Urbanization Causing Habitat Destruction and Loss of Birds Diversity in District Sargodha by Asif Bilal*

Urbanization Causing Habitat Destruction and Loss of Birds Diversity in District Sargodha by Asif Bilal* in Open Access Journal of Biogeneric Science and Research 

ABSTRACT

Rural “natural” landscape regions differ greatly from urban settings. The gap between urban regions' anthropogenic constructions and resilient surfaces and non-urban places' natural green ecosystems is significant. The conversion of agricultural fields to urban areas is a significant disadvantage and source of habitat degradation for bird species. Pollution levels rise as a result of a lack of flora and tree chopping, posing a hazard to birds and other living things. Birds must adapt to new conditions to survive in urban settings, or they will be forced to migrate. With the construction of highways and buildings, the expansion of the metropolitan area has resulted in patchy regions that function as barriers between appropriate habitats, even for high flying animals. The habitat structure of bird fauna has significantly changed as a result of these restored circumstances. Many species are vulnerable, endangered, or have low population density as a result this major biodiversity is lost in the surrounding regions.

 Keywords: Avian fauna, Environmental stress, Habitat fragmentation

A brief history of urbanization in district Sargodha

For ages, with the human settlements in different land areas, destruction and deforestation are continued [1]. Now, urbanization has become a global phenomenon that causes harsh implications for birds as well as other animals. The industrial revolution in developing countries is also increasing day by day which is also a threat for living creatures if safe zones are not implemented in industries. However, the impact of urbanization is expected to increase. Climate change and urbanization, both are considered the largest threats to wildlife including many bird species. One of the notable threat is habitat loss and fragmentation, forces immediate migrations towards the suitable places and the other option is to stay unfavorable places and cope with the new conditions [2, 3]. All over the world, two key factors are responsible for the unplanned and messy growth of urban areas and over-exploitation of agricultural land, Rural-urban settlement, and industrialization. This issue has become more complex and worse with time as these are associated with cities mainly in the built areas. The rapid increase in population resulted in overcrowding of urban areas which eventually become burdened for available community resources. This condition forces the people to move far from heavily populated areas towards the free areas across the city and enhance the resources [4]. The extended residential areas, commercial and industrial areas, road facilities, and infrastructure of cities and other constructions fulfill the space in cities and transformed into no built-up space area all over the Sargodha region. The most prominent conversion as evident through the map is in cultivated land into non-cultivated or built-up areas. Fig shows the whole process of starting to the built-up land show a remarkable change during 1992 to 2010. Figure 1 and 2 define two major types of the usage of land that is built-up and non-built up and these noticeable figures show specifically the transformation of valued agricultural land into built-up areas. Table 1 discloses the change in statistics and answers to study questions related to “how” and “where” these vibrant and historical changes have taken place.

Figure 1: Land use Maps of Tehsil Sargodha 1992-2015

Table 1 and 2 illustrates the relative changes in land usage from 1992 to 2015 in Sargodha region. During 1992-2015, the overall change observed in water area is -38926.5 hectares and -16.4 percent. The urban areas are expanded rapidly. In 1992, the total urban area of Sargodha city was 2361.9 hectares and in 2015 it was recorded 27742.7 hectares. Over the past 24 years, Sargodha has experienced variation in urbanization speed which remains some and some low. During this time, the growth rate trend to increase over time. The land for human colonization is also more consumed. The overall land usage is 25380.8 hectares and it is 17.4 %. All the other observations are showing a decline or negative trend as compared to the use of land for colonization. The overall bare soil land area is 9492.7 hectares and 6.5 %. The agricultural land is showing continuously decreasing trend during the whole time. The agricultural land area is -11008.5 hectares and -7.5 % which is an alarming situation not only for birds but also for all other creatures of the area. The agricultural land is continuously transformed into urban areas. The urban/built-up land is increasing in 2000, 2005, 2010, and 2015 and at the rate of 2.2%, 4.1%, 9.2% and 17.4% respectively. These noticeable changes in usage of agricultural land into urban areas are a highly important target for high authorities as agricultural land is decreasing day by day.

Table 1: Change in land use from 1992-2015.

Table 2: Build up and non built up area from 1992-2015.

Birds and the City

About 10,000 bird species are present in the world [5], more than 50 species are found in the Sargodha region. Some cosmopolitan species are also present and found in cities across the globe (e.g., Feral Pigeon Columba livia, House Sparrow Passer domesticus, Common Starling Sturnus vulgaris, Barn Swallow Hirundo rustica [5], most of the species represent the biogeographical species pool of the region. Birds can be divided into three groups depending upon the reliability of human resources: urban avoiders, urban adaptors, and urban exploiters [6]. Due to the difference in responses to urbanization, the species response will be change, as some species tend to adapt towards the new environment and the others vanishing when an area is urbanized once. 34 bird species are observed in the Sargodha region including rural and urban areas [7]. Most of the species at that time are threatened due to loss of habitat and availability of resources. Over urbanization is a major cause of these losses in the Sargodha region.

Species under threat in the City

Habitat destruction is a key driver of this decline in avian biodiversity and a clear negative association has been observed between the density of avian species and urban areas [5,8]. Out of 34 species present in Sargodha these species Brown rock chat (Cercomela fusca), Black drongo (Dicrurus macrocercus), Red-wattled lapwing (Vanellus indicus), Common cuckoo (Cuculus canorus), Temminck's stint (Calidris temminckii), Little stint (Calidris minutus), Greater coucal (Centropus sinensis), White-throated kingfisher (Halcyon smyrnesis), Crested lark (Galerida cristata), Spotted owlet (Athene brama),  Pied bushchat (Saxicola caprata), Indian Roller (Coracias benghalensis), Alexandrine parakeet (Psittacula eupatria), Sind sparrow (Passer pyrrhonotus), Red avadavat (Amandava amandava), Little green bee-eater (Merops orientalis) are threatened species [9].

Urban Environment as a Barrier for Movement

Reproduction is an important phenomenon for the survival of a species besides all other factors. A species needs tend to increase in several individuals to increase genetic diversity. For a long time, urban landscapes were not considered the main barrier for flying creatures such as birds. Although, over-exploitation of vegetative lands and extension of urban areas lead towards habitat loss due to cutting of old trees has proved a major problem for the birds as well as other species as this all resulted in limited resources and viability and lethargic and sluggish habitats [10]. By studying the genetic diversity of a population is another tactic to check the strength of a genetic barrier. Isolated population and founder effects population, both are estimated to show low genetic diversity as compared to conspecifics specie population [11, 12]. A population with low genetic diversity means that natural selection has less variation to act on environmental changes. Populations with reduced genetic diversity are more sensitive to environmental alarms [13, 14].

The Urban Drivers

All the geographical zones have at least four drivers (environmental stress factors) that are directly correlated with urban landscape viz, noise, chemical pollution, artificial lights at night (ALAN), and the presence of human beings. Urban areas are highly polluted mainly due to excessive usage of chemicals, which are excessively generated by traffic- the combustion of fuels which give high rise to the level of nitrogen oxides (NOx) and soot [15], chemicals produced from different factories that are the major cause of water pollution, air pollution noise pollution. Apart from all the factors which are mentioned above, some factors are required to be highlighted such as pathogens, perching, the abundance of food, and predation [16]. These all environmental factors are the foremost cause of the loss of avian fauna in the Sargodha region.

Concluding Remarks

Urbanization has an immense cause of change in the avifauna. Most of the species have vanished, threatened in response to urbanization. It is an obvious clear image that urbanization is a basic threat to the loss of biodiversity. So, zoologists, conservationists, and District authorities have an important task for the future. Necessary actions will have positive effects on bird species if green areas are managed for birds in urban areas by planting more and more trees and this step must be continued throughout the years and if construction is reduced in surrounding areas. In the Sargodha region, the population is increasing day by day rapidly because of the settlement of people from rural to urban areas for useful resources and a better lifestyle. Due to these factors, more land is required for the human population. These all factors lead towards the conversion of agricultural lands into housing societies which resulted in a reduction in bird diversity in Sargodha. It is also a fact that many people made these housing schemes as a business. Due to an increase in environmental stress, avian fauna is also leading towards destruction.

Recommendations

The study required serious recommendations. The number of parks, gardens enriched with trees should be increased rapidly for the birds. Factors that are a major cause of pollution must be reduced at a safe level. Deforestation should be banned immediately in rural areas. Old trees should be protected with the help of agriculturists and botanical experts. For local and migratory bird species, feeding sites should be constructed in an open field area. Campaigns should be started which create awareness among the local habitants to protect the local species.

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Skin Toxicities of Immune Check Point Inhibitors in Solid Tumors and Managment: Review of Literature

Skin Toxicities of Immune Check Point Inhibitors in Solid Tumors and Managment: Review of Literature by Mohamed réda KHMAMOUCHE in Open Access Journal of Biogeneric Science and Research 

ABSTRACT

Skin toxicities are the most prevalent immune-related adverse events. Various reactions have been reported few weeks after initiation treatment by immune checkpoint inhibitors. In this review, we summarized the clinicopathologic manifestations of different lesions and principles of their management .

Keywords: Skin toxicities, pruritis, immune check point inhibitors, adverse events.

Introduction

Immune checkpoint inhibitors (ICIs) are currently used in the treatment of several cancers in adjuvant and metastatic situations such as melanoma , classical Hodgkin disease, urothelial carcinomas, non small cell lung cancers , renal clear cell carcinomas, Merkel cell carcinoma and cutaneous squamous cell carcinoma due to their inhibitory effects on cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) or anti-programmed death-1 (anti-PD1) and its ligand (anti PDL-1) [1].

The most frequent  immune related adverse events affect skin, endocrine organs, colon, liver and lungs. However, very serious lesions, even lethal, such as neurological disorders and myocarditis are rare [2-6].

Among the most frequently described cutaneous side effects in the literature, pruritus is frequently reported as a side effect of these treatments [7,8], followed by rush and vitiligo [2]. Other toxicities have been reported more rarely with checkpoint inhibitors: alopecia areata, stomatitis, xerosis cutis , psoriasis and photosensitivity [9,10]. The principal aim of this review is to describe skin lesions in patients treated with ICIs for solid tumors and to discuss the principles of their therapeutic management.

Material & Methods

A bibliographic search was carried out in different databases, highlighting PUBMED, SCIENCE DIRET, SCIELO, OVID, SCHOLAR GOOGLE, from 2015 to 2021 our keywords were: antibodies, Covid-19, Pregnant, Lactating, Vaccines. The initial results showed a total of 125 studies, of which those works published in any language other than English or Spanish and those that did not have full text available were excluded, thus we have a total of 15 articles for our review, highlighting reviews , meta-analysis, clinical trials, systematic reviews, later the studies found were read, which describes physiological and anatomical aspects in pregnancy, the physiology of the maternal-fetal immune response, the different mechanisms with which vaccines generate antibodies and how these antibodies can be transmitted from mother to infant.

Different ICIs used in treatment of cancers

Immune checkpoint therapy affects the anti-tumor immune response at the level of T cell activation by antigen presenting cells (APCs). The CTLA-4 protein is expressed on T cells, and competes with CD28 for linking up to B7 [11]. It is thus a competitive inhibitor of T cell activation. Pharmacologic CTLA-4 inhibition increases binding of CD28 to B7 and there by promotes T cell activation [11].

T cells also express the Programmed Death 1 receptor (PD-1), which is activated by PD ligands 1 and 2 (PD-L1 and PD-L2) to decrease T cell activation by inhibiting proliferation, decreasing cytokine production, and promoting apoptosis [11]. ICIs are medications that act at the level of T cell costimulation to increase immune activation, with the goal of promoting an anti-tumor immune response. All ICIs are monoclonal antibodies. Ipilimumab is the lone FDA-approved inhibitor of CTLA-4 [12]. However, there is a number of FDA approved PD-1 inhibitors : nivolumab and pembrolizumab. Combination CTLA-4 and anti PD-1 has been shown to be more effective than monotherapy ; but, combination therapy may be substantially more toxic, and needs to select carefully patients [13].

The first use of ICI to achieve true remissions in metastatic melanoma was obtained with ipililumab. Inhibition of the PD-1 axis has found application in the treatment of a variety of solid tumors. Pembrolizumab and nivolumab are both approved for the treatment of non-small cell lung cancer and other solid tumors and hematologic malignancies [13]. Cemiplimab is a new PD-1 inhibitor developed and is approved specifically for metastatic or unresectable squamous cell carcinoma [14]. In addition, atezolizumab, durvalumab and avelumab are PD-L1 inhibitors, approved for the treatment of many solid tumors including small and non-small cell lung cancers, urothelial carcinoma, and Merkel cell carcinoma [13]. The names of the main ICIs approved by the FDA , and their indications are summarized in Table 1.

Table 1: FDA approved ICI and their indications.

Grading of immune cutaneous adverse events

Adverse events can be classified by grades based on the degree of severity and associated morbidity. It is according The Common Terminology Criteria for Adverse Events (CTCAE). Familiarity with the CTCAE grading system is important in communicating with a patient’s oncology team and dermatologist. Depending the severity of cutaneous toxicity, we can grade maculopapular eruptions and bullous lesions on four grades: Macules/papules or blisters covering <10% BSA is defined Grade1, grade 2 if covering 10 to 30% BSA, and >30% is defined grade 3. Any life-threatening cutaneous toxicity is considered grade 4 [13-15].

Skin Immunorelated Adverse Events

Skin toxicities are the most common complications reported of ICI therapy and the earliest to occur. Many cutaneous irAEs present similarly to primary dermatoses and may share properties with autoimmune skin disorders [13]. Fortunately, these cutaneous adverse events are typically mild, and can usually be managed without interruption of immunotherapy [13].

The incidences of all-grade dermatologic immuno related adverse events range from 17% to 40% for PD-1/PD-L1 inhibitors and 37% to 70% for ipilimumab, while grade 3 or higher cutaneous toxicities are found in 1% to 3% of patients treated with ICIs [16-18].

There is a difference cutaneous toxicities between PD-1/PD-L1 inhibitors and CTLA-4 inhibitors. Psoriasis, pemphigoid, and cutaneous sarcoidosis were mainly reported with PD-1/PD-L1 inhibitors, whereas Sweet syndrome and erythema nodosum were almost exclusively observed with CTLA-4 inhibitors [19]. The most common side effect reported with ICIs is pruritus (7, 8), with an estimated incidence between 11 and 47% [10,20]. Pruritus, in the absence of rash occurs in 11 to 18% of patients treated with PD-1 inhibitors and up to 30% of patients treated with anti-CTLA-4 inhibitors [7,21,22]. Pruritus can deeply affect quality of life of patients and may lead to treatment discontinuation. However, physiopathology and etiology of ICI-related pruritus has been unknown [1].

Pembrolizumab, nivolumab, ipilimumab, and cemiplimab were caused pruritus in Salinas study [1]. It’s appeared after a mean of 8.1 months after ICIs initiation treatment and it was diffuse in 48 % of cases [1]. It is essentiel to consider prodromal bullous pemphigoid in the evaluation of severe and refractory pruritus. Patients are generally treated with topical anti-pruritics such as camphor-menthol ,topical steroids, anti-histamines, and occasionally other anti-pruritic drugs such as pregabalin or gabapentin, opioid antagonists such as naloxone and naltrexone, and the neurokinin-1 receptor antagonist aprepitant; phototherapy can also used [13,22,23]. The treatment prescribed for patients who present pruritus was emollients, antihistamines and topical steroids with favorable evolution of symptomatology [1]. Other skin diseases reported in this study in order of frequency of occurrence in 21.5% of cases were: vitiligo, eczema, maculopapular exanthema, psoriasis lichen, and folliculitis and urticaria [1].

Only severe and debilitating cases of pruritus require discontinuation of immunotherapy and systemic steroids [23]. Cutaneous rash is reported in 24% of the patients treated with ipilimumab, in 15% of those receiving anti-PD-1 and in 40% with the combination of nivolumab and ipilimumab [24,25]. Vitiligo is observed in about 8% of patients with metastatic melanoma treated with anti-PD-1  or with the combination of checkpoint inhibitors, but is rarely with ipilimumab alone [26]. The evaluation of severity of skin adverse events must be careful by the physicians and needs physical examination including the mucosal areas, and appreciation of the general status of the patient (fever, ...), and if needed, a biological checkup [2].

It is important to eliminate the possibility of a dermatological emergency such as drug rash with eosinophilia and systemic symptoms (DRESS), acute febrile neutrophilic dermatosis (Sweet syndrome), Stevens- Johnson syndrome or toxic epidermal necrolysis (TEN). In these life-threatening situations, the treatment with ICIs should be definitively discontinued, the patient necessit emergency hospitalisation, and symptomatic treatment should be initiated immediately by a dermatologist [2].

Management of Cutaneous rash

For grade 1 (mild) :Macular or papular eruption ,asymptomatic lesions

Treatment by immunotherapy can be continued and symptoms can be treated with topical steroids, oral antihistamines.

For grade 2 (moderate) : Pruritic symptoms ≤ 50% of skin surface

treatment with immunotherapy drugs can be continued but should be checked weekly for improvement. If not resolved, treatment should be discontinued until the skin lesions has reverted to grade 1. Symptomatic treatment consists of topical steroid cream, oral antihistamines and oral steroids: prednisolone 1mg/kg/day x 3-7 days-max: 60mg/day or equivalent depending on severity and extent of rash. If the symptoms persist more than 5 days or worse or relapse, we omit the next dose of immunotherapy and we start oral corticosteroid therapy, if not commenced already and topical emollient . The monitoring must be daily by the physician.

For grades 3/4 (Severe or life threatening): defined as any of the following

 >50% skin surface, generalised , exfoliative, ulcerative or bullous dermatitis

The severe skin AE require immediate interruption of ICIs, until these are back to grade 1. Treatment includes topical emollients cream, oral antihistamines and high strength topical steroids . Systemic corticosteroids 0.5–1 mg/kg can be considered, depending on the severity of the symptoms. Patients should be need urgently a biopsy for confirmation of diagnosis and admitted to intensive care unit for monitoring. Treatment consists of high dose intravenous corticosteroids (methyl prednisolone 1–2mg/kg with tapering when the toxicity resolves to grade1. We must not forget IV antibiotics if patient had signs of infection.

If symptoms resolve or improve to grade 2: discontinuation of immunotherapy must be permanent and we initiate corticosteroid taper over ≥2 months [2,27].

CONCLUSION

Immunotherapy is associated with immune-related adverse events (irAEs).Skin irAEs are among the most frequent toxicities observed within the first few weeks after initiation of ICIs. Severe cutaneous lesions can become life-threatening that’s why oncologists must know how to recognize these lesions and refer the patient to the dermatologis. These dermatological toxicities can be managed effectively by using established international guidelines

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Antibodies for Sars Cov 2 in Infant Children of Mothers Vaccinated Against Covid19

Antibodies for Sars Cov 2 in Infant Children of Mothers Vaccinated Against Covid19 by Néstor Fabián Sanabria Duarte in Open Access Journal of Biogeneric Science and Research 

ABSTRACT

Since the beginning of the covid-19 pandemic, there have been multiple unknowns to be solved about this new disease, one of these has been the process to generate a vaccine, obtaining in 2020 the first vaccines, new doubts arise such as what special considerations pregnant women will have regarding vaccination and if there is the possibility of transferring antibodies from the newborn mother through the placenta, The current scientific evidence reflects that there is the possibility of transferring antibodies against covid-19 in infants whose mothers have been previously vaccinated against this disease, based on studies of serum, breast milk and umbilical cord, with positive findings about the presidency of these antibodies and the possibility of their existence in infants born to these mothers.

KEYWORDS: Antibodies; covid 19; vaccines.

Introduction

The current SARS VOC 2 pandemic is having a huge impact around the world; started in Wuhan, China, in December 2019 causing the COVID-19 disease. This is primarily a respiratory illness that presents with symptoms including fever, cough and shortness of breath, which can progress to respiratory failure, this can present with a wide spectrum of symptoms including sore throat, headache, loss of taste or smell, nausea, vomiting and diarrhea [1,2]. The groups most vulnerable to presenting serious disease and complications are those over 60 years of age, people with coexisting diseases such as high blood pressure, cardiovascular disease, diabetes mellitus, lung disease, obesity, kidney disease, neoplasms and pregnant women, among others. [1,2,3]

Pregnant women are in a higher risk group for acquiring respiratory diseases due to the series of physiological changes that occur in pregnancy, such as increased oxygen demand, elevated diaphragm, among others. [4,6,7]

There is a series of pathologies where there is the possibility of maternal-fetal transmission, such as HIV, influenza, toxoplasmosis, and the possible maternal-fetal transmission of Covid -19 has been investigated [5,7]

As a result of this, the efforts by the World Health Organization have been aimed at the production of a vaccine, in order to prevent the transmission and the severity of the clinical picture, the scientific literature shows the possibility of transmission of antibodies through the placenta not only for covid-19 disease. [8,9,10].

Vaccines are designed to prevent different diseases such as chickenpox, hepatitis, meningitis, influenza, among others. When a pregnant woman receives a dose of any vaccine, there is the possibility of transferring antibodies from mother to fetus, since there is scientific evidence that shows us antibodies present in newborns whose mothers received some type of vaccine. The objective of this study is to review the presence of antibodies to SARS COV 2 in infants of mothers vaccinated against COVID 19.

Material & Methods

A bibliographic search was carried out in different databases, highlighting PUBMED, SCIENCE DIRET, SCIELO, OVID, SCHOLAR GOOGLE, from 2015 to 2021 our keywords were: antibodies, Covid-19, Pregnant, Lactating, Vaccines. The initial results showed a total of 125 studies, of which those works published in any language other than English or Spanish and those that did not have full text available were excluded, thus we have a total of 15 articles for our review, highlighting reviews , meta-analysis, clinical trials, systematic reviews, later the studies found were read, which describes physiological and anatomical aspects in pregnancy, the physiology of the maternal-fetal immune response, the different mechanisms with which vaccines generate antibodies and how these antibodies can be transmitted from mother to infant.

Result

Pregnancy and its relationship with Covid-19. Pregnant women are particularly prone to respiratory pathogens, such as SARS-CoV-2, due to physiological changes during pregnancy; the increase in oxygen demand and the elevation of the diaphragm, for this reason it is explained that pregnant women are susceptible to hypoxia, the first data do not indicate that pregnant women have a greater risk of morbidity, but they do indicate a greater risk of admission and ventilation in the ICU. Furthermore, due to the increased concentration of ACE2 receptors in the placenta, there is concern about the possibility of vertical transmission from mother to child. In fact, case studies have shown that SARS-CoV-2 can infect the placenta. (figure 1) [2,5,6].

Maternal-Fetal Antibodies

The placenta plays an important role that intervenes in the interaction of the mother and the developing fetus, this is a multifaceted organ, among the crucial functions of this organ to protect the fetus from the maternal immune response in order to prevent it from being rejected by the same, in addition this conditions the transfer of maternal antibodies. It is worth noting that the fetus represents a graft once implanted in the mother, since it produces foreign proteins for the maternal immune system, capable of being synthesized by the genetic information that the father provides, therefore a compatibilizer mechanism intervenes that inhibits the rejection of the fetus, which is caused by various factors such as immunosuppressants and modulators from the placenta [4,5].

Immunity is considered as a set of integrated processes or mechanisms that play an important role in our body's defense response to different foreign agents, whether internal or external, to which we are exposed [2]. In the uterus, the fetus is protected by the mother from all external agents, therefore it does not need a functioning immune system. Once outside, the fetus has a complete but immature immune system, even so, it is capable of responding to antigenic stimuli. Maternal immunity provides maternal immune cells and antibodies that are capable of protecting newborns, but temporarily, this transfer of antibodies can be carried out by the placenta in the prenatal stage, by colostrum and in breast milk [4,5,6].

In the fetus, the immune system is given by the cells that are derived from the precursor cells of the hematopoietic system, which until the third fetal week come from the germ sac, in the eighth week of the fetal liver and after the fifth month of gestation is given by the bone marrow. All these cells carry out different processes in order to create an innate and adaptive immune system. In weeks 9-10 of gestation, innate immunity begins complement synthesis and NK cells can be found in the liver. In weeks 12-14, humoral immunity presents pre-B cells with IgD, IgG and IgA, and in this stage the passive transfer of maternal IgG begins. Between weeks 20-30, in humoral immunity, B cells secrete antibodies and transplacental transport of IgG gradually increases. Taking into account the above, with regard to fetal life, serum immunity during is limited to the transfer of maternal IgG that has the ability to reach the fetal circulation, and that is why newborns only have a limited percentage of antibodies. This immunoglobulin has the competence to cross the placental barrier, primarily in the last trimester of pregnancy where its percentage in circulation increases [4,5,7].

In this way, it can be explained how maternal antibodies give neonates partial protection against various viral infections; however, so far there is very little knowledge of the perinatal humoral immune response to SARS-CoV-2 [2]. A study carried out in China set out to describe the dynamic changes in antibody levels in 6 newborns of mothers who developed coronavirus disease during the second and third trimesters of pregnancy. It was found that the 6 of the patients who suffered from the infection in the second and third trimesters presented different immune responses. Of the three patients infected with SARS-CoV-2 in the third trimester they showed positive results in the PCR, in addition that levels of IgG and IgM were detected until the moment of delivery, while the neonates of these mothers did not have viral results positive, but I did have detectable IgG at delivery, and one had IgM. In both three women infected in the second trimester and their newborns, SARS-CoV-2 nucleic acids were not found at the time of delivery, but specific IgG for the virus was detected, but not IgM. It was also found that after delivery, women infected in the second trimester and their children had a long-lasting IgG response compared to those infected in the third trimester and their children. The conclusion reached in the study was that it was found that those asymptomatic infants who were born to mothers infected with COVID-19 in the second trimester of pregnancy have a stronger immune response. This could be explained by the above, by the transfer of IgG from the mother to the fetus through the placenta, which begins at the end of the second trimester and reaches its highest levels in the third trimester at the time of delivery [3,4,5,6].

 Antibodies Against Covid -19 And Infants.

Since the beginning of the pandemic caused by the SARS COV 2 virus, there have been many attempts to produce a vaccine that is highly effective against it and that manages to generate an immunity that lasts over time and manages to combat the different variants. Among these, multiple mechanisms of action stand out that will eventually lead to the production of antibodies, (Table 1) [8,9].

Table1: Main mechanisms of vaccine antibody production

All of these ultimately what they seek is to induce an active immunity similar to that caused by infection, but without contracting it. This virus has multiple proteins; which cause an immune response in the host mediated by CD4 and CD8 T lymphocytes together with the production of specific neutralizing antibodies. The CD4 T lymphocyte response against protein S is one of the largest and is consistent with the magnitude of IgA and IgG titers. This S protein plays a fundamental role in the development of vaccines since it helps the virus to bind to the receptors of the Angiotensin Converting Enzyme (ACE 2), therefore, it is attractive for the creation of vaccines [9,10,11].

Recommendations from different organisms have justified the efficacy and safety of these vaccines in pregnant patients and during the lactation period, in addition to the fact that it has been proven that they could also produce temporary immunity in the newborn [3]. The prospective cohort study carried out by Gray et al in which a total of 131 women of reproductive age who received messenger RNA vaccines against SARS CoV 2 were included, 84 of them were pregnant, 31 were lactating, 16 were not pregnant, and from whom serum samples were taken from 10 of them, samples were also taken from the umbilical cord, and from breast milk to study IgG, IgM and IgA titers; found that these antibodies were found in all samples taken from both umbilical cord and breast milk, although in the umbilical cord sample they were lower than in the maternal serum sample, the difference was not significant; Immune transfer to newborns was also shown to occur through the placenta and breast milk [4]. On the other hand, the prospective cohort study carried out by Perl et al and in which a sample of 84 women of breast milk was taken after vaccination with Pfizer BioNTech and who were studied for the presence of IgA and IgG antibodies, showed that after 6 weeks after vaccination, these antibodies were still being secreted in breast milk; the antibodies found in the breast milk of these women showed strong neutralizing effects, suggesting a possible protective effect against infection in the infant [13].

Although the information available about studies carried out in infants is very limited due to the ethical implications that studying newborns brings, it is important to highlight the studies carried out in mothers who are breastfeeding since current evidence reflects the possibility of transmission of antibodies against covid-19 already being vaccinated, it has been possible to obtain information about studies carried out in breast milk, serum and umbilical cord, giving as a positive finding the presence of antibodies against covid-19 in these samples suggesting a possible transmission to the newborn born, providing immune protection during the first weeks of life against this disease [4,6].

Figure1: Anatomical changes in pregnancy

Discussion

Multiple studies have been carried out in order to study the effectiveness of vaccines by studying the production of antibodies over time. As is the case of the study carried out by the Bogotá district health secretariat, in which 241 (of which 41 were excluded because they were seropositive prior to the application of the vaccine) patients who were vaccinated with the biological Pfizer- BioNTech and who underwent a semi-quantitative study of total Ig and specific IgG for SARS CoV 2, resulting in that at three weeks after the application of the first dose, 95% and 96% of the immunized individuals, show reactivity for total Ig and IgG, anti-S, respectively, evidencing the appearance of antibodies in this sample, which is not far from the results obtained in our investigation [14,16].

The objective of our study was to describe the antibodies to sars cov 2 in infants of mothers vaccinated against covid-19, thus finding that if samples from mothers vaccinated against covid-19 are studied, whether serum, breast milk or even umbilical cord , there are positive data about the transmission of antibodies, which suggests the possibility of the presence of antibodies in newborns and possible immunological protection against Covid-19, comparing these results with information obtained in other studies that look for the immune response in newborns faced with different diseases, such as the flu or influenza, we have the study carried out by Shabir and collaborators where they carried out a study characterized by double-blind randomized controlled trials, where 2116 HIV-uninfected women included 194 HIV-infected women using placebo and inactivated trivalent influenza vaccine (IIV3) evaluating immunoglobulin enicity, safety and efficacy of the vaccine in pregnant women and their babies up to 24 weeks after birth, measuring immune responses using hemagglutination assays and PCR testing, finding that the influenza vaccine was immunogenic in both infected and non-infected pregnant women infected by HIV, presenting a partial proportion of protection against confirmed influenza in both groups and in babies, thus evidencing the transmission of antibodies from the mother to the fetus and providing immunity in the first weeks of life, when comparing these results with our research , we can investigate that there is a particular mechanism of transmission of maternal-fetal antibodies for various vaccines [12,14,15].

CONCLUSION

We conclude that there is the presence of antibodies against covid-19 in infants whose mothers have been previously vaccinated against this disease, this always when breast milk or umbilical cord serum is studied, suggesting the presence of antibodies in infants in the first weeks of life, further studies are recommended to deepen these findings.

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Wilms’s Tumor Gene Mutations: Loss of Tumor Suppresser Function: A Bioinformatics Study by Uzma Jabbar in Open Access Journal of Biogeneric Science and Research

Wilms’s Tumor Gene Mutations: Loss of Tumor Suppresser Function: A Bioinformatics Study by
Uzma Jabbar in Open Access Journal of Biogeneric Science and Research 

ABSTRACT

Introduction: Mutation in the Wilms’s Tumor (WT1) gene product has been detected in both sporadic and familial cases suggesting that alteration in WT1 may disrupt its normal function. The study aims to find the protagonist amino acid in WT1 proteins by mutating these residues with other amino acids.

Material and Methods: The 3D modeling approach by MODELLER 4 was utilized to build a homology of WT1 proteins. Quality of the WT1 model was verified by predicting 10 models of WT1 and hence selecting the best one. Stereochemistry of model was evaluated by PROCHECK. Mutational studies were done by WHAT IF. Five human WT1 mutations were modeled which were Lys371→Ala371, Ser415→Ala415, Cys416→Ala416, His434→Asp434 and His434→Arg434.

Result: Based on active side of WT1 protein and its role in DNA binding mutation. No significant change was observed when Lys371 was mutated to Ala371, Ser415 was mutated to Ala415. Significant change was observed in Cys416 mutated to Ala416. In mutant Ala416, loss of coordination with the metal ion Zn was also predicted. In case of Mutants His434→Asp434, there was a loss of coordination of metal ion (Zn203) with mutant Asp434. In case of mutant His434→Arg434, there was a loss of Zn203 coordination with Arg434. His434 does not interact directly with any DNA base, whereas mutated Arg434 is predicted to interact directly with DNA base.

Conclusion: It is concluded that mutation of amino acid residue Cys416→Ala416, His434→Asp434 and His434→Arg434 may lose the proto-oncogenic function of WT1.

 

Keywords: WT1 protein, MODELLER9.0, Mutation, Active side residues

Introduction

WT1, is a protein, which in humans is encoded by the WT1 gene on chromosome 11p13. The WT1 is responsible for the normal kidney development.  Mutations in this gene are reported to develop tumors and developmental abnormalities in the genitourinary system. Conversion of proto-oncogenic function to oncogenic in WT1 has also been documented cause of various hematological malignancies. (***)

Multifaceted protein of WT1 gene has transcriptional factor activity [1]. It regulates the expression of insulin-like growth factor and transforming growth factor system, implicated in breast tumorigenesis [2]. A main function of WT1 is to regulate transcription, which control the expression of genes involved in the process of proliferation and differentiation [3]. In wide range of tumor, WT1 is shown to be predisposing factor for cancer, therefore it has become hot target in research to find out it’s inhibitor which can be safely used as a treatment of cancer. It can induce apoptosis in embryonic cancer cell, presumably through the withdrawal of required growth factor survival signal [4]. WT1 is involved in the normal tissue homeostasis and as an oncogene in solid tumors, like breast cancer [5]. Increased expression of WT1 is related with poor prognosis in breast cancer6. A number of hypotheses are postulated for the relationship of WT1 with tumorigenesis. Acceding to one of the hypothesis, elevated levels of WT1 in tumors may be related with increased proliferation because normally WT1 have a role with apoptosis [7,8]. Another study proposed that WT1 can alter many genes of the the family of BCL2 [9,10] and also have a role to regulate with Fas-death signaling pathway [11]. Furthermore, it is suggested that WT1 can encourage cell proliferation by up-regulation of protein cyclin D1 [12].

A group of workers hypothesized that WT1 has been observed in the vasculature of some tumour types [13]and its expression may be related with angiogenesis especially in endometrial cancer [14]. Another hypothesis based on the fact that WT1 is a main regulator of the epithelial/mesenchymal balance and may have a role in the epithelial-to-mesenchymal transition of tumor cells [3]. Expression of WT1 is higher in estrogen receptor (ER) positive than in ER negative tumors. It is therefore possible that WT1 not only interact with ER alpha, but it may orchestrate its expression [15]. A study, on triple negative breast cancers [7] has shown that high WT1 levels associate with poor survival due to increased angiogenesis [16,17], altered proliferation/apoptosis10,11, and induction of cancer- epithelial-to-mesenchymal transition4. In breast tumors, WT1 is mainly related with a mesenchymal phenotype and increased levels of CYP3A4 [18]. A mutation in the zinc finger region of WT1 protein has been identified in the patients that abolished its DNA binding activity [19]. A study also observed that the mutation in the WT1 gene product has been detected in both sporadic and familial cases suggesting that alteration in WT1 may disrupt its normal function [20].  Bioinformatics approaches are being utilized to resolve the biological problems. Efforts start with the prediction of 3D structures. To achieve the aim, study was designed to view 3D structure of WT1, tumor suppressor protein predicted by homology modeling and to study the role of crucial residues in WT1 proteins by mutating these residues with other amino acids.

Material and Methods

3D structure of WT1 was taken as target of human WT1. Figure 1 shows the normal interaction of WT1 with DNA strands based on the crystal structure of a zinc finger protein.

Figure 1: Homology model of the C-terminal fragment of Human Wilms Tumor protein with bound DNA strands based on the crystal structure of a zinc finger protein, znf268, (PDB; id:1aay) and a five-finger protein, GLI (PDB; id:2gli).

The binding of protein-DNA complex involves four zinc finger binding domain in the C-terminal/Zn finger region of WT1. These are;

• Cys325, Cys330 and His339, His343: figure 2; yellow highlighted.
• Cys355, Cys360 and His373, His377: figure 3; yellow highlighted.
• Cys385, Cys388 and His397, His401: figure 4; yellow highlighted.
• Cys416, Cys421 and His434, His435: figure 5; yellow highlighted.

Figure 2

Figure 3

Figure 4

Figure 5

The 449 amino acid sequences of WT1 were used for homology modeling. Sequences of WT1 were retrieved from Swiss Prot Data Bank in FASTA format [21]. The best suitable templates were used for 3D-structure prediction. The retrieved amino acid sequences of WT1 were subjected to BLAST [22]. Templates were retrieved on the base of query coverage and identity. The 3D structures were predicted by MODELLER 9.0 [23] that is the requirement of 3D structure building of target protein. Tools including stereochemistry and Ramchandran plots were used for the structure evaluation [24]. Identification of Template was carried out, and Sequence Alignment was carried out by using FASTA, BLAST. Quality of the WT1 model was verified. Stereochemistry of model was evaluated by PROCHECK [25]. Mutational studies were done by WHAT IF [26]. Five human WT1 mutants are modeled. These were: Lys371→Ala371, Ser415→Ala415, Cys416→Ala416, His434→Asp434 and His434→Arg434.

Results and Discussion

The study was largely based on active side of the WT1 and its role in DNA binding mutation. Zinc finger binding domain interact selectively and non-covalently. This zinc finger-binding domain is the classical zinc finger domain, in which two conserved cysteine and histidine co-ordinate a zinc ion at the active site.

Cys416®Ala416 MUTANT

Significant change was observed in Cys416 mutated to Ala416. In mutant Ala416, reduction in the Van der Waal’s contact between the amino acids. Loss of coordination with the metal ion Zn was also predicted (Figure 6 A and B).

                                                       Figure 6A                                                                   Figure 6B

Figure 6 A and B: Wild Type (Cys416) and mutated (Ala416) WT1.  Distance between Zn and Cys416 is increased in mutated (Ala416) model. Cys416 is predicted to be found in the vicinity of His434 and His438 which are implicated in catalysis (6A) while Ala416 can only interact with His434 and not with His438 in the mutated model (6B).

Cys416 is located at the domain interface with its polar side chain completely buried (0.00 Å). Replacement of this amino acid may account for considerable changes in the interior of protein (Table 1). We have predicted the possible changes that arise due to the mutation of Cys to Ala by molecular modeling experiments. Amino acids, Pro419, Ser420, Cys421, His434 and some atoms of His438 (ND1, NE2, CD2 and CE1) are present near Cys416. Zinc (Zn203) is also present in the vicinity (1.82 Å) of Cys416 (Figure 6). The mutated residue, Ala is also predicted to remain buried (0.00 Å) in the interior of protein. Significant change is observed however, in the surrounding area of the mutated Ala416. Only a few atoms of His434 (CD2 and NE2) and His438 (CE1) were seen in the surrounding. This may reduce the Van der Waal's contacts between the respective amino acids. The loss of coordination with the metal ion, zinc was also predicted as the distance is increased from 1.82 Å to3.12 Å.   It is therefore predicted that Cys416 plays a vital role in the interaction with other amino acid residues as well as in the metal coordination. It is observed that there is a possibility of loss of these interactions in case of Cys416 replacement.

His434®Arg434 MUTANTS

In case of mutant His434→Arg434, there was a loss of zn203 coordination with Arg434.  His434 does not interact directly with any DNA base, whereas mutated Arg434 is predicted to interact directly with DNA base, A1. This suggests that change might effect on the DNA binding pattern, Figure 7 A and B.

                                                       Figure 7A                                                                   Figure 7B

FIGURE 7 A and B: Wild Type (His434) and mutated (Arg434) WT1.  Distance between Zn and His434 is increased in mutated model. Arg434 is predicted to bind DNA base A1 (B) while His434 in the original model (A) show no bonding with DNA base.

In case of mutation of His434®Arg434, the distance between the mutated Arg and zinc (Zn203) was increased from 2.28 Å to5.00 Å suggesting that there could be a loss of coordination with the metal ion. Mutational studies proved that hydrogen bonding network close to the zinc-binding motif plays a significant role in stabilizing the coordination of the zinc metal ion to the protein23. The mutated amino acid, Arg434 also moved considerably form buried to relatively exposed environment (2.28 Å to 5.35 Å). Presence of positively charged Arg on the surface could account for additional interaction of the protein with other proteins or with the surrounding water molecules. His434 does not interact directly with any DNA base whereas mutated Arg434 is predicted to interact directly with DNA base Adenine, A1. (Figure 7). This suggests that the change might cause the DNA binding pattern.

TABLE 1: Comparison of surface accessibilities (Å) of the wild type and mutated residues and those in the vicinity of the mutated residues in the five WT1 mutants

Lys371®Ala371 and Ser415®Ala415 MUTANT

No significant change was observed when Lys371 was mutated to Ala371, and Ser415 was mutated to Ala415. It is observed in this mutation that the change that arise in the overall structure and surrounding amino acid residues (Table 1). Lys371 is present on the surface (accessibility = 47.04 Å) of the WT1 molecule. It was observed that the internal protein structure was not affected considerably, as Lys371 is present on the outer most surface of the protein. In the original model, Lys371 stacks against thymine. It also forms a water-mediated contact with side chain hydroxyl of Ser367. Although, Ala371 also stacks against the same DNA base but the distance is slightly altered. The hydrogen bond between Ala371 and Ser367 has not been predicted in the mutated model.  It has been demonstrated that mutation within finger 2 and 4 abolished sequence specific binding of WT1 to DNA bases19. The mutation of the corresponding lysine in a peptide could reduce its affinity for DNA seven folds [27].  On the other hand, it is reported [28] that a surface mutation would not cause a significant change in the internal structure of protein.  However, the replacement of a basic polar residue with a non-polar one could account for a reduction in polarity.  The modeling studies of Lys to Ala mutation do not however support this finding and require further analysis.

Mutation of Ser415®Ala415 in the WT1 model (Table 1). Ser415 is located near the active center of WT1. It has been demonstrated that Ser415 makes a water-mediated contact with phosphate of DNA base, guanine [20]. In our predicted model of WT1, Ser415 makes two water (numbers 516 and 568) mediated contacts. Mutation of this Ser with Ala resulted in the loss of one of these contacts leading to the loss of binding. The replacement of relatively polar residue, Ser to a non-polar one, Ala could account for this reduced interaction. This is also evident by a slight decrease in the accessibility of Ala (Ser415 = 7.96 Å; Ala415 = 7.61 Å).

His434®Asp434 MUTANTS

In case of mutants His434→Asp434, there was a loss of coordination of metal ion (zn203) with mutant Asp434. Glu430 move from relatively exposed to completely buried environment. His434 is also present at the active center of WT1. We predicted two mutants; His434®Asp434 and His434®Arg434 mutants by molecular modeling (Table 1). In case of His434®Asp434 mutation, the water mediated contact is lost. The distance between mutated Asp and zinc (Zn203) was also increased from 2.28 Å to 3.57 Å suggesting that there could be a loss of coordination with the metal ion as well. The amino acid Glu340 that is present near His434 also moved considerably form relatively exposed to completely buried environment (14.83 Å to 00.0 Å).

Conclusion

It is concluded that mutation of amino acid residue Cys416→Ala416, His434→Asp434 and His434→Arg434 of WT1 may lose its function to regulate the function of genes by binding to specific parts of DNA. Besides the mutation of above-mentioned amino acid residue, the role of WT1 in cell growth, cell differentiation, apoptosis and tumor suppressor function is also lost.

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