The diagnostic conundrum in necrotizing otitis externa.

Necrotizing otitis externa (NOE) is an aggressive and fast-evolving infection of the external auditory canal. Late diagnoses and untreated cases can lead to severe, even fatal consequences and so early diagnosis and treatment are paramount. NOE is a notoriously challenging diagnosis to make. It is therefore important to understand what diagnostic modalities are available and how otolaryngologists can use them to accurately treat such an aggressive disease. This review aims to evaluate the different diagnostic options available in NOE and discuss their advantages and limitations, thus, providing an up-to-date picture of the multimodal approach required in the diagnosis of this disease.

Evaluation of the Efficacy of LASER, Desensitizing Agents, and their Combined Effect on Dentinal Hypersensitivity in Bicuspids: In Vitro Study.

Aim: This study aimed to know the potential of diode light amplification by stimulated emission of radiation (LASER) and desensitizing agents on blocking the dentinal tubules, which may further help in reducing the most common dental problem named dentinal hypersensitivity (DH). Materials and Methods: Sixty human permanent bicuspids were selected, and preparation was performed in the cervical region measuring 2.5 mm × 2.5 mm × 2.5 mm, followed by acid etching for 15 seconds. These are then divided according to the groups mentioned: group 1-nano-hydroxyapatite (HA) was applied for 15 minutes; group 2-biosilicate was applied for 15 minutes; group 3-diode LASER application was performed twice for 60 seconds in noncontact mode; group 4-nano-HA plus diode LASER application; and group 5-biosilicate plus diode LASER application. The same procedure was followed on the 1st, 7th, and 14th days and then rinsed and stored in artificial saliva, and the saliva was changed every 24 hours. The dentinal tubular occlusion was observed under a scanning electron microscope (SEM) after the 14th day. Result: The maximum dentinal tubular occlusion was observed in group 4, where nano-HA and diode LASER application was performed. Conclusion: All the investigated treatment groups have promising occluding potential, but the maximum was found in group 4 >group 5 >group 3 >group 1 >group 2. LASER plus desensitizing together prove to be potent and effective in reducing dentinal tubular diameter.

Mitochondria in biology and medicine - 2023.

Mitochondria are an indispensable part of the cell that plays a crucial role in regulating various signaling pathways, energy metabolism, cell differentiation, proliferation, and cell death. Since mitochondria have their own genetic material, they differ from their nuclear counterparts, and dysregulation is responsible for a broad spectrum of diseases. Mitochondrial dysfunction is associated with several disorders, including neuro-muscular disorders, cancer, and premature aging, among others. The intricacy of the field is due to the cross-talk between nuclear and mitochondrial genes, which has also improved our knowledge of mitochondrial functions and their pathogenesis. Therefore, interdisciplinary research and communication are crucial for mitochondrial biology and medicine due to the challenges they pose for diagnosis and treatment. The ninth annual conference of the Society for Mitochondria Research and Medicine (SMRM)- India, titled "Mitochondria in Biology and Medicine" was organized at the Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India, on June 21-23, 2023. The latest advancements in the field of mitochondrial biology and medicine were discussed at the conference. In this article, we summarize the entire event for the benefit of researchers working in the field of mitochondrial biology and medicine.

Powering prescription: Mitochondria as "Living Drugs" - Definition, clinical applications, and industry advancements.

Mitochondria's role as engines and beacons of metabolism and determinants of cellular health is being redefined through their therapeutic application as "Living Drugs" (LDs). Artificial mitochondrial transfer/transplant (AMT/T), encompassing various techniques to modify, enrich, or restore mitochondria in cells and tissues, is revolutionizing acellular therapies and the future of medicine. This article proposes a necessary definition for LDs within the Advanced Therapeutic Medicinal Products (ATMPs) framework. While recognizing different types of LDs as ATMPs, such as mesenchymal stem cells (MSCs) and chimeric antigen receptor T (CAR T) cells, we focus on mitochondria due to their unique attributes that distinguish them from traditional cell therapies. These attributes include their inherent living nature, diverse sources, industry applicability, validation, customizability for therapeutic needs, and their capability to adapt and respond within recipient cells. We trace the journey from initial breakthroughs in AMT/T to the current state-of-the-art applications by emerging innovative companies, highlighting the need for manufacturing standards to navigate the transition of mitochondrial therapies from concept to clinical practice. By providing a comprehensive overview of the scientific, clinical, and commercial landscape of mitochondria as LDs, this article contributes to the essential dialogue among regulatory agencies, academia, and industry to shape their future in medicine.

To Evaluate the Antimicrobial Activity of PRP and PRF with and without Nanosilver.

Aim: To evaluate the antimicrobial activity of PRP and PRF with and without nanosilver. Materials and Methods: The materials were tested in powdered form is nanosilver. The nanosilver particles was mixed to form with PRP and PRF so as to placed in a wells followed the groups are experimental groups; Group I: PRP + nanosilver particles, Group II: PRF + nanosilver and control group: PRP and PRF and normal saline. Silver nanoparticles was tested at concentrations of 50 µ gram per mL. The powder was prepared for each group with identical amount of the powder (milligram/mg) and then mixed with 1 milliliter liquid. The plates are then incubated at 37°C under appropriate atmospheric conditions (80% N2, 10% CO2, 10% H2) for 24 hours, 48 hours, and 72 hours under anaerobic conditions in a CO2 incubator. The diameters of the zones of bacterial and fungal growth inhibition around the wells containing the test substances are then recorded after the period of incubation. The inhibitory zone determined in millimeter by measuring scale the shortest distance between the outer margin of the well and initial microbial as well as fungal growth. The experiments were performed 20 times and the mean and standard deviations of the inhibitory zones were calculated. Result: Platelet rich fibrin is mixed with nanosilver particles showed higher antimicrobial efficacy than platelet rich plasma with nanosilver and simple platelet rich plasma and platelet rich fibrin are equivalent when it is placed against the anaerobic bacteria E.faecalis and yeast like fungi Candida albicans, respectively. Conclusion: Groups presented with antimicrobial efficacy in this order- Group IV > Group II > Group III > Group I.

Inferring Recombination Events in SARS-CoV-2 Variants In Silico.

Over the last 34 months, at least 10 severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) distinct variants have evolved. Among these, some were more infectious while others were not. These variants may serve as candidates for identification of the signature sequences linked to infectivity and viral transgressions. Based on our previous hijacking and transgression hypothesis, we aimed to investigate whether SARS-CoV-2 sequences associated with infectivity and trespassing of long noncoding RNAs (lncRNAs) provide a possible recombination mechanism to drive the formation of new variants. This work involved a sequence and structure-based approach to screen SARS-CoV-2 variants in silico, taking into account effects of glycosylation and links to known lncRNAs. Taken together, the findings suggest that transgressions involving lncRNAs may be linked with changes in SARS-CoV-2-host interactions driven by glycosylation events.

Exploring the role of mitochondria transfer/transplant and their long-non-coding RNAs in regenerative therapies for skin aging.

Advancing age and environmental stressors lead to mitochondrial dysfunction in the skin, inducing premature aging, impaired regeneration, and greater risk of cancer. Cells rely on the communication between the mitochondria and the nucleus by tight regulation of long non-coding RNAs (lncRNAs) to avoid premature aging and maintain healthy skin. LncRNAs act as key regulators of cell proliferation, differentiation, survival, and maintenance of skin structure. However, research on how the lncRNAs are dysregulated during aging and due to stressors is needed to develop therapies to regenerate skin's function and structure. In this article, we discuss how age and environmental stressors may alter lncRNA homeodynamics, compromising cell survival and skin health, and how these factors may become inducers of skin aging. We describe skin cell types and how they depend on mitochondrial function and lncRNAs. We also provide a list of mitochondria localized and nuclear lncRNAs that can serve to better understand skin aging. Using bioinformatic prediction tools, we predict possible functions of lncRNAs based on their subcellular localization. We also search for experimentally determined protein interactions and the biological processes involved. Finally, we provide therapeutic strategies based on gene editing and mitochondria transfer/transplant (AMT/T) to restore lncRNA regulation and skin health. This article offers a unique perspective in understanding and defining the therapeutic potential of mitochondria localized lncRNAs (mt-lncRNAs) and AMT/T to treat skin aging and related diseases.

Severe acute respiratory syndrome coronaviruses contributing to mitochondrial dysfunction: Implications for post-COVID complications.

Mitochondria play a central role in oxidative phosphorylation (OXPHOS), bioenergetics linked with ATP production, fatty acids biosynthesis, calcium signaling, cell cycle regulation, apoptosis, and innate immune response. Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infection manipulates the host cellular machinery for its survival and replication in the host cell. The infectiaon causes perturbed the cellular metabolism that favours viral replication leading to mitochondrial dysfunction and chronic inflammation. By localizing to the mitochondria, SARS CoV proteins increase reactive oxygen species (ROS) levels, perturbation of Ca2+ signaling, changes in mtDNA copy number, mitochondrial membrane potential (MMP), mitochondrial mass, and induction of mitophagy. These proteins also influence the fusion and fission kinetics, size, structure, and distribution of mitochondria in the infected host cells. This results in compromised bioenergetics, altered metabolism, and innate immune signaling, and hence can be a key player in determining the outcome of SARS-CoV infection. SARS-CoV infection contributes to stress and activates apoptotic pathways. This review summarizes how mitochondrial function and dynamics are affected by SARS-CoV and how the mitochondria-SARS-CoV interaction benefits viral survival and growth by evading innate host immunity. We also highlight how the SARS-CoV-mediated mitochondrial dysfunction contributes to post-COVID complications. Besides, a discussion on targeting virus-mitochondria interactions as a therapeutic strategy is presented.

Advancing mitochondria as a therapeutic agent.

This article intends to provide an update of the needs in the field working in the artificial mitochondrial transfer/transplant (AMT/T), and an overview of the highlights from the articles in the special issue "Advances of Mitochondria as a therapeutic agent". In the last 4 decades, scientists have developed innovative therapeutic applications based on the AMT/T, inspired by the natural transfer of mitochondria between cells to repair cellular damage or treat diseases. The clinical application of AMT has become the priority for the field involving the replacement or augmentation of healthy mitochondria in the harmed tissue, especially in the treatment of organ ischemia-reperfusion injury. However, we remark in our article that key questions remain to be answered such as which one is the best isolation protocol, tissue or cell source for isolation, and others of great importance to move the field forward.

The role of mitochondria in the pathogenesis of Kawasaki disease.

Kawasaki disease is a systemic vasculitis, especially of the coronary arteries, affecting children. Despite extensive research, much is still unknown about the principal driver behind the amplified inflammatory response. We propose mitochondria may play a critical role. Mitochondria serve as a central hub, influencing energy generation, cell proliferation, and bioenergetics. Regulation of these biological processes, however, comes at a price. Release of mitochondrial DNA into the cytoplasm acts as damage-associated molecular patterns, initiating the development of inflammation. As a source of reactive oxygen species, they facilitate activation of the NLRP3 inflammasome. Kawasaki disease involves many of these inflammatory pathways. Progressive mitochondrial dysfunction alters the activity of immune cells and may play a role in the pathogenesis of Kawasaki disease. Because they contain their own genome, mitochondria are susceptible to mutation which can propagate their dysfunction and immunostimulatory potential. Population-specific variants in mitochondrial DNA have also been linked to racial disparities in disease risk and treatment response. Our objective is to critically examine the current literature of mitochondria's role in coordinating proinflammatory signaling pathways, focusing on potential mitochondrial dysfunction in Kawasaki disease. No association between impaired mitochondrial function and Kawasaki disease exists, but we suggest a relationship between the two. We hypothesize a framework of mitochondrial determinants that may contribute to ethnic/racial disparities in the progression of Kawasaki disease.

ROCK2 inhibition: A futuristic approach for the management of Alzheimer's disease.

Neurons depend on mitochondrial functions for membrane excitability, neurotransmission, and plasticity. Mitochondrial dynamics are important for neural cell maintenance. To maintain mitochondrial homeostasis, lysosomes remove dysfunctional mitochondria through mitophagy. Mitophagy promotes mitochondrial turnover and prevents the accumulation of dysfunctional mitochondria. In many neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), mitophagy is disrupted in neurons. Mitophagy is regulated by several proteins; recently, Rho-associated coiled-coil containing protein kinase 2 (ROCK2) has been suggested to negatively regulate the Parkin-dependent mitophagy pathway. Thus, ROCK2 inhibition may be a promising therapy for NDDs. This review summarizes the mitophagy pathway, the role of ROCK2 in Parkin-dependent mitophagy regulation, and mitophagy impairment in the pathology of AD. We further discuss different ROCK inhibitors (synthetic drugs, natural compounds, and gene therapy-based approaches) and examine their effects on triggering neuronal growth and neuroprotection in AD and other NDDs. This comprehensive overview of the role of ROCK in mitophagy inhibition provides a possible explanation for the significance of ROCK inhibitors in the therapeutic management of AD and other NDDs.

Impaired Mitochondria Promote Aging-Associated Sebaceous Gland Dysfunction and Pathology.

Mitochondrial dysfunction is one of the hallmarks of aging. Changes in sebaceous gland (SG) function and sebum production have been reported during aging. This study shows the direct effects of mitochondrial dysfunction on SG morphology and function. A mitochondrial DNA (mtDNA) depleter mouse was used as a model for introducing mitochondrial dysfunction in the whole animal. The effects on skin SGs and modified SGs of the eyelid, lip, clitoral, and preputial glands were characterized. The mtDNA depleter mice showed gross morphologic and histopathologic changes in SGs associated with increased infiltration by mast cells, neutrophils, and polarized macrophages. Consistently, there was increased expression of proinflammatory cytokines. The inflammatory changes were associated with abnormal sebocyte accumulation of lipid, defective sebum delivery at the skin surface, and the up-regulation of key lipogenesis-regulating genes and androgen receptor. The mtDNA depleter mice expressed aging-associated senescent marker. Increased sebocyte proliferation and aberrant expression of stem cell markers were observed. These studies provide, for the first time, a causal link between mitochondrial dysfunction and abnormal sebocyte function within sebaceous and modified SGs throughout the whole body of the animal. They suggest that mtDNA depleter mouse may serve as a novel tool to develop targeted therapeutics to address SG disorders in aging humans.

A comprehensive SARS-CoV-2 and COVID-19 review, Part 1: Intracellular overdrive for SARS-CoV-2 infection.

COVID-19, the disease caused by SARS-CoV-2, has claimed approximately 5 million lives and 257 million cases reported globally. This virus and disease have significantly affected people worldwide, whether directly and/or indirectly, with a virulent pathogen that continues to evolve as we race to learn how to prevent, control, or cure COVID-19. The focus of this review is on the SARS-CoV-2 virus' mechanism of infection and its proclivity at adapting and restructuring the intracellular environment to support viral replication. We highlight current knowledge and how scientific communities with expertize in viral, cellular, and clinical biology have contributed to increase our understanding of SARS-CoV-2, and how these findings may help explain the widely varied clinical observations of COVID-19 patients.

Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster.

Rare actinomycetes represent an underexploited source of new bioactive compounds. Here, we report the use of a targeted metabologenomic approach to identify piperazyl compounds in the rare actinomycete Lentzea flaviverrucosa DSM 44664. These efforts to identify molecules that incorporate piperazate building blocks resulted in the discovery and structural elucidation of two dimeric biaryl-cyclohexapeptides, petrichorins A and B. Petrichorin B is a symmetric homodimer similar to the known compound chloptosin, but petrichorin A is unique among known piperazyl cyclopeptides because it is an asymmetric heterodimer. Due to the structural complexity of petrichorin A, solving its structure required a combination of several standard chemical methods plus in silico modeling, strain mutagenesis, and solving the structure of its biosynthetic intermediate petrichorin C for confident assignment. Furthermore, we found that the piperazyl cyclopeptides comprising each half of the petrichorin A heterodimer are made via two distinct nonribosomal peptide synthetase (NRPS) assembly lines, and the responsible NRPS enzymes are encoded within a contiguous biosynthetic supercluster on the L. flaviverrucosa chromosome. Requiring promiscuous cytochrome p450 crosslinking events for asymmetric and symmetric biaryl production, petrichorins A and B exhibited potent in vitro activity against A2780 human ovarian cancer, HT1080 fibrosarcoma, PC3 human prostate cancer, and Jurkat human T lymphocyte cell lines with IC50 values at low nM levels. Cyclic piperazyl peptides and their crosslinked derivatives are interesting drug leads, and our findings highlight the potential for heterodimeric bicyclic peptides such as petrichorin A for inclusion in future pharmaceutical design and discovery programs.

COVID-19: Impact on linguistic and genetic isolates of India.

The rapid expansion of coronavirus SARS-CoV-2 has impacted various ethnic groups all over the world. The burden of infectious diseases including COVID-19 are generally reported to be higher for the Indigenous people. The historical knowledge have also suggested that the indigenous populations suffer more than the general populations in the pandemic. Recently, it has been reported that the indigenous groups of Brazil have been massively affected by COVID-19. Series of studies have shown that many of the indigenous communities reached at the verge of extinction due to this pandemic. Importantly, South Asia also has several indigenous and smaller communities, that are living in isolation. Till date, despite the two consecutive waves in India, there is no report on the impact of COVID-19 for indigenous tribes. Since smaller populations experiencing drift may have greater risk of such pandemic, we have analysed Runs of Homozygosity (ROH) among South Asian populations and identified several populations with longer homozygous segments. The longer runs of homozygosity at certain genomic regions may increases the susceptibility for COVID-19. Thus, we suggest extreme careful management of this pandemic among isolated populations of South Asia.

The Omic Insights on Unfolding Saga of COVID-19.

The year 2019 has seen an emergence of the novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease of 2019 (COVID-19). Since the onset of the pandemic, biological and interdisciplinary research is being carried out across the world at a rapid pace to beat the pandemic. There is an increased need to comprehensively understand various aspects of the virus from detection to treatment options including drugs and vaccines for effective global management of the disease. In this review, we summarize the salient findings pertaining to SARS-CoV-2 biology, including symptoms, hosts, epidemiology, SARS-CoV-2 genome, and its emerging variants, viral diagnostics, host-pathogen interactions, alternative antiviral strategies and application of machine learning heuristics and artificial intelligence for effective management of COVID-19 and future pandemics.

Non-linear Response to Cell Number Revealed and Eliminated From Long-Term Tracheid Measurements of Scots Pine in Southern Siberia.

Dendroclimatic research offers insight into tree growth-climate response as a solution to the forward problem and provides reconstructions of climatic variables as products of the reverse problem. Methodological developments in dendroclimatology have led to the inclusion of a variety of tree growth parameters in this field. Tree-ring traits developed during short time intervals of a growing season can potentially provide a finer temporal scale of both dendroclimatic applications and offer a better understanding of the mechanisms of tree growth reaction to climatic variations. Furthermore, the transition from classical dendroclimatic studies based on a single integral variable (tree-ring width) to the modern multitude of quantitative variables (e.g., wood anatomical structure) adds a lot of complexity, which mainly arises from intrinsic feedbacks between wood traits and muddles seasonality of registered climatic signal. This study utilized life-long wood anatomical measurements of 150- to 280-year-old trees of Pinus sylvestris L. growing in a moisture-sensitive habitat of the forest-steppe of Southern Siberia (Russia) to investigate and eliminate legacy effect from cell production in tracheid traits. Anatomical parameters were calculated to describe the results of the three main subsequent stages of conifer xylem tracheid development, namely, cell number per radial file in the ring, mean and maximum cell radial diameter, and mean and maximum cell-wall thickness. Although tree-ring width was almost directly proportional to cell number, non-linear relationships with cell number were revealed in tracheid measurements. They exhibited a stronger relationship in the areas of narrow rings and stable anatomical structure in wider rings. The exponential models proposed in this study demonstrated these relationships in numerical terms with morphometric meaning. The ratio of anatomical measurements to their modeled values was used to develop long-term anatomical chronologies, which proved to retain information about climatic fluctuations independent of tree-ring width (cell number), despite decreased common signal.

SARS-CoV-2 transgressing LncRNAs uncovers the known unknowns.

SARS-CoV-2 harbors many known unknown regions in the form of hypothetical open reading frames (ORFs). Although the mechanisms underlying the disease pathogenesis are not clearly understood, molecules such as long noncoding RNAs (lncRNAs) play a key regulatory role in the viral pathogenesis from endocytosis. We asked whether or not the lncRNAs in the host are associated with the viral proteins and argue that lncRNA-mRNAs molecules related to viral infection may regulate SARS-CoV-2 pathogenesis. Toward the end of the perspective, we provide challenges and insights into investigating these transgression pathways.

Mitochondrial respiration is controlled by Allostery, Subunit Composition and Phosphorylation Sites of Cytochrome c Oxidase: A trailblazer's tale - Bernhard Kadenbach.

In memoriam of Bernhard Kadenbach: Although the main focus of his research was the structure, function, and regulation of mitochondrial cytochrome c oxidase (CytOx), he earlier studied the mitochondrial phosphate carrier and found an essential role of cardiolipin. Later, he discovered tissue-specific and developmental-specific protein isoforms of CytOx. Defective activity of CytOx is found with increasing age in human muscle and neuronal cells resulting in mitochondrial diseases. Kadenbach proposed a theory on the cause of oxidative stress, aging, and associated diseases stating that allosteric feedback inhibition of CytOx at high mitochondrial ATP/ADP ratios is essential for healthy living while stress-induced reversible dephosphorylation of CytOx results in the formation of excessive reactive oxygen species that trigger degenerative diseases. This article summarizes the main discoveries of Kadenbach related to mammalian CytOx and discusses their implications for human disease.