Preventive Strategies against Human Papillomaviruses

Human papillomavirus (HPV) infection is among the most common viral infections of the reproductive tract. Out of more than 100 different types of HPV identified so far, only a few (termed as “high-risk” subtypes) are associated with cervical cancer. On the other hand, “low-risk” subtypes are associated with genital warts and other benign changes in cervical and oral mucosa. Majority of the HPV infections usually clear up without any intervention within a few months. However, a fraction of HPV infections, such as those with types 16 and 18, can become persistent which may lead to the development of anogenital or cervical cancers. HPV subtypes 16 and 18 together are responsible for approximately 70% of all cervical cancer cases, the fourth major cause of cancer-related deaths in women. In the absence of any specific treatment options, preventive measures are considered as cornerstone of strategies aimed at curbing the burden of this disease. This chapter presents a comprehensive review of strategies that can be employed to prevent and eradicate HPV infection. Minimizing the exposure to HPV risk factors such as unprotected sex, multiple sex partners, early age sex, and not being circumcised, can reduce the chances of getting HPV infection to a significant level. Mass screening programs have also been effective in HPV eradication. Nevertheless, immunization against HPV has proven to be the most promising strategy in fight against HPV. Virus-like particles based on bivalent, quadrivalent, and nonavalent anti-HPV vaccines have been licensed and are available in market under the trade names of Cervarix®, Gardasil®, and Gardasil9®, respectively. Various clinical trials and population-based studies have demonstrated high levels of efficacy for all the three vaccines in preventing type-specific malignancies

A Short Overview on Hearing Loss and Related Auditory Defects

Hearing is the ability of a person to recognize sound in the surroundings and it makes communication possible. Ear is the human organ serving as a transducer that perceives signals from the environment and converts it into detectable forms for interpretation by the brain. The auditory system is among one of the most highly studied systems. Researchers have described the physiological function of the system in detail but due to its complexity, the genetic mechanisms and genes implicated in auditory function are still being revealed. Numerous studies on the genetics of hearing indicate hearing loss as one of the most common and prevalent disorders as it affects approximately five million people worldwide. Besides hearing loss, there are several other pathologies of auditory system which are common and have an established genetic basis. In this chapter, we will introduce the genetics of some common auditory pathologies including syndromic and non-syndromic hearing loss, auditory neuropathy, age-related hearing loss, and tinnitus. These understandings will 1 day lead to better diagnosis, management, and cures

Novel GPR156 variants confirm its role in moderate sensorineural hearing loss

Hereditary hearing loss (HL) is a genetically heterogeneous disorder affecting people worldwide. The implementation of advanced sequencing technologies has significantly contributed to the identification of novel genes involved in HL. In this study, probands of two Turkish families with non-syndromic moderate HL were subjected to exome sequencing. The data analysis identified the c.600G > A (p.Thr200Thr) and c.1863dupG (p.His622fs) variants in GPR156 , which co-segregated with the phenotype as an autosomal recessive trait in the respective families. The in silico predictions and a minigene assay showed that the c.600G > A variant disrupts mRNA splicing. This gene belongs to the family of G protein-coupled receptors whose function is not well established in the inner ear. GPR156 variants have very recently been reported to cause HL in three families. Our study from a different ethnic background confirms GPR156 as a bona fide gene involved in HL in humans. Further investigation towards the understanding of the role of GPCRs in the inner ear is warranted

Human Organoids for Rapid Validation of Gene Variants Linked to Cochlear Malformations

Developmental anomalies of the hearing organ, the cochlea, are diagnosed in approximately one-fourth of individuals with congenital deafness. Most patients with cochlear malformations remain etiologically undiagnosed due to insufficient knowledge about underlying genes or the inability to make conclusive interpretations of identified genetic variants. We used exome sequencing for genetic evaluation of hearing loss associated with cochlear malformations in three probands from unrelated families. We subsequently generated monoclonal induced pluripotent stem cell (iPSC) lines, bearing patient-specific knockins and knockouts using CRISPR/Cas9 to assess pathogenicity of candidate variants. We detected FGF3 (p.Arg165Gly) and GREB1L (p.Cys186Arg), variants of uncertain significance in two recognized genes for deafness, and PBXIP1 (p.Trp574*) in a candidate gene. Upon differentiation of iPSCs towards inner ear organoids, we observed significant developmental aberrations in knockout lines compared to their isogenic controls. Patient-specific single nucleotide variants (SNVs) showed similar abnormalities as the knockout lines, functionally supporting their causality in the observed phenotype. Therefore, we present human inner ear organoids as a tool to rapidly validate the pathogenicity of DNA variants associated with cochlear malformations.Developmental anomalies of the hearing organ, the cochlea, are diagnosed in approximately one-fourth of individuals with congenital deafness. Most patients with cochlear malformations remain etiologically undiagnosed due to insufficient knowledge about underlying genes or the inability to make conclusive interpretations of identified genetic variants. We used exome sequencing for genetic evaluation of hearing loss associated with cochlear malformations in three probands from unrelated families. We subsequently generated monoclonal induced pluripotent stem cell (iPSC) lines, bearing patient-specific knockins and knockouts using CRISPR/Cas9 to assess pathogenicity of candidate variants. We detected FGF3 (p.Arg165Gly) and GREB1L (p.Cys186Arg), variants of uncertain significance in two recognized genes for deafness, and PBXIP1 (p.Trp574*) in a candidate gene. Upon differentiation of iPSCs towards inner ear organoids, we observed significant developmental aberrations in knockout lines compared to their isogenic controls. Patient-specific single nucleotide variants (SNVs) showed similar abnormalities as the knockout lines, functionally supporting their causality in the observed phenotype. Therefore, we present human inner ear organoids as a tool to rapidly validate the pathogenicity of DNA variants associated with cochlear malformations

Identification of novel MYH14 variants in families with autosomal dominant sensorineural hearing loss

Autosomal dominant sensorineural hearing loss (ADSNHL) is a genetically heterogeneous disorder caused by pathogenic variants in various genes, including MYH14. However, the interpretation of pathogenicity for MYH14 variants remains a challenge due to incomplete penetrance and the lack of functional studies and large families. In this study, we performed exome sequencing in six unrelated families with ADSNHL and identified five MYH14 variants, including three novel variants. Two of the novel variants, c.571G > C (p.Asp191His) and c.571G > A (p.Asp191Asn), were classified as likely pathogenic using ACMG and Hearing Loss Expert panel guidelines. In silico modeling demonstrated that these variants, along with p.Gly1794Arg, can alter protein stability and interactions among neighboring molecules. Our findings suggest that MYH14 causative variants may be more contributory and emphasize the importance of considering this gene in patients with nonsyndromic mainly post-lingual severe form of hearing loss. However, further functional studies are needed to confirm the pathogenicity of these variants

Identification and application of biocontrol agents against Cotton leaf curl virus disease in Gossypium hirsutum under greenhouse conditions

Biological control is a novel approach in crop protection. Bacteria, such as Bacillus spp. and Pseudomonas spp., are reported for this purpose and some of their products are already commercially available. In this study, the rhizosphere and phyllosphere of healthy cotton plants were used as a source of bacterial isolates with properties of potential biocontrol agents. The isolates were screened for phosphate solubilization activity, indole acetic acid (IAA) production and antifungal activity. Two isolates, S1HL3 and S1HL4, showed phosphate solubilization and IAA production simultaneously, while another two, JS2HR4 and JS3HR2, demonstrated potential to inhibit fungal pathogens. These bacteria were identified as Pseudomonas aeruginosa (S1HL3), Burkholderia sp. (S1HL4) and Bacillus sp. (JS2HR4 and JS3HR2) based on biochemical and molecular characteristics. The isolates were tested against Cotton leaf curl virus (CLCuV) in greenhouse conditions, both as individual bacterial isolates and consortia. Treated plants were healthy as compared to control plants, where up to 74% of the plants were symptomatic for CLCuV infection. Maximum inhibition of CLCuV was observed in the plants treated with a mixture of bacterial isolates: the viral load in the treated plants was only 0.4% vs. up to 74% in controls. This treatment consortium included P. aeruginosa S1HL3, Burkholderia sp. S1HL4 and Bacillus spp. isolates, JS2HR4 and JS3HR2. The principal-component biplot showed a highly significant correlation between the viral load percentage and the disease incidence

Genetic heterogeneity in hereditary hearing loss: Potential role of kinociliary protein TOGARAM2

Hearing loss (HL) is a heterogenous trait with pathogenic variants in more than 200 genes that have been discovered in studies involving small and large HL families. Over one-third of families with hereditary HL remain etiologically undiagnosed after screening for mutations in the recognized genes. Genetic heterogeneity complicates the analysis in multiplex families where variants in more than one gene can be causal in different individuals even in the same sibship. We employed exome or genome sequencing in at least two affected individuals with congenital or prelingual-onset, severe to profound, non-syndromic, bilateral sensorineural HL from four multiplex families. Bioinformatic analysis was performed to identify variants in known and candidate deafness genes. Our results show that in these four families, variants in a single HL gene do not explain HL in all affected family members, and variants in another known or candidate HL gene were detected to clarify HL in the entire family. We also present a variant in TOGARAM2 as a potential cause underlying autosomal recessive non-syndromic HL by showing its presence in a family with HL, its expression in the cochlea and the localization of the protein to cochlear hair cells. Conclusively, analyzing all affected family members separately can serve as a good source for the identification of variants in known and novel candidate genes for HL

Dispersed DNA variants underlie hearing loss in South Florida’s minority population

Abstract Background We analyzed the genetic causes of sensorineural hearing loss in racial and ethnic minorities of South Florida by reviewing demographic, phenotypic, and genetic data on 136 patients presenting to the Hereditary Hearing Loss Clinic at the University of Miami. In our retrospective chart review, of these patients, half self-identified as Hispanic, and the self-identified racial distribution was 115 (86%) White, 15 (11%) Black, and 6 (4%) Asian. Our analysis helps to reduce the gap in understanding the prevalence, impact, and genetic factors related to hearing loss among diverse populations. Results The causative gene variant or variants were identified in 54 (40%) patients, with no significant difference in the molecular diagnostic rate between Hispanics and Non-Hispanics. However, the total solve rate based on race was 40%, 47%, and 17% in Whites, Blacks, and Asians, respectively. In Non-Hispanic Whites, 16 different variants were identified in 13 genes, with GJB2 (32%), MYO7A (11%), and SLC26A4 (11%) being the most frequently implicated genes. In White Hispanics, 34 variants were identified in 20 genes, with GJB2 (22%), MYO7A (7%), and STRC-CATSPER2 (7%) being the most common. In the Non-Hispanic Black cohort, the gene distribution was evenly dispersed, with 11 variants occurring in 7 genes, and no variant was identified in 3 Hispanic Black probands. For the Asian cohort, only one gene variant was found out of 6 patients. Conclusion This study demonstrates that the diagnostic rate of genetic studies in hearing loss varies according to race in South Florida, with more heterogeneity in racial and ethnic minorities. Further studies to delineate deafness gene variants in underrepresented populations, such as African Americans/Blacks from Hispanic groups, are much needed to reduce racial and ethnic disparities in genetic diagnoses