pancreatic, renal, small bowel, rectal, adenocystic carcinomas, melanoma, sarcoma, thymoma, liposarcoma, and leiomyosarcoma compared with healthy controls [35]. Extracellular protein kinase A (ECPKA) autoantibody is thus a potential serologic autoantibody for early-stage cancers diagnosis since it presents at high levels before surgical removal of solid tumours and diminishes after tumour removal [36]. An ELISA-based test for anti-ECPKA IgG was developed and the sensitivity and specificity of this biomarker for detecting 20 different cancers were reported to be 90 and 87% respectively, with the anti-ECPKA autoantibody being detected in 90% of the patient samples but in only 13% of the control samples [35].

Autoantibody-based screening for a variety of other cancers has also been carried out in laboratory environments. For example, Xie et al. developed a test platform by combining the detection of six autoantibodies directed against prostate cancer with PSA levels, increasing the accuracy of detection from 65% using PSA alone to 81% with both methods [37]. A similar outcome was achieved in breast cancer diagnosis using a panel of six autoantigens to detect ductal carcinoma *in situ* and lung cancer with specificity of 85 and 92%, respectively [38]. It is thus evident that having an increased level of specific circulating autoantibodies may reflect the overall state of the immune response of an individual, whilst the presence of such autoantibodies in otherwise healthy individuals might be an indicator of future autoimmune or other disorders.

#### **3.2. Disease staging and treatment monitoring**

52/SSA, and La/SSB, with 81% of the patients who became seropositive after diagnosis having autoantibodies in pre-diagnostic serum samples. More importantly, these autoantibodies were present in the earliest available serum sample of 95% of the patients who expressed

RA is a chronic autoimmune disease characterised by inflammation of synovial joints, leading to joint erosion and deterioration. Rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) are detected in the blood of 80% and 60–70% of RA-affected individuals, respectively. Anti-CCP autoantibodies were detected in some patient sera samples 12–14 years prior to the development of RA and 34–40% of the RA patients were anti-CCP positive prior to

The presence of autoantibodies has also been implicated in AD. Aβ-autoantibodies were reported to show promise as an effective blood biomarker for AD and a positive association between Aβ-autoantibody titres and cognitive status have been reported [29]. Glial autoantibody markers to glutamate were detected in the plasma of AD patients and, interestingly, the level of that autoantibody in patients with moderate and severe dementia was 2-fold higher than that in patients with mild dementia [30]. In addition, autoantibodies to ATP synthase were reported to be found frequently in the sera of AD patients but not in age-matched healthy subjects or in patients with Parkinson's disease or atherosclerosis, suggesting anti-

In addition to autoimmune diseases, multiple studies have described autoantibody production prior to cancer diagnosis, including in lung cancer [31], prostate cancer [32] and ovarian cancer [33]. Autoantibody production in cancer is thought to be a product of immunosurveillance - a process in which the body's own systems recognise and eliminate abnormal cells during early tumorigenesis [34] - suggesting that detection of disease-associated autoantibodies may be feasible in the asymptomatic stages of cancer and may predate the clinical signs of tumour progression by months or years, thus enabling their use in early diagnosis [35].

By way of example, in healthy mammalian cells, cAMP-dependent protein kinase A (PKA) is an intracellular enzyme, while in most cancers it is secreted into the circulatory system as ECPKA. The level of ECPKA was found to be elevated in various stages of a wide range of cancers including bladder, breast, cervical, colon, esophageal, gastric, liver, lung, ovarian, prostate, pancreatic, renal, small bowel, rectal, adenocystic carcinomas, melanoma, sarcoma, thymoma, liposarcoma, and leiomyosarcoma compared with healthy controls [35]. Extracellular protein kinase A (ECPKA) autoantibody is thus a potential serologic autoantibody for early-stage cancers diagnosis since it presents at high levels before surgical removal of solid tumours and diminishes after tumour removal [36]. An ELISA-based test for anti-ECPKA IgG was developed and the sensitivity and specificity of this biomarker for detecting 20 different cancers were reported to be 90 and 87% respectively, with the anti-ECPKA autoantibody being detected in 90% of the patient samples but in only 13% of the control

Autoantibody-based screening for a variety of other cancers has also been carried out in laboratory environments. For example, Xie et al. developed a test platform by combining the

autoantibodies before diagnosis and before the onset of first symptoms [27].

ATP synthase autoantibodies could be a specific biomarker for AD [29].

disease onset [28].

166 Autoantibodies and Cytokines

samples [35].

An accurate pathology diagnosis is of central importance in precision medicine, since it should guide choice of the most effective treatment and management regimens. Reliable biomarkers for monitoring and prediction of disease course, stage and progression will be therefore invaluable, particularly in therapeutic decision-making to treat disease at an early stage. Current research has not only established the presence of autoantibodies in several diseases but has also shown that they have the potential to be used as biomarkers capable of diagnosis and staging various degrees of pathology. One such example is Type 1 insulindependent diabetes - a chronic autoimmune disease that impairs the insulin-producing beta cells in the pancreas, preventing the body from producing enough insulin to regulate blood glucose levels. This disease can be characterised into well-defined stages, and the rate of progression to symptomatic disease can be predicted with appreciable accuracy [39]. Stage 1 is defined by the presence of two or more islet autoantibodies and progressing at a variable rate to a second stage of glucose intolerance or dysglycaemia, before becoming clinically symptomatic (stage 3).

In another example, Cai et al. reported that anti-p53 antibodies develop several years before the clinical diagnosis of certain cancers and suggested that monitoring the change of serum p53 antibodies before and after treatment of patients diagnosed with oesophageal carcinoma with radiotherapy would be useful for evaluating the prognosis and response to the treatment. This study showed that the positive rate of p53-antibodies in patients with oesophageal carcinoma was related to histological grade, stage of the disease and lymph node metastasis but not to age, gender, or site of tumour formation. The study also reported a significant difference in the level of serum p53 antibodies before and after radiotherapy treatment, with the positive rate of p53 antibodies in patients who responded to radiotherapy being much lower than the patients who did not respond to radiotherapy [40]. A separate study by Shimada et al. showed that seropositive oesophageal squamous cell carcinoma patients, whose serum anti-p53 titre did not decrease after surgery, exhibited worse prognosis than patients who showed seroconversion. Thus, a correlative study between the level of tumour autoantibodies and the overall survival outcome of cancer patients (reflected in the change in tumour status or tumour burden related to the therapy) could be extremely informative for evaluating therapeutic interventions [41]. Stage-specific autoantibody biomarkers screening is thus in principle useful in predicting onset of disease, thereby providing an opportunity to intervene and delay or prevent the onset of clinical symptoms.

#### **3.3. Immune-related adverse events**

Immunotherapies have been changing the outlook for many cancer patients in recent years and immune checkpoint inhibitors represent one of several strategies now targeting the immune system for therapeutic benefits. The immune checkpoint proteins cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) play essential roles in central immune tolerance and are prominent targets for cancer vaccines now since inhibition of CTLA-4 and PD-1 can (re)activate the immune system to target cancer cells. Alone or in combination, clinical trials of anti-CTLA-4 and anti-PD-1 antibodies, such as Ipilimumab, Nivolumab and Pembrolizumab, have shown promising results for the treatment of melanoma, non-small cell lung-, kidney-, prostate- and head and neck cancers, as well as renal cell carcinomas, with reported therapeutic response rates approaching 70% in some cases, albeit positive immunotherapy outcomes remain cancer- and patientspecific [42].

Ipilimumab was the first anti-CTLA-4 antibody to prolong survival in patients with advanced melanoma [43, 44], with long term analysis indicating a 3-year survival of 22% across all patients with sufficient follow-up [45]. Similarly, PD-1 blockade with Nivolumab or Pembrolizumab has improved survival for metastatic melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) patients [46–50]. In one trial, advanced melanoma patients treated with pembrolizumab showed a response rate of 34% and a survival rate of 74% [51]. Nivolumab has been reported to result in increased response rates, survival and progression-free survival when compared to intravenous docetaxel in NSCLC [52], whilst stage III/IV melanoma patients achieved a partial tumour response, with a median progression free survival of 172 days, with only 18% experiencing grade 2 or 4 adverse events [53].

Combination check-point inhibitor treatments, targeting both CTLA-4 and PD-1, have also shown strong promise, with clinical trial data in untreated melanoma patients reporting objective response rates up to 72% (amongst patients with PD-L1-positive tumours) and with median progression-free survival of 11.5 months for ipilimumab plus nivolumab, compared to 2.9 months with ipilimumab alone and 6.9 months with nivolumab alone [54]. However, high grade immune-related adverse events (irAEs) occurred in 55% of those in the combination treatment group [54] and similarly high rates of irAEs have been reported elsewhere for anti-CTLA-4 and anti-PD-1 treatments [55].

Indeed, clinical findings on monoclonal antibody-induced adverse effects in general show that this is a wider phenomenon across different disease areas [56], which potentially compromises the effectiveness of such immunotherapies. Efforts are being channelled therefore towards predicting and monitoring undesirable immunotoxic effects and a panel of potential antibodies associated with irAE has been proposed (**Table 1**). Further exploratory studies involving autoantibody-based immunotoxicity profiling in immunotherapy patients are underway to better characterise the role and diagnostic potential of these circulating autoantibodies in irAE.

**4. Classical technological approaches to autoantibody-based**

**Table 1.** List of proposed potential seromic autoantibodies that can be used for identifying irAEs [55].

Since its introduction in 1979, immunoblotting, or 'western blotting', has become a ubiquitous protein analysis technique in which proteins are separated by electrophoresis according to

CCP, cyclic citrullinated peptide; GAD, glutamate decarboxylase; RNP, ribonucleoprotein; Sm, small nuclear ribonucleoprotein; SSA, Sjogren's syndrome-related antigen A; Scl, Sclerosis systemic; SSB, Sjogren's syndrome-related

**biomarker discovery and validation**

**4.1.  List of proposed potential seromic autoantibodies that can be used for identifying irAEs [55].


**2. Results**

### *2.1. T3, TOS, and T3E Suppressed the Increase in Protein Levels of NFE2L1 Induced by Bortezomib Treatment*

NFE2L1 is known to stabilize and translocate from cytoplasm to nucleus under proteasome inhibition [30]. First, we confirmed the protein levels of NFE2L1 in the cytoplasm and nucleus by immunoblotting. For solid cancer, we used the malignant pleural mesothelioma, H2452, due to its reported resistance to bortezomib [13,31]. As shown in Figure 1a, two bands were identified in the cytoplasmic fraction under bortezomib treatment, and the lower band was clearly identified in the nuclear fraction. Therefore, we assumed that the upper band is unprocessed NFE2L1 without transcriptional activity and the lower band is processed NFE2L1 with transcriptional activity.

Next, we used an immunoblot to evaluate the effect of TP (α-tocopherol), T3, TOS, and T3E on the protein levels of NFE2L1 under bortezomib treatment. As shown in Figure 1b, bortezomib alone demonstrated a significant increase in protein levels of unprocessed and processed NFE2L1 compared to the control group, while the combination group with bortezomib and T3, TOS, and T3E did not show this increase. Also, TOS, and T3E alone groups showed a trend toward a decrease in NFE2L1 protein level. These results suggest that T3, TOS, and T3E modulate protein levels of NFE2L1 under proteasome inhibition.

#### *2.2. T3, TOS, and T3E Suppressed the Increase in Expression Levels of Proteasome-Related Proteins Induced by Bortezomib Treatment*

It is known that the expression levels of proteasome-related proteins are increased by NFE2L1 under proteasome inhibition [14,32]. We also speculated that T3, TOS, and T3E might also moderate expression levels of proteasome-related proteins under proteasome inhibition. Consequently, we next evaluated the effects of TP, T3, TOS, and T3E on the expression levels of the proteasome-component proteins, PSMA7, PSMB7, and PSMC4, as well as POMP, a proteasome maturing protein, under bortezomib treatment by RT-PCR assay. As demonstrated in Figure 2a, the bortezomib alone group showed a significant increase in the mRNA expression levels of each protein compared to the control group, while the combination groups of bortezomib with T3, TOS, and T3E did not show as significant an increase as that in the bortezomib alone group. These results suggest that T3, TOS, and T3E modulate the expression levels of proteasome-related proteins under proteasome inhibition.

**Figure 1.** Effects of vitamin E on protein level of NFE2L1 in treatment of bortezomib. (**a**) H2452 cells were treated with bortezomib (50 nM) for 12 h and fractionated into cytoplasm and nucleus by NE-PER™ nuclear and cytoplasmic extract reagent kit. Protein levels in both fractions were assessed by immunoblotting. (**b**) H2452 cells were treated with bortezomib 50 nM or bortezomib 50 nM +TP 20 μM, T3 20 μM, TOS 20 μM, and T3E 20 μM for 12 h, and the protein levels were assessed of NFE2L1 by immunoblotting. α-Tubulin protein levels served as the loading control. A densitometric analysis was performed as described in the Materials and Methods section. Data are means ± SD, n = 3. \* *p* < 0.05, \*\* *p* < 0.01 vs. as indicated. BTZ; bortezomib, TP; α-tocopherol, T3; α-tocotrienol, TOS; α-tocopheryl succinate, T3E; 6-O-Carboxypropyl-alpha-tocotrienol.

**Figure 2.** Effects of vitamin E on mRNA level of proteasome related proteins in the treatment of bortezomib. H2452 cells were treated with bortezomib 50 nM or bortezomib 50 nM +TP 20 μM, T3 20 μM, TOS 20 μM, T3E 20 μM for 12 h, and the mRNA levels of PSMA7, PSMB7, PSMC4, and POMP were assessed by real-time quantitative PCR as described in the Materials and Methods section. RPL32 mRNA levels served as the loading control. Data are means ± SD, n = 3. \*\* *p* < 0.01 vs. as indicated. BTZ; bortezomib, TP; α-tocopherol, T3; α-tocotrienol, TOS; α-tocopheryl succinate, T3E; 6-O-Carboxypropyl-alpha-tocotrienol.


*Introduction to the Volcanology DOI: http://dx.doi.org/10.5772/intechopen.102771*

**Figure 12.** *Dyke at Ponza Island (Italy) [30].*

**Figure 13.** *Lava flow plateau (author's collection).*

rifts (**Figure 13**). The most important manifestations of effusive volcanism are lava flows. The mobility of the flow depends on the viscosity of the lava: (1) Basaltic lavas have high temperatures ( 1100°C) and less silica (<50%), and therefore, they have a low viscosity. Due to these characteristics, they can flow for tens of kilometers. (2) Andesitic lavas have temperatures of 900– 800°C and silica ( 57%), and therefore, have a high viscosity, which prevents excessive flow so that the lava tends to break as it flows. (3) The rhyolitic lavas have temperatures of about 700°C and silica >60%. They are so viscous that the lava accumulates at the volcanic mouth giving dome shapes or even spire-like extrusions. The lava flow can be defined in different forms—(1) pahoehoe lava: Characteristic surface form of basaltic lava. It is formed by high temperature and low viscosity. Characteristic form of lava poor in silica (**Figure 14**). (2) AA lava: They are lava morphologies typical of basaltic magmas that give the form of scoria type (**Figure 15**). They are characterized by a lower temperature and a higher viscosity than the basaltic magmas that give the pahoehoe lavas. Flow lava levée: The AA lava and pahoehoe while flowing build levée for fast cooling of the external parts of the flow (**Figure 16**). Lava-tube flow: It can happen that even when the surface of a large basaltic flow has solidified, the inner part continues to flow into a channel below the solid surface of the flow. If the lava flows go out from this channel, an empty space is formed that produces a lava tunnel (**Figure 17**). Block lava flow: A typical form of high viscosity rhyolitic andesitic acid lavas form block lava-like as Paricutin volcano (Mexico) (**Figure 18**). Cooling structures in subareal lava flows: During the final stages of cooling, the inner part of a lava flow contracts in almost hexagonal-shaped columns acquiring a

**Figure 14.** *Pahoehoe lava flow (author's collection).*

**Figure 15.** *Lava flow AA (author's collection). A solidified flow from the last eruption of Vesuvius (1944 AD).*

**Figure 16.** *Lava flow with levee (author's collection). Levee grew during a Hawaiian eruption.*

typical columnar crack (**Figure 19**). Submarine lava flows: In underwater basaltic flows, the lava cools much faster, and therefore solidifies and forms a bubble of vitreous lava or cushions that temporarily blocks the advance of the flow. After a while, the internal pressure lava breaks the crust, and a new bubble comes out. The process is repeated several times, forming layers of pillows on top of each other (**Figure 20**).

d. *Explosive volcanism*: The development of explosive volcanism requires viscous magma with a high content of silica and water. These characteristics are

**Figure 17.** *Lavatube flow with a growth stalactite melt (unknown volcano).*

**Figure 18.** *Block lava flow. Modified from Schmincke [14].*

generally acquired by processes of differentiation of basaltic magmas in the magma chamber or by direct melting of the continental crust by basaltic magmas or by the direct mixing with external water. Headings are from **Table 2**.

**Figure 19.** *Columnar lava (author's collection).*

**Figure 20.** *Pillow lava formed under the sea (author's collection).*

#### **Table 3.**

*Types of explosive volcanism.*


**11. Future and challenges**

296 Smart Actuation and Sensing Systems – Recent Advances and Future Challenges

with efficient and reliable actuating functions.

macroscopic and microscopic.

al., 2003a).

(Lee et al., 2009).

Smela et al., 2007).

**10. Published papers and patents evolution**

companies that are being incorporated by large multinationals. So Creganna Tactx Medical and Bayer MaterialScience recently acquired a pair of companies working in the field, indicating the potential of these technologies. Also EAMEX from Japan is developing actuators for biomedical and robotic applications. NASA and ESA space agencies consider polymeric actuators as preferential technologies, and the European Scientific Network for Artificial Muscles (ESNAM) has started funded by the European Union. Many different applications can be found in literature. The following is a summary of a few of them, both

An indication of the initiation and fast growth of the field is given by bibliographic and patents evolution. As can be observed, the literature related to conducting polymers

al.,2010 ; Naka et al., 2010; Ramírez-García & Diamond, 2007; Wu et al., 2005). - **Propulsion or locomotion devices**: Systems based on trilayer configuration were proposed in aquatic devices (Alici et al., 2007; James et al., 2007; McGovern & et al., 2009; McGovern et al., 2010) for creating enough thrust for propulsion. Also bending actuators like cilia can be used in mini-robotic devices (Alici & Gunderson, 2009). - **Microcatheters**: By depositing two conducting polymer films around a passive catheter and using a fast conductor solid state electrolyte, it is possible to control the movement of the catheter tip (DellaSanta et al., 1996; Shoa et al., 2008). This kind of microcatheters can be used in Optical Coherence Tomography to enable high-resolution 3D imaging

> Although a hard work has been performed, it does not exist yet an uncontroversial model for the description of the new reactive polymers and devices based on these reactive polymer gels whose composition and properties mimic those from artificial organs in mammals. New models should include concepts from very different fields of knowledge as electrochemistry, mechanics, polymer science and thermodynamics. In those systems, electrochemical reactions produce structural (conformational) changes in the polymeric chains and macroscopic volume changes related to the composition change of the material. Those aspects are not considered in the classical chemical kinetic models. Conducting polymer films should be used as models for the study and quantification of chemical kinetics under structural control with the aim to develop a new structural chemical model, able to quantify conformational changes and structural information in conducting polymers and in biological reactions originating life in living cells.

> This model will allow the synthesis of new conducting polymers providing a more precise control of structural changes and intermolecular forces (polymer-ion interactions) with the

reaction. Those materials should be used in a new generation of polymeric actuators able to overcome current limitations, opening possibilities for new applications.

Other factors, such as configuration, manufacture of the actuators, design of the electric contacts or electrolytic media (solid or liquid) are also very important for the improvement of the electrochemomechanical actuators. This is a multidisciplinary field, a lot of work performed by specialists from different disciplines is required in order to attain a good control and modelling of both, devices and soft robots.


Parkinson's disease. Environ Health Perspect, v. 119, p. 866-872, 2011.

Hodgkin's lymphoma among men. Occup Environ Med, v. 60, p.11, 2003.

terbuthylazine and carbofuran. Toxicology Letters, v. 211, p. 62-69, 2012.

case-control studies. Leuk Lymp, v. 43, p. 1043-1049, 2002.

col., v. 71, 193-197, 1997.

Therapeutics, v. 342, p. 81-90, 2012b.

roscience, v. 141, p. 2155-2165, 2006.

chester, v. 22, n. 4, p. 249-255, 2002.

[157] Gebel, T.; Kevekordes, S.; Pav, K.; Edenharder, R.; Dunkelberg, H. *In vivo* genotoxici‐ ty of selected herbicides in the mouse bone-marrow micronucleus test. Arch. Toxi‐ col., v. 71, 193-197, 1997.

[145] Bassil, K.L.; VAKIL, C.; SANBORN, M.; COLE, D.C.; KAUR, J.S.; KERR, K.J. Cancer health 585 effects of pesticides: systematic review. Can. Fam. Physician, v. 53, p.

[146] Parrón, T.; Requena, M.; Hernández, A.F.; Alarcón, R. Association between environ‐ mental exposure to pesticides and neurodegenerative diseases. Toxicol. Appl. Phar‐

[147] Hanke, W.; Jurewicz, J., The risk of adverse reproductive and developmental disor‐ ders due to occupational pesticide exposure: an overview of current epidemiological

[148] Hernández, A.F.; Parrón, T.; Alarcón, R. Pesticides and asthma. Curr. Opin. Allergy

[149] Doll, R.; Peto, R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. Journal National Cancer Institute, v. 66, p.

[150] Hernández, A.F.; Parrón, T.; Tsatsakis, A.M.; Requena, M.; Alarcón; López-Guarnido, O. Toxic effects of pesticide mixtures at a molecular level: Their relevance to human

[151] Jones, F.; Fawell, J.K. Lessons learnt from the river DEE Pollution Incident. Public Health in Proceedings of the Word conference on chemicals accidents, Harvard, v. 4,

[152] Waters, M.D.; Stack, H.F.; Jackson, M.A. Genetic toxicology data in the evaluation of potential human environmental carcinogens. Mutation Research, Amsterdam, v. 437,

[153] USEPA. Atrazine: Carcinogenicity characterization and hazard assessment, office of pesticide programs, health effects division. 1999. Http:/ www.epa.gov/scipoly/sap/

[154] EPA, 2003. US Environmental Protection Agency. October 31, 2003, revised atrazine interim reregistration eligibility decision (IRED). Office of Prevention, Pesticides and

[155] Jowa, L.; HOWD, R. Should atrazine and related chlorotriazines be considered carci‐ nogenic for human health risk assessment? J Environ Sci Health C Environ Carcinog

[156] Mladinic, M.; Perkovic, P.; Zeljezic, D. Characterization of chromatin instabilities in‐ duced by glyphosate, terbuthylazine and carbofuran using cytome FISH assay. Toxi‐

evidence. Int. J. Occup. Med. Environ. Health, v. 17, p. 223-243, 2004.

1704-1711, 2007.

442 Herbicides - Current Research and Case Studies in Use

1191-1308, 1981.

p. 223-226, 1987.

p. 21-49, 1999.

Toxic Substances, 2003.

Ecotoxicol Rev., v. 29 (2), p. 91-144, 2011.

cology Letters, v. 189, p. 130-137, 2009b.

#jan

macol., v. 256, p. 379-385, 2011.

Clin. Immunol., v. 11, p. 90-96, 2011.

health. Toxicology, 2012 (*in press*).

**Chapter 17**

**Herbicide Resistant Weeds:**

Additional information is available at the end of the chapter

Jamal R. Qasem

**1. Introduction**

http://dx.doi.org/10.5772/56036

**The Technology and Weed Management**

Pest resistance to control methods in general is not an isolated phenomenon but usually expected and well demonstrated when any method is repeatedly applied over a long period of time without being changed or modified in nature, structure, principals of application or formulation. All pests that growers must control in agricultural land have the capacity to become resistant to whatever tactic is used to control them [11]. It is usually expressed as a gradual adaptation or "fitness" of some individuals or populations of the targeted pest or organism to the frequently applied control methods and available conditions. This adaptation may be physical, morphological or phenological, physiological, anatomical or biochemical or could result from the interaction between any two or more of these. It may also be due to some genetic changes as mutations occur on the key site at which a specific method operates. These mutations are at least partially dominant and inherited. Traits are conferred by modifications to single nuclear genes. This indicates that the rate of resistance evolution will be driven by mutation, the intensity of selection, the dominance and relative fitness of mutations in presence or absence of the herbicide and by dispersal of resistance alleles within and between weed populations [28]. However, no proof that the herbicides cause the mutations leads to resistance [37]. However, most often resistance is controlled by a single, dominant or semi-dominant gene [38] although recessive genes control of herbicide resistant trait in natural weed popula‐ tions has been also implicated in resistance to dintroanaline, while wild populations exposed to herbicide stresses for the first time may efficiently express herbicide-resistant genes.

Most weed modifications and adaptations, if not all, are advantageous to the pest, since allow its escape on time and/or place and thus avoid external hazard or threat to its existence and genetic line. Resistance therefore should not be confused with natural tolerance or low

> © 2013 Qasem; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 Qasem; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

distribution, and reproduction in any medium, provided the original work is properly cited.


**3. Transjugular Liver Biopsy (TJLB)**

TJLB was initially introduced in dogs as an experimental application by Dotter [29]. Rosch [7, 8] then reported its clinical application for transjugular cholangiography in 1973 and 1975. TJLB eliminates the need to traverse the peritoneal cavity and puncture the liver cap‐ sule. Furthermore, this technique is a safer biopsy option for patients with massive ascites, coagulopathy (prothrombin time greater than 3 seconds over the control value), thrombocy‐ topenia (less then 60,000/cm3 ), or those undergoing ancillary procedures such as measure‐ ment of pressures or opacification of the hepatic vein and inferior vena cava. It can also be applied for patients in whom PLB has failed, or those with morbid obesity, a small cirrhotic liver, suspected vascular tumor or peliosis hepatitis, or medical conditions associated with bleeding disorders such as hemophilia for whom PLB is contraindicated [11, 30, 31], as any bleeding is returned to the venous system rather than leaking into the abdomen.

However, there are several particular complications associated with TJLB, including hemor‐ rhage, subcapsular or neck hematoma and ventricular arrhythmia. The rate of such compli‐ cations ranges from 0% to 20% [11]. Hardman et al. [4] reported a large subcapsular hematoma caused by TJLB requiring embolization and prolonged admission. Lebrec et al. [9] also reported a fatal case of intraperitoneal hemorrhage due to perforation of the liver capsule caused by excessive of the needle. Therefore, such forward rotation must be avoided or carefully limited. Furthermore, there have been several direct instances of perforation of the liver capsule that resulted in aspiration of ascitic fluid, bile from the gallbladder, or renal tissue in patients with a small cirrhotic liver. In such patients, TJLB should be avoided or employed only with caution by advancing the needle into the liver parenchyma by only 1 cm instead of the usual 2 cm, or contrast medium should be injected after the biopsy to eval‐ uate the integrity of liver capsule. The major drawback of TJLB is the size of the biopsy specimens obtained; they are generally smaller (p <0.001) and more fragmented (p <0.01) than those obtained by PLB [12]. Pathologically, in terms of the number of portal tracts (p <0.0001) and the utility of specimens for histological evaluation (p <0.05), the quality of TJLB samples appears to be significantly lower compared than those of PLB and LLB specimens [14]. With regard to technical success rate, that of TJLB (82%: 84/102) is significantly lower (P=0.005) than PLB (100%: 100/100) or LLB (99%: 111/112) [14]. However, Bull et al. [10] re‐ ported a success rate of 97% (188/197) in 1983, and a recent meta-analysis including more than 7500 cases revealed a technical success rate of 96.8% [13]. These reports suggest that there is no significant difference between TJLB and others techniques in terms of success rate. The most common reason for failure was inability to catheterize the right hepatic vein. In actual practice, TJLB requires a longer procedure time (40 min) than PLB. A few deaths after TJLB have been reported, with a mortality rate of 0-0.5% [10, 32, 33]; mortality was due to hemorrhage from the liver or ventricular arrhythmia.

Therefore, TJLB should be attempted only by a skilled interventional radiologist or physi‐ cian experienced in catheterization and cannulation of the internal jugular vein due to its more time-consuming nature, use of intravenous contrast, and the need for a dedicated fluo‐ roscopy suite. In fact, TJLB can be valuable in cases for which PLB is hazardous, or when pressure measurement or venography is also required [34]. Despite the smaller biopsy sam‐ ples obtained, the impact of TJLB on clinical decision-making appears to be comparable to that of PLB and LLB. In particular, it may help to determine the need for liver transplanta‐ tion in patients with acute liver failure.


**6. Conclusions**

496 Numerical Simulation – From Theory to Industry

Symbol of quantities

component,

Regime of the network

Resonance I0

10% Overcompensated I0

I0

I0

corresponding values obtained by numeric simulation.

The significance of the symbols from the table is as follows:

Values obtained by

> Simulation

Experiment

simulation and the values measured during the experiment are reasonably small.

Table 1, campare some of the values measured during the experiment with the

From Table 1. results that the differences between the values obtained by the numerical

Error [%]

Rt[Ω]

5 250 500

Simulation

Error [%]

Values obtained by

> Simulation

Experiment

Error [%]

Values obtained by

Experiment

max[A] 21,7 24,6 13,4 4,8 4,5 6,3 2,8 2,6 7,1

IB [A] 26,16 24,3 7,1 17,81 16,2 9,1 14,37 12,84 10,6

stab[A] 2,28 2,42 6,1 1,94 1,75 9,8 1,64 1,49 9,1

tam [ms] 126 130 3,2 38 34 10,5 57 54 5,3

U0 [kV] 3,6 3,55 1,4 2,62 2,43 7,3 2,31 2,17 6,1

Uf [kV] 6,22 6,03 3,1 5,6 5,46 2,5 5,3 4,78 9,8

max[A] 17,8 58 226 4,2 4,5 7,1 3,2 2,9 9,4

IB [A] 26,69 24,82 7,0 19,6 18,3 6,6 15,16 13,86 8,6

stab[A] 2,2 2,06 6,4 2,64 2,42 8,3 2,53 2,27 10,3

tam ms] 80 86 7,5 35 32 8,6 41 37 9,8

U0 [kV] 3,63 3,55 2,2 2,73 2,47 9,5 1,91 1,7 9,9

Uf [kV] 6,24 5,96 4,5 5,69 5,21 8,4 4,38 4,76 8,7

The numerical simulator designed by us allows the analysis of transients caused by diferent types of faults, such as simple groundings, double groundings, or broken conductor grounded towards the consumer.

We have compared results obtained by simulation with measured values only for simple grounding faults.

In this type of fault the simulator is validated by the measurements, no matter how the neutral point of the medium voltage network is grounded and whatever are the functioning conditions of the electrical network.

The results from Table 1. show that the simplificatory conditions, taken into account for developing the simulator, are correct.

The numerical simulation of the transient regimes caused by simple grounding faults produced in medium voltage networks shows to be an efficient method for analyzing such faults.

The most dangerous transient regimes occur when the initial phase of the voltage of the faulty line is near 90°.

The initial phase of the voltage, that happen to be in the very moment of producing the fault, was taken with the same value in simulation. The differences between the maximal

values of zero sequence component, obtained by the two methods, are quite acceptable from a technical point of view and this concordance validates the model.

Numerical Methods for Analyzing the Transients in Medium Voltage Networks 499

*Electric Power Systems High Voltages, Electric Machines Control & Signal Processing,*

Curcanu, G., Toader, D. & Pandia, T. (2006). Determination of overvoltages in high voltage networks at single phase faults by numarical simulation and experiments, *Proceedings*

Danyek, M., Handl, P.& Raisz, D. (2002). Comparison of Simulation Tools ATP-EMTP and MATLAB-Simulink for Time Domain Power System Transient Studies, *Proceedings of the*

Dessaint, L.-A., Al-Haddad, K., Le-Huy, H., Sybille, G. & Brunelle, P. (1999). *A power system simulation tool based on Simulink*, IEEE Trans. on Ind. Electronics, vol. 46, no. 6, pp. 1252-

Dommel, H.W. (1995). *ElectroMagnetic Transient Program. Theory Book*, Bonneville Power

Drapela, J. (2009). Performance of a Voltage Peak Detection-Based Flichermeter, *Proceedings of the 8thWSEAS International Conference on Circuits, Systems, Electronics, Control & Signal*

Foltin, M., Ernek, M. & Hnat, J. (2006). SimPowerSystems in Education, *Mezinarodni*

Hasler, M. & Neirynck, J. (1985). *Circuits non lineares*, Presses Polytechniques Romandes,

Iordache, M. & Mandache, A. (2004). *Computer Aided Analyse of Nonlinear Circuits (in*

Istrate, M., Gavrilas, M., Istrate, C. & Ursuleanu, R. (2009). Algorithms in Transmission Grids Using ATP Simulations, *Proceedings of the 9thWSEA/IASMES International Conference on Electric Power Systems High Voltages, Electric Machines Control & Signal*

Karlsson, A. (2005). *Evaluation of Simulink/SimPowerSystems and other Commercial Simulation Tools for the Simulation of Machine System Transient*, Swedish Royal Institute of

Mandache, L. & Topan, D. (2009). *Algorithms for Electric Circuit Simulation,* Universitaria

Radoi , C. (1994). *SPICE Simulation and Analysis of Electronic Circuits,* Ameo Press Bucureşti. Rashid, M.H. & Rashid, H.M. (2006) *SPICE for Power Electronics and Electric Power,* Taylor &

Sybille, G., Brunelle, P., Hoang Le-Huy, Dessaint, L.A. & Al-Haddad, K., (2000). *Theory and applications of power system blockset, a MATLAB/Simulink-based simulation tool for power systems*, Power Engineering Society Winter Meeting 2000, IEEE, Vol.1, pp.774-

Genova, Italy, October 17-19, 2009, pp.65-70

*12th International IGTE Symposium,* Gratz

*Konference Technical Computing,* Prague

*Romanian)* , Politehnica Press Bucharest

1254, Dec. 1999

Lausannes.

Administration, Portland

Technology, Stockholm

Francis Group, Boca Raton

Press Craiova

779

*European EMTP-ATP Conference*, Sopron, Hungary

Chuco, B. (2005). Electrical Software Tools Overview *in* SINATEC-IEEE

DeCarlo, R & Lin, P. (2001). *Linear Circuit Analysis,* Oxford University Press

*Processing,* Teneriffe, Spain, December 14-16, 2009, pp.296-301

*Processing,* Genova, Italy, October 17-19, 2009, pp.109-114

Ross, C.C. (2004). *Differential Equations,* Springer Science, pp.51-56

The resistance of the broken conductor to ground is extremely important, small values of Rt implying long damping periods. If this undesirable condition happens the currents might have high values, as well as important values of the over voltages leading to important supplementary mechanical stress and damages of the insulating devices and, eventually a simple fault can turn to a multiple fault situation.

For small values of the grounding resistance at the fault location (Rt < 10Ω) difference between measured and simulated values is a litle higher than in the case of greater values (Rt > 100Ω).

The model is very useful by giving the values of the voltages on the healthy lines (over voltages that might jeopardize the insulation) and zero sequence currents of the faulty lines (fixing the condition of the fault detection by protection devices).

Using the conclusions of the simulation of a MVN for the values of the currents and voltages during different types of faults it is possible to adjust the prescribed values of the protection.

Simulation of the broken conductor fault, either connected to the ground or not, shows that resonance might occur, over voltages due to this resonances being dangerous to the equipments.

When double phase to ground fault was simulated the values of the voltages showed dangerous voltages for step or touch voltage.

The numerical simulator has the advantage of analyzing rapidly several variants as models of different possible situations.

The simulator is flexible and all kinds of faults can be simulated for different MVN, just by making the proper modification in the parameters of the simulator. These modifications are slightly easier to be performed when PSPICE simulating model is used.

Either using PSPICE or Mathlab-Simulink the accuracy of the analysis is similarly good.

The precision of the results obtained by simulation depends essentially on the accuracy of the MVN parameters.


**3. Future**

The elderly population is growing year-by-year, and therefore, assistive robotics could help to improve their standard of living and quality of life. Additionally, it can also go beyond this group of people and help others that also currently live with disabilities and impairments. Machine learning techniques will help in developing robust methods in this area, creating products (robots, devices, etc.) and solutions that live together with humans on a daily basis.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflicts of interest.


**3. Results and Discussion**

Figure 7a illustrates the released normal force sensor. The interference fingers in the diaphragm and supporting fingers indicated that these structures were temporarily bonded to the substrate due to the stiction effect. The stiction strength during the stiction process was estimated using the longest unattached cantilever to be higher than 7.06 kPa and lower than 22.31 kPa, as shown in Figure 7b.

Figure 8 depicts the integrated normal force sensor, the size of which is approximately equal to those of LMV358, 1070 µm × 640 µm × 525 µm. The maximum alignment error of eutectic bonding was measured to be approximately 1.5 µm, sufficient for the proposed integration process. A Dage Series 4000 bond tester (Nordson DAGE, UK) was used to test the shear strength of Au–Si eutectic bonding. The shear strength of the bonded test structure was approximately 30.74 MPa. The serial resistance of the Au–Si eutectic bonding area is lower than 2 Ω [32], which is much lower than that of polysilicon piezoresistors and can be neglected.

The stress in the transferred normal force sensor caused by the Au–Si eutectic flip-chip bonding process was estimated by comparing the output voltages of the Wheatstone bridge before and after the transfer. The change in the output voltage was in the range of −7.76 to +7.25 mV. Therefore, the stress produced by the Au–Si eutectic flip-chip bonding process was calculated to be in the range of −9.95 MPa to +9.30 MPa, which can be neglected.

**Figure 7.** Optical images of released structures; (**a**) diaphragm supported by four beams; (**b**) cantilever array. Cantilevers longer than 80 µm are colorful due to the interference patterns of uneven gaps, while those shorter than 60 µm exhibit uniform color, which indicates that all cantilevers longer than 80 µm adhered to the substrate. Stiction strength is estimated using the longest unstuck cantilever and shortest stuck cantilever.

**Figure 8.** (**a**) Scanning electron micrographs of the integrated normal force sensor; (**b**) close-up view of the transferred diaphragm.

The integrated normal force sensor was measured using a set of homemade copper wire weights [24]. The source voltage of the Wheatstone bridge was set to 5 V using Agilent E3631A (Agilent, Santa Clara, CA, USA), and the corresponding output voltage of the instrumentation amplifier was recorded using Agilent 34401A (Agilent, USA), when different masses of the beam-shaped copper wire weights were placed on the diaphragm of the transferred normal force sensor under the microscope; Figure 9 presents the measurement results. The sensitivity was calculated to be 93.5 µV/µN/V. The sensitivity of the piezoresistive Wheatstone bridge was calculated to be 18.8 µV/µN/V at an amplification of 4.96. Nonlinearity was approximately 4%, which was quite large and mainly caused by the uncertainty of the point-of-force application. Five sensors were measured. The deviation of sensitivity was less than 20%. System noise was measured at approximately 200 µV.

**Figure 9.** Measurement results of the integrated normal force sensor. Sensitivity was calculated to be 93.5 µV/µN/V.

Shear force sensors can also be developed with flat diaphragms [33] by modifying piezoresistive Wheatstone bridge routing. When shear force in the x direction is applied on the center of the diaphragm, the left side of the diaphragm moves down while the right side moves up, as shown in Figure 10a. The stress of piezoresistor R1 in Figure 10b is tensile, while that of R3 is compressive. When the piezoresistors are connected, as in the Wheatstone bridge in Figure 10c, the output is sensitive to shear force and insensitive to normal force. The bumps in the center of the diaphragm can be used as a mesa to improve shear force sensitivity.

**Figure 10.** Shear force sensors developed by modifying routing of piezoresistive Wheatstone bridges. (**a**) When shear force in the x direction is applied on the center of the diaphragm, the left side of the diaphragm moves down while the right side moves up. (**b**) Released shear force sensor. (**c**) Wheatstone bridge of the shear force sensor.

### **4. Conclusions**

Although the integration of sensors with readout circuits is a crucial technology required for large-area, high-resolution tactile sensing, to date, few integrated tactile sensors have been identified, owing to strict thermal budgets and process compatibility. Tactile sensors are typically integrated with the readout circuit in system levels [1–13]. In this study, an integrated piezoresistive normal force sensor was presented. The surface micromachined normal force sensor was transferred to the readout circuit chip, with a temporary stiction effect handling process.

The piezoresistive normal force sensor was manufactured using surface micromachining. The readout circuit chip comprised two CMOS operational amplifiers, which were redistributed to form an instrumentation amplifier. The SETH process was used to transfer the released sensor to the readout circuit chip. Because the MEMS structure and readout circuits were manufactured separately, they were optimized independently. Because the MEMS structures were released before transfer, readout circuits did not undergo etching for release and could be manufactured using a normal IC foundry. These processes feature excellent compatibility with IC chips.

The normal force sensor was designed for pulse diagnosis instruments. The size of the transferred normal force sensor was 180 µm × 180 µm × 1.2 µm. The maximum misalignment in the flip-chip bonding process was approximately 1.5 µm. The sensitivity was measured to be 93.5 µV/µN/V. The routing of the piezoresistive Wheatstone bridge can be modified to develop shear force sensors; hence, this technique can be used to develop tactile sensors, capable of sensing both normal and shear forces.

The size of the integrated normal force sensors is approximately equal to those of the readout circuit chips, because the sensors are significantly smaller and sit on top of the readout circuit chips. In our experiments, the wafers of a very-old-version operational amplifier (LMV358) were employed to verify the technology, owing to ease of accessibility. The LMV358 chip size is approximately 1070 µm × 640 µm × 525 µm, and of approximately 0.5 µm minimum line width. Hence, extremely compact sensors can be developed with modern instrumentational amplifiers.

**Author Contributions:** N.L. contributed to the design and testing of the device; P.Z. contributed to the fabrication and part of the testing of the device; K.S. contributed to the test idea; C.Z. helped implement part of the fabrication; Y.Z. contributed to the research guidance for the work; H.Y. contributed to the research idea and provided guidance for the work. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was funded by the Shanghai Municipal Science and Technology Commission (Project No. 18dz1100600).

**Institutional Review Board Statement:** The study was conducted in accordance with the Declaration of Helsinki, and approved by the ethical committee of Longhua Hospital (2019LCSY035, 2020.08.27), Shanghai University of Traditional Chinese Medicine.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The authors appreciate financial support from the Shanghai Municipal Science and Technology Commission (project 18dz1100600). The authors also appreciate the assistance of engineers at the State Key Laboratory of Transducer Technology and the staff of Longhua Hospital, Shanghai University of Traditional Chinese Medicine.

**Conflicts of Interest:** The authors declare no conflict of interest.

### **References**


**Author details**

develops faster. Combination tools have shown to increase the protection efficiency against

The growing and widespread of insecticide resistance among vector species have been a major challenge in vector control and managing resistance. The resistant vectors have developed different mechanisms to tolerate the insecticides [53]. Each of the mechanism has its own target site for an insecticide [53]. The main insecticides used for the treatment of LLINs are pyreth‐ roids, to which the major malaria vectors have shown tolerance [21]. The main challenge is that there is no other new class of insecticide to be used for LLINS and IRS [53, 61, 127]. Malaria control programs in East Africa and most sub-Saharan Africa rely heavily on donor-funded programs for LLINs distribution and IRS implementation. Insecticide resistance monitoring and management and operational research were not the primary agenda for the main donors. The control programs of East African countries have also not yet established a mechanism (s) for generating local funds to foster malaria control efforts [128]. This makes the whole effort of vector control program more challenging with the risk of malaria resurgence in some foci along the emergence and widespread of resistance in large areas of East Africa [59, 129, 130]. In general, insecticide resistance data in East Africa are patchy, and in some countries such as Burundi and Rwanda nearly non-existent. Therefore, countries need to create a national insecticide resistance data base for insecticide resistance monitoring data to understand the trend of insecticide resistance for timely decision-making and sharing of information..

Insecticides resistance against malaria vectors has spread throughout the East African countries. Some of the countries like Tanzania and Rwanda have already established a national insecticide resistance monitoring and management plan, and others are in the process of developing the plan mainly to prevent the emergence of resistance or as a response to detected resistance. However, effective implementation of the plan requires national capacities in terms of trained human power and infrastructure to undertake surveillance and monitoring of resistance to advice policy to look for alternate control options or new vector control tools or ensure that current interventions remain a choice in vector control program. Effective imple‐ mentation of insecticide resistance monitoring and management also needs coordination and

The lack of enough funds in East African countries may delay the implementation of resistance monitoring and management strategies. This may hinder to start monitoring of resistance or responding to resistance, use of suggested insecticide of choice for vector control, change control strategy as soon as strong evidence on resistance is available. Internal sources of funding, internally driven resource mobilization and allocation of adequate resources are of

vectors and maintain reduced susceptibility status of the vectors for longer period.

**9. Challenges in insecticide resistance management**

202 Insecticides Resistance

**10. Conclusions and future directions**

inter-sectorial collaboration in the respective countries.

Delenasaw Yewhalaw1\* and Eliningaya J. Kweka2,3

\*Address all correspondence to<EMAIL_ADDRESS>
1 Tropical and Infectious Diseases Research Center, College of Public Health and Medical Sciences, Jimma University, Jimma, Ethiopia

2 Mosquito Section, Division of Livestock and Human Diseases Vector Control, Tropical Pesticides Research Institute, Arusha, Tanzania

3 Department of Medical Parasitology and Entomology, Catholic University of Health and Allied Sciences, Mwanza, Tanzania


*4.2. Cultivation of hMSC*

Bone marrow derived hMSC harvested from the iliac crest of two healthy donors were kindly provided by the group of Prof. Martin Bornhäuser (Medical Clinic I, University Hospital Dresden). Written informed consent from the donors was obtained for the use of these samples in research. Cells were characterized as hMSC according to the criteria of the International Society of Cellular Therapy [39]. All procedures were approved by the Ethical Commission of the Medical Faculty of Technische Universität Dresden. Cells were expanded in Dulbecco s modified Eagle s Medium (DMEM, Gibco) supplemented with 10% fetal calf serum, 2 mM L-glutamine, 100 U/mL penicillin and 100 μg/mL streptomycin (all from Biochrom, Berlin, Germany) (expansion medium) until passage five.

General seeding preparation for porous collagen scaffolds: Scaffolds were immersed with expansion medium for 24 h, which was removed before seeding wet scaffolds were placed on sterile filter paper to remove excess immersion medium from the scaffold pores.


**Appendix B**

**Figure A2.** Variation of friction drag coefficients on blockage ratio and (**a**) Re, (**b**) Mach number. Insets represent the variation of drag.

**Figure A3.** Variation of pressure drag coefficients on blockage ratio and (**a**) Re, (**b**) Mach number. Insets represent the variation of drag.