Corrigendum: Cytokinins: a genetic target for increasing yield potential in the CRISPR era.

[This corrects the article DOI: 10.3389/fgene.2022.883930.].

Polarity kinases that phosphorylate F-BAR protein Cdc15 have unique localization patterns during cytokinesis and contributions to preventing tip septation in Schizosaccharomyces pombe.

The Schizosaccharomyces pombe F-BAR protein, Cdc15, facilitates the linkage between the cytokinetic ring and the plasma membrane. Cdc15 is phosphorylated on many sites by four polarity kinases and this antagonizes membrane interaction. Dephosphorylation of Cdc15 during mitosis induces its phase separation, allowing oligomerization, membrane association, and protein partner binding. Here, using live cell imaging we examined whether spatial separation of Cdc15 from its four identified kinases potentially explains their diverse effects on tip septation and the mitotic Cdc15 phosphorylation state. We identified a correlation between kinase localization and their ability to antagonize Cdc15 cytokinetic ring and membrane localization.

Crosstalk between long noncoding RNA and microRNA in Cancer.

miRNAs and lncRNAs play a central role in cancer-associated gene regulations. The dysregulated expression of lncRNAs has been reported as a hallmark of cancer progression, acting as an independent prediction marker for an individual cancer patient. The interplay of miRNA and lncRNA decides the variation of tumorigenesis that could be mediated by acting as sponges for endogenous RNAs, regulating miRNA decay, mediating intra-chromosomal interactions, and modulating epigenetic components. This paper focuses on the influence of crosstalk between lncRNA and miRNA on cancer hallmarks such as epithelial-mesenchymal transition, hijacking cell death, metastasis, and invasion. Other cellular roles of crosstalks, such as neovascularization, vascular mimicry, and angiogenesis were also discussed. Additionally, we reviewed crosstalk mechanism with specific host immune responses and targeting interplay (between lncRNA and miRNA) in cancer diagnosis and management.

The paradigm of intracellular parasite survival and drug resistance in leishmanial parasite through genome plasticity and epigenetics: Perception and future perspective.

Leishmania is an intracellular, zoonotic, kinetoplastid eukaryote with more than 1.2 million cases all over the world. The leishmanial chromosomes are divided into polymorphic chromosomal ends, conserved central domains, and antigen-encoding genes found in telomere-proximal regions. The genome flexibility of chromosomal ends of the leishmanial parasite is known to cause drug resistance and intracellular survival through the evasion of host defense mechanisms. Therefore, in this review, we discuss the plasticity of Leishmania genome organization which is the primary cause of drug resistance and parasite survival. Moreover, we have not only elucidated the causes of such genome plasticity which includes aneuploidy, epigenetic factors, copy number variation (CNV), and post-translation modification (PTM) but also highlighted their impact on drug resistance and parasite survival.

Multiple polarity kinases inhibit phase separation of F-BAR protein Cdc15 and antagonize cytokinetic ring assembly in fission yeast.

The F-BAR protein Cdc15 is essential for cytokinesis in Schizosaccharomyces pombe and plays a key role in attaching the cytokinetic ring (CR) to the plasma membrane (PM). Cdc15's abilities to bind to the membrane and oligomerize via its F-BAR domain are inhibited by phosphorylation of its intrinsically disordered region (IDR). Multiple cell polarity kinases regulate Cdc15 IDR phosphostate, and of these the DYRK kinase Pom1 phosphorylation sites on Cdc15 have been shown in vivo to prevent CR formation at cell tips. Here, we compared the ability of Pom1 to control Cdc15 phosphostate and cortical localization to that of other Cdc15 kinases: Kin1, Pck1, and Shk1. We identified distinct but overlapping cohorts of Cdc15 phosphorylation sites targeted by each kinase, and the number of sites correlated with each kinases' abilities to influence Cdc15 PM localization. Coarse-grained simulations predicted that cumulative IDR phosphorylation moves the IDRs of a dimer apart and toward the F-BAR tips. Further, simulations indicated that the overall negative charge of phosphorylation masks positively charged amino acids necessary for F-BAR oligomerization and membrane interaction. Finally, simulations suggested that dephosphorylated Cdc15 undergoes phase separation driven by IDR interactions. Indeed, dephosphorylated but not phosphorylated Cdc15 undergoes liquid-liquid phase separation to form droplets in vitro that recruit Cdc15 binding partners. In cells, Cdc15 phosphomutants also formed PM-bound condensates that recruit other CR components. Together, we propose that a threshold of Cdc15 phosphorylation by assorted kinases prevents Cdc15 condensation on the PM and antagonizes CR assembly.

The paradigm of miRNA and siRNA influence in Oral-biome.

Short nucleotide sequences like miRNA and siRNA have attracted a lot of interest in Oral-biome investigations. miRNA is a small class of non-coding RNA that regulates gene expression to provide effective regulation of post-transcription. On contrary, siRNA is 21-25 nucleotide dsRNA impairing gene function post-transcriptionally through inhibition of mRNA for homologous dependent gene silencing. This review highlights the application of miRNA in oral biome including oral cancer, dental implants, periodontal diseases, gingival fibroblasts, oral submucous fibrosis, radiation-induced oral mucositis, dental Pulp, and oral lichenoid disease. Moreover, we have also discussed the application of siRNA against the aforementioned disease along with the impact of miRNA and siRNA to the various pathways and molecular effectors pertaining to the dental diseases. The influence of upregulation and downregulation of molecular effector post-treatment with miRNA and siRNA and their impact on the clinical setting has been elucidated. Thus, the mentioned details on application of miRNA and siRNA will provide a novel gateway to the scholars to not only mitigate the long-lasting issue in dentistry but also develop new theragnostic approaches.

Cellular Landscaping of COVID-19 and Gynaecological Cancers: An Infrequent Correlation.

COVID-19 resulted in a mortality rate of 3-6% caused by SARS-CoV-2 and its variant leading to unprecedented consequences of acute respiratory distress septic shock and multiorgan failure. In such a situation, evaluation, diagnosis, treatment, and care for cancer patients are difficult tasks faced by medical staff. Moreover, patients with gynaecological cancer appear to be more prone to severe infection and mortality from COVID-19 due to immunosuppression by chemotherapy and coexisting medical disorders. To deal with such a circumtances oncologists have been obliged to reconsider the entire diagnostic, treatment, and management approach. This review will provide and discuss the molecular link with gynaecological cancer under COVID-19 infection, providing a novel bilateral relationship between the two infections. Moreover, the authors have provided insights to discuss the pathobiology of COVID-19 in gynaecological cancer and their risks associated with such comorbidity. Furthermore, we have depicted the overall impact of host immunity along with guidelines for the treatment of patients with gynaecological cancer under COVID-19 infection. We have also discussed the feasible scope for the management of COVID-19 and gynaecological cancer.

The emergence of metal oxide nanoparticles (NPs) as a phytomedicine: A two-facet role in plant growth, nano-toxicity and anti-phyto-microbial activity.

Anti-microbial resistance (AMR) has recently emerged as an area of high interest owing to the rapid surge of AMR phenotypes. Metal oxide NPs (MeONPs) have been identified as novel phytomedicine and have recently peaked a lot of interest due to their potential applications in combating phytopathogens, besides enhancing plant growth and yields. Numerous MeONPs (Ti2O, MgO, CuO, Ag2O, SiO2, ZnO, and CaO) have been synthesized and tested to validate their antimicrobial roles without causing toxicity to the cells. This review discusses the application of the MeONPs with special emphasis on anti-microbial activities in agriculture and enlists how cellular toxicity caused through reactive oxygen species (ROS) production affects plant growth, morphology, and viability. This review further highlights the two-facet role of silver and copper oxide NPs including their anti-microbial applications and toxicities. Furthermore, the factor modulating nanotoxicity and immunomodulation for cytokine production has also been discussed. Thus, this article will not only provide the researchers with the potential bottlenecks but also emphasizes a comprehensive outline of breakthroughs in the applicability of MeONPs in agriculture.

Phage-tail-like bacteriocins as a biomedical platform to counter anti-microbial resistant pathogens.

Phage Tail Like bacteriocins (PTLBs) has been an area of interest in the last couple of years owing to their varied application against multi-drug resistant (MDR), anti-microbial resistant (AMR) pathogens and their evolutionary link with the dsDNA virus and bacteriophages. PTLBs are defective phages derived from Myoviridae and Siphoviridae phages, PTLBs are distinguished into R-type (Rigid type) characterized by a non-flexible contractile nanotube resembling Myoviridae phage contractile tails, and F-type (Flexible type) with a flexible non-contractile rod-like structure similar to Siphoviridae phages. In this review, we have discussed the structural association, mechanism, and characterization of PTLBs. Moreover, we have elucidated the symbiotic biological function and application of PTLBs against MDR and XDR pathogens and highlighted the evolutionary role of PTLBs. The difficulties that must be overcome to implement PTLBs clinically are also discussed. It is imperative that these issues be addressed by academics in future studies before being implemented in clinical settings. This article is novel in its way as it will not only provide us with a gateway that acts as a novel strategy for scholars to mitigate and control the uprising issue of AMR pathogens but also promote the development of clinical studies for PTLBs.

Governing HPV-related carcinoma using vaccines: Bottlenecks and breakthroughs.

Human papillomavirus (HPV) contributes to sexually transmitted infection, which is primarily associated with pre-cancerous and cancerous lesions in both men and women and is among the neglected cancerous infections in the world. At global level, two-, four-, and nine-valent pure L1 protein encompassed vaccines in targeting high-risk HPV strains using recombinant DNA technology are available. Therapeutic vaccines are produced by early and late oncoproteins that impart superior cell immunity to preventive vaccines that are under investigation. In the current review, we have not only discussed the clinical significance and importance of both preventive and therapeutic vaccines but also highlighted their dosage and mode of administration. This review is novel in its way and will pave the way for researchers to address the challenges posed by HPV-based vaccines at the present time.

Theragnostic strategies harnessing the self-renewal pathways of stem-like cells in the acute myeloid leukemia.

Acute myelogenous leukemia (AML) is a genetically heterogeneous and aggressive cancer of the Hematopoietic Stem/progenitor cells. It is distinguished by the uncontrollable clonal growth of malignant myeloid stem cells in the bone marrow, venous blood, and other body tissues. AML is the most predominant of leukemias occurring in adults (25%) and children (15-20%). The relapse after chemotherapy is a major concern in the treatment of AML. The overall 5-year survival rate in young AML patients is about 40-45% whereas in the elderly patients it is less than 10%. Leukemia stem-like cells (LSCs) having the ability to self-renew indefinitely, repopulate and persist longer in the G0/G1 phase play a crucial role in the AML relapse and refractoriness to chemotherapy. Hence, novel treatment strategies and diagnostic biomarkers targeting LSCs are being increasingly investigated. Through this review, we have explored the signaling modulations in the LSCs as the theragnostic targets. The significance of the self-renewal pathways in overcoming the treatment challenges in AML has been highlighted.

Cellular landscaping of cisplatin resistance in cervical cancer.

Cervical cancer (CC) caused by human papillomavirus (HPV) is one of the largest causes of malignancies in women worldwide. Cisplatin is one of the widely used drugs for the treatment of CC is rendered ineffective owing to drug resistance. This review highlights the cause of resistance and the mechanism of cisplatin resistance cells in CC to develop therapeutic ventures and strategies that could be utilized to overcome the aforementioned issue. These strategies would include the application of nanocarries, miRNA, CRIPSR/Cas system, and chemotherapeutics in synergy with cisplatin to not only overcome the issues of drug resistance but also enhance its anti-cancer efficiency. Moreover, we have also discussed the signaling network of cisplatin resistance cells in CC that would provide insights to develop therapeutic target sites and inhibitors. Furthermore, we have discussed the role of CC metabolism on cisplatin resistance cells and the physical and biological factors affecting the tumor microenvironments.

Theragnostic application of nanoparticle and CRISPR against food-borne multi-drug resistant pathogens.

Foodborne infection is one of the leading sources of infections spreading across the world. Foodborne pathogens are recognized as multidrug-resistant (MDR) pathogens posing a significant problem in the food industry and healthy consumers resulting in enhanced economic burden, and nosocomial infections. The continued search for enhanced microbial detection tools has piqued the interest of the CRISPR-Cas system and Nanoparticles. CRISPR-Cas system is present in the bacterial genome of some prokaryotes and is repurposed as a theragnostic tool against MDR pathogens. Nanoparticles and composites have also emerged as an efficient tool in theragnostic applications against MDR pathogens. The diagnostic limitations of the CRISPR-Cas system are believed to be overcome by a synergistic combination of the nanoparticles system and CRISPR-Cas using nanoparticles as vehicles. In this review, we have discussed the diagnostic application of CRISPR-Cas technologies along with their potential usage in applications like phage resistance, phage vaccination, strain typing, genome editing, and antimicrobial. we have also elucidated the antimicrobial and detection role of nanoparticles against foodborne MDR pathogens. Moreover, the novel combinatorial approach of CRISPR-Cas and nanoparticles for their synergistic effects in pathogen clearance and drug delivery vehicles has also been discussed.

Phage delivered CRISPR-Cas system to combat multidrug-resistant pathogens in gut microbiome.

The Host-microbiome interactions that exist inside the gut microbiota operate in a synergistic and abnormal manner. Additionally, the normal homeostasis and functioning of gut microbiota are frequently disrupted by the intervention of Multi-Drug Resistant (MDR) pathogens. CRISPR-Cas (CRISPR-associated protein with clustered regularly interspersed short palindromic repeats) recognized as a prokaryotic immune system has emerged as an effective genome-editing tool to edit and delete specific microbial genes for the expulsion of bacteria through bactericidal action. In this review, we demonstrate many functioning CRISPR-Cas systems against the anti-microbial resistance of multiple pathogens, which infiltrate the gastrointestinal tract. Moreover, we discuss the advancement in the development of a phage-delivered CRISPR-Cas system for killing a gut MDR pathogen. We also discuss a combinatorial approach to use bacteriophage as a delivery system for the CRISPR-Cas gene for targeting a pathogenic community in the gut microbiome to resensitize the drug sensitivity. Finally, we discuss engineered phage as a plausible potential option for the CRISPR-Cas system for pathogenic killing and improvement of the efficacy of the system.

Cytokinins: A Genetic Target for Increasing Yield Potential in the CRISPR Era.

Over the last decade, remarkable progress has been made in our understanding the phytohormones, cytokinin's (CKs) biosynthesis, perception, and signalling pathways. Additionally, it became apparent that interfering with any of these steps has a significant effect on all stages of plant growth and development. As a result of their complex regulatory and cross-talk interactions with other hormones and signalling networks, they influence and control a wide range of biological activities, from cellular to organismal levels. In agriculture, CKs are extensively used for yield improvement and management because of their wide-ranging effects on plant growth, development and physiology. One of the primary targets in this regard is cytokinin oxidase/dehydrogenase (CKO/CKX), which is encoded by CKX gene, which catalyses the irreversible degradation of cytokinin. The previous studies on various agronomically important crops indicated that plant breeders have targeted CKX directly. In recent years, prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has been increasingly used in editing the CKO/CKX gene and phenomenal results have been achieved. This review provides an updated information on the applications of CRISPR-based gene-editing tools in manipulating cytokinin metabolism at the genetic level for yield improvement. Furthermore, we summarized the current developments of RNP-mediated DNA/transgene-free genomic editing of plants which would broaden the application of this technology. The current review will advance our understanding of cytokinins and their role in sustainably increase crop production through CRISPR/Cas genome editing tool.

Mechanistic role of HPV-associated early proteins in cervical cancer: Molecular pathways and targeted therapeutic strategies.

PURPOSE: Cervical cancer (CC), one of the major causes of death of women throughout the world is primarily caused due to Human Papilloma Virus (HPV) 16 and 18. The early region (E) oncoproteins of HPV are associated with the etiopathogenesis and contribute to the progression of cancer. The present article comprehensively discussed the structural organization and biological functions of all E proteins of HPV and their contribution to progression of CC with an intent to decipher the pathological hallmarks and their relationship. Additionally, the role of E proteins in reference to therapeutics will also be presented. METHODS: A systematic search has been carried out for articles published in PubMed database by using combinations of different keywords with Boolean operators (AND, OR, NOT) including cervical cancer, HPV, E proteins, and signaling. RESULTS: From the analysis of literature review, its apparent that E proteins are the major contributor to disease progression. E1, E2, and E4 forms are mainly associated with viral integration, replication, and transcription whereas E6 and E7 act as an oncoprotein and are associated with the progression of cancer. E5 regulates cell proliferation, apoptosis, and facilitates the activity of E6 and E7. Additionally, E proteins were observed associated with numerous cell signaling pathways including PI3K/AKT, Wnt, Notch and reasonably contribute to the initiation of malignancy, cell proliferation, metastasis, and drug resistance. Knowing the role and interplay of each protein in initiation to progression of CC, their therapeutic significance has been elucidated. The present study observations demonstrate that E6 and E7 are the major cause of HPV-mediated CC progression. E1, E2, and E5 also act as a backbone for E6 and E7 and most of the current approaches have targeted E6 and E7 mediated action only. CONCLUSION: The present review illustrates the structural organization as well as function and regulation of all early proteins of HPV and their association with several cellular signaling pathways. The observations provide clue on the regulatory aspect of these proteins in initiation to progression and reasonably represent that targeting these proteins could be a novel therapeutic strategy for CC. In particular, its seemingly appears that inhibition of the activity of E6 and E7 oncoproteins may be a better selective target to delay the progression of CC. The review reaffirms the role of E proteins and encourages future studies on developing diagnostics, and most importantly therapeutics strategies targeting E6 and E7 oncoproteins to tackle CC related morbidity and mortality.

Molecular Insights into Therapeutic Potentials of Hybrid Compounds Targeting Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most complex progressive neurological disorders involving degeneration of neuronal connections in brain cells leading to cell death. AD is predominantly detected among elder people (> 65 years), mostly diagnosed with the symptoms of memory loss and cognitive dysfunctions. The multifarious pathogenesis of AD comprises the accumulation of pathogenic proteins, decreased neurotransmission, oxidative stress, and neuroinflammation. The conventional therapeutic approaches are limited to symptomatic benefits and are ineffective against disease progression. In recent years, researchers have shown immense interest in the designing and fabrication of various novel therapeutics comprised of naturally isolated hybrid molecules. Hybrid therapeutic compounds are developed from the combination of pharmacophores isolated from bioactive moieties which specifically target and block various AD-associated pathogenic pathways. The method of designing hybrid molecules has numerous advantages over conventional multitarget drug development methods. In comparison to in silico high throughput screening, hybrid molecules generate quicker results and are also less expensive than fragment-based drug development. Designing hybrid-multitargeted therapeutic compounds is thus a prospective approach in developing an effective treatment for AD. Nevertheless, several issues must be addressed, and additional researches should be conducted to develop hybrid therapeutic compounds for clinical usage while keeping other off-target adverse effects in mind. In this review, we have summarized the recent progress on synthesis of hybrid compounds, their molecular mechanism, and therapeutic potential in AD. Using synoptic tables, figures, and schemes, the review presents therapeutic promise and potential for the development of many disease-modifying hybrids into next-generation medicines for AD.

Revealing a Novel Antigen Repressor of Differentiation Kinase 2 for Diagnosis of Human Visceral Leishmaniasis in India.

Visceral leishmaniasis (VL) is one of the major global health concerns due to its association with morbidity and mortality. All available diagnostic tools have been, until now, unable to provide a very specific and cost-effective mode of detection for VL globally. Therefore, the design of robust, specific, and commercially translatable diagnostic tests is urgently required. Currently, we are attempting to identify and explore the diagnostic potential of a novel parasite antigen. Repressor of differentiation kinase 2 (RDK2), a serine/threonine kinase, has a versatile role in parasite life cycle progression. However, its role as a diagnostic candidate for VL has not been investigated. Herein, we cloned and over-expressed LdRDK2 and studied the recombinant RDK2 for the diagnosis of human VL using serum and urine samples. In silico analysis predicted that RDK2 is conserved among Leishmania species with the least conservation in humans. RDK2 developed immune-reactive bands with antibodies present in VL patients' sera, and it demonstrated no cross-reactivity with sera from healthy controls and other diseases. Additionally, RDK2 antigen demonstrated a significant reactivity with IgG antibodies of VL patients' sera, with 78% sensitivity and 86.67% specificity as compared to healthy controls and other diseases. Furthermore, we evaluated its utility for non-invasive diagnosis of VL using patients' urine samples and found 93.8% sensitivity and 85.7% specificity. RDK2 was found to have better sensitivity and treatment response in patients' urine compared to serum samples, indicating its role as a promising point of care (POC) antigen. In a nutshell, we explored the role of RDK2 as a potential diagnostic marker for VL in both invasive and non-invasive modes as well as its utility as a promising POC antigen for treatment response cases.

Fission yeast paxillin contains two Cdc15 binding motifs for robust recruitment to the cytokinetic ring.

The F-BAR protein Cdc15 mediates attachment of the cytokinetic ring (CR) to the plasma membrane and is essential for cytokinesis in Schizosaccharomyces pombe. While its N-terminal F-BAR domain is responsible for oligomerization and membrane binding, its C-terminal SH3 domain binds other partners at a distance from the membrane. We previously demonstrated that the essential cytokinetic formin Cdc12, through an N-terminal motif, directly binds the cytosolic face of the F-BAR domain. Here, we show that paxillin-like Pxl1, which is important for CR stability, contains a motif highly related to that in formin Cdc12, and also binds the Cdc15 F-BAR domain directly. Interestingly, Pxl1 has a second site for binding the Cdc15 SH3 domain. To understand the importance of these two Pxl1-Cdc15 interactions, we mapped and disrupted both. Disrupting the Pxl1-Cdc15 F-BAR domain interaction reduced Pxl1 levels in the CR, whereas disrupting Pxl1's interaction with the Cdc15 SH3 domain, did not. Unexpectedly, abolishing Pxl1-Cdc15 interaction greatly reduced but did not eliminate CR Pxl1 and did not significantly affect cytokinesis. These data point to another mechanism of Pxl1 CR recruitment and show that very little CR Pxl1 is sufficient for its cytokinetic function.

Recent Advances in Chronotherapy Targeting Respiratory Diseases.

Respiratory diseases contribute to a significant percentage of mortality and morbidity worldwide. The circadian rhythm is a natural biological process where our bodily functions align with the 24 h oscillation (sleep-wake cycle) process and are controlled by the circadian clock protein/gene. Disruption of the circadian rhythm could alter normal lung function. Chronotherapy is a type of therapy provided at specific time intervals based on an individual's circadian rhythm. This would allow the drug to show optimum action, and thereby modulate its pharmacokinetics to lessen unwanted or unintended effects. In this review, we deliberated on the recent advances employed in chrono-targeted therapeutics for chronic respiratory diseases.