Parkinson's Disease and Mitotherapy-Based Approaches towards α-Synucleinopathies.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain and the formation of intracellular protein aggregates known as Lewy bodies, of which a major component is the protein α-synuclein. Several studies have suggested that mitochondria play a central role in the pathogenesis of PD, encompassing both familial and sporadic forms of the disease. Mitochondrial dysfunction is attributed to bioenergetic impairment, increased oxidative stress, damage to mitochondrial DNA, and alteration in mitochondrial morphology. These alterations may contribute to improper functioning of the central nervous system and ultimately lead to neurodegeneration. The perturbation of mitochondrial function makes it a potential target, worthy of exploration for neuroprotective therapies and to improve mitochondrial health in PD. Thus, in the current review, we provide an update on mitochondria-based therapeutic approaches toward α-synucleinopathies in PD.

Sirtuins, a key regulator of ageing and age-related neurodegenerative diseases.

Sirtuins are Nicotinamide Adenine Dinucleotide (NAD+) dependent class ІΙΙ histone deacetylases enzymes (HDACs) present from lower to higher organisms such as bacteria (Sulfolobus solfataricus L. major), yeasts (Saccharomyces cerevisiae), nematodes (Caenorhabditis elegans), fruit flies (Drosophila melanogaster), humans (Homo sapiens sapiens), even in plants such as rice (Oryza sativa), thale cress (Arabidopsis thaliana), vine (Vitis vinifera L.) tomato (Solanum lycopersicum). Sirtuins play an important role in the regulation of various vital cellular functions during metabolism and ageing. It also plays a neuroprotective role by modulating several biological pathways such as apoptosis, DNA repair, protein aggregation, and inflammatory processes associated with ageing and neurodegenerative diseases. In this review, we have presented an updated Sirtuins and its role in ageing and age-related neurodegenerative diseases (NDDs). Further, this review also describes the therapeutic potential of Sirtuins and the use of Sirtuins inhibitor/activator for altering the NDDs disease pathology.

Synthetic and phytocompounds based dipeptidyl peptidase-IV (DPP-IV) inhibitors for therapeutics of diabetes.

Currently antidiabetic therapeutic strategies are mainly based on synthetic hypoglycemic agent. Antidiabetic drugs are associated with significant adverse effects of hypoglycemia, dysfunction of insulin and weight gain. Nowadays, the novel Dipeptidyl peptidase-IV (DPP-IV) inhibitors unique approach for the management of diabetes has been considered to be safe, as DPP-IV inhibitors reduce blood glucose level by monitoring hyperglycemia including positive effects on body weight as it remains neutral, improves glycated hemoglobin levels and do not induce hypoglycemia. Inhibitors help to protect degradation of Glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), gut hormones which helps to suppresses postprandial glucagon release, delay gastric emptying and regulate satiety. Therefore, the innovation of DPP-IV inhibitor based drugs regulates activity of incretin hormones such as GLP-1 and GIP. Commercially available DPP-IV inhibitors are chemically synthesized with good therapeutic value. However, the durability and long-term safety of DPP-IV inhibitors remains to be established. On the other hand, phytocompounds-based DPP-IV inhibitors are alternative and safe to use as compared to synthetic. Numerous novel antidiabetic compounds and group of compounds emerging in clinical development are through DPP-IV inhibition. This review summarized recent progress made on DPP-IV inhibitors from both synthetic as well as from natural sources.

Focal length calibration of an electrically tunable lens by digital holography.

The electrically tunable lens (ETL) is a novel current-controlled adaptive optical component which can continuously tune its focus in a specific range via changing its surface curvature. To quantitatively characterize its tuning power, here we assume the ETL to be a pure phase object and present a novel calibration method to dynamically measure its wavefront by use of digital holographic microscopy (DHM). The least squares method is then used to fit the radius of curvature of the wavefront. The focal length is obtained by substituting the radius into the Zemax model of the ETL. The behavior curve between the focal length of the ETL and its driven current is drawn, and a quadratic mathematic model is set up to characterize it. To verify our model, an ETL and offset lens combination is proposed and applied to ETL-based transport of intensity equation (TIE) phase retrieval microscopy. The experimental result demonstrates the calibration works well in TIE phase retrieval in comparison with the phase measured by DHM.

Drug repurposing for cancer.

In the dynamic landscape of cancer therapeutics, the innovative strategy of drug repurposing emerges as a transformative paradigm, heralding a new era in the fight against malignancies. This book chapter aims to embark on the comprehension of the strategic deployment of approved drugs for repurposing and the meticulous journey of drug repurposing from earlier times to the current era. Moreover, the chapter underscores the multifaceted and complex nature of cancer biology, and the evolving field of cancer drug therapeutics while emphasizing the mandate of drug repurposing to advance cancer therapeutics. Importantly, the narrative explores the latest tools, technologies, and cutting-edge methodologies including high-throughput screening, omics technologies, and artificial intelligence-driven approaches, for shaping and accelerating the pace of drug repurposing to uncover novel cancer therapeutic avenues. The chapter critically assesses the breakthroughs, expanding the repertoire of repurposing drug candidates in cancer, and their major categories. Another focal point of this book chapter is that it addresses the emergence of combination therapies involving repurposed drugs, reflecting a shift towards personalized and synergistic treatment approaches. The expert analysis delves into the intricacies of combinatorial regimens, elucidating their potential to target heterogeneous cancer populations and overcome resistance mechanisms, thereby enhancing treatment efficacy. Therefore, this chapter provides in-depth insights into the potential of repurposing towards bringing the much-needed big leap in the field of cancer therapeutics.

Drug repurposing for neurodegenerative diseases.

Neurodegenerative diseases (NDDs) are neuronal problems that include the brain and spinal cord and result in loss of sensory and motor dysfunction. Common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS) etc. The occurrence of these diseases increases with age and is one of the challenging problems among elderly people. Though, several scientific research has demonstrated the key pathologies associated with NDDs still the underlying mechanisms and molecular details are not well understood and need to be explored and this poses a lack of effective treatments for NDDs. Several lines of evidence have shown that NDDs have a high prevalence and affect more than a billion individuals globally but still, researchers need to work forward in identifying the best therapeutic target for NDDs. Thus, several researchers are working in the directions to find potential therapeutic targets to alter the disease pathology and treat the diseases. Several steps have been taken to identify the early detection of the disease and drug repurposing for effective treatment of NDDs. Moreover, it is logical that current medications are being evaluated for their efficacy in treating such disorders; therefore, drug repurposing would be an efficient, safe, and cost-effective way in finding out better medication. In the current manuscript we discussed the utilization of drugs that have been repurposed for the treatment of AD, PD, HD, MS, and ALS.

Framework for gradient integration by combining radial basis functions method and least-squares method.

A framework with a combination of the radial basis functions (RBFs) method and the least-squares integration method is proposed to improve the integration process from gradient to shape. The principle of the framework is described, and the performance of the proposed method is investigated by simulation. Improvement in accuracy is verified by comparing the result with the usual RBFs-based subset-by-subset stitching method. The proposed method is accurate, automatic, easily implemented, and robust and even works with incomplete data.

Well-Differentiated Papillary Mesothelial Tumor: An Unusual Radiologic Presentation: A Case Report.

Well-differentiated papillary mesothelial tumor (WDPMT) is an uncommon tumor, formerly named well-differentiated papillary mesothelioma in the 2015 World Health Organization classification. It has a characteristic papillary architecture, bland cytologic features, a tendency toward superficial spread without invasion, and a good prognosis due to its clinically indolent behavior with prolonged survival. Rare cases with superficial invasion are termed WDPMT with invasive foci. WDPMT occurs primarily in the peritoneum of reproductive-age women, but also rarely in the pleura. We report a case of a 60-year-old woman who developed WDPMT with minimal invasion in the pleura with atypical radiological features and a family history of mesothelioma and indirect asbestos exposure.

Synthetic receptors in medicine.

Cellular signaling is controlled by ligand receptor interaction and subsequent biochemical changes inside the cell. Manipulating receptors as per need that can be a strategy to alter the disease pathologies in various conditions. With recent advances in synthetic biology, now it is possible to engineer the artificial receptor "synthetic receptors." Synthetic receptors are the engineering receptors that have potential to alter the disease pathology by altering/manipulating the cellular signaling. Several synthetic receptors are being engineered that have shown positive regulation in several disease conditions. Thus, synthetic receptor-based strategy opens a new avenue in the medical field to cope up with various health issues. The current chapter summarizes updated information about the synthetic receptors and their applications in the medical field.

Epigenetic regulons in Alzheimer's disease.

Alzheimer's disease is one of the most prevalent forms of dementia that occur genetically or sporadically (with increasing age) in the population of 65 years and above. The pathological hallmarks of AD include the formation of extracellular senile plaques of amyloid beta peptides 42 (Aß42) and intracellular neurofibrillary tangles associated with hyperphosphorylated tau protein. AD has been reported as an outcome of multiple probabilistic factors such as age, lifestyle, oxidative stress, inflammation, insulin resistance, mitochondrial dysfunction, and epigenetics. Epigenetics are heritable changes in gene expression that give a phenotype without altering the DNA sequences. Epigenetic mechanisms include DNA methylation, hydroxymethylation, histone modifications, regulation of miRNAs and long non-coding RNAs, which are reported to be dysregulated in AD. Further, epigenetic mechanisms have been shown as a key player as they regulate memory development, where DNA methylation and post-translational modifications of histone tails are the prime epigenetic markers. Also, alterations of AD-related genes cause pathogenesis on the transcriptional level. In the current chapter, we summarize the role of epigenetics in the onset and progression of AD and the use of epigenetic therapeutics to ameliorate the constraints of AD.

Epigenetic control of heredity.

Epigenetics is the field of science that deals with the study of changes in gene function that do not involve changes in DNA sequence and are heritable while epigenetics inheritance is the process of transmission of epigenetic modifications to the next generation. It can be transient, intergenerational, or transgenerational. There are various epigenetic modifications involving mechanisms such as DNA methylation, histone modification, and noncoding RNA expression, all of which are inheritable. In this chapter, we summarize the information on epigenetic inheritance, its mechanism, inheritance studies on various organisms, factors affecting epigenetic modifications and their inheritance, and the role of epigenetic inheritance in the heritability of diseases.

Aging: Epigenetic modifications.

Aging is one of the most complex and irreversible health conditions characterized by continuous decline in physical/mental activities that eventually poses an increased risk of several diseases and ultimately death. These conditions cannot be ignored by anyone but there are evidences that suggest that exercise, healthy diet and good routines may delay the Aging process significantly. Several studies have demonstrated that Epigenetics plays a key role in Aging and Aging-associated diseases through methylation of DNA, histone modification and non-coding RNA (ncRNA). Comprehension and relevant alterations in these epigenetic modifications can lead to new therapeutic avenues of age-delaying contrivances. These processes affect gene transcription, DNA replication and DNA repair, comprehending epigenetics as a key factor in understanding Aging and developing new avenues for delaying Aging, clinical advancements in ameliorating aging-related diseases and rejuvenating health. In the present article, we have described and advocated the epigenetic role in Aging and associated diseases.

Structural and functional characteristics of the SARS-CoV-2 Omicron subvariant BA.2 spike protein.

The Omicron subvariant BA.2 has become the dominant circulating strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in many countries. Here, we have characterized structural, functional and antigenic properties of the full-length BA.2 spike (S) protein and compared replication of the authentic virus in cell culture and an animal model with previously prevalent variants. BA.2 S can fuse membranes slightly more efficiently than Omicron BA.1, but still less efficiently than other previous variants. Both BA.1 and BA.2 viruses replicated substantially faster in animal lungs than the early G614 (B.1) strain in the absence of pre-existing immunity, possibly explaining the increased transmissibility despite their functionally compromised spikes. As in BA.1, mutations in the BA.2 S remodel its antigenic surfaces, leading to strong resistance to neutralizing antibodies. These results suggest that both immune evasion and replicative advantage may contribute to the heightened transmissibility of the Omicron subvariants.

Structural and functional impact by SARS-CoV-2 Omicron spike mutations.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), bearing an unusually high number of mutations, has become a dominant strain in many countries within several weeks. We report here structural, functional, and antigenic properties of its full-length spike (S) protein with a native sequence in comparison with those of previously prevalent variants. Omicron S requires a substantially higher level of host receptor ACE2 for efficient membrane fusion than other variants, possibly explaining its unexpected cellular tropism. Mutations not only remodel the antigenic structure of the N-terminal domain of the S protein but also alter the surface of the receptor-binding domain in a way not seen in other variants, consistent with its remarkable resistance to neutralizing antibodies. These results suggest that Omicron S has acquired an extraordinary ability to evade host immunity by excessive mutations, which also compromise its fusogenic capability.

Structural and functional characteristics of SARS-CoV-2 Omicron subvariant BA.2 spike.

The Omicron subvariant BA.2 has become the dominant circulating strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in many countries. We have characterized structural, functional and antigenic properties of the full-length BA.2 spike (S) protein and compared replication of the authentic virus in cell culture and animal model with previously prevalent variants. BA.2 S can fuse membranes more efficiently than Omicron BA.1, mainly due to lack of a BA.1-specific mutation that may retard the receptor engagement, but still less efficiently than other variants. Both BA.1 and BA.2 viruses replicated substantially faster in animal lungs than the early G614 (B.1) strain in the absence of pre-existing immunity, possibly explaining the increased transmissibility despite their functionally compromised spikes. As in BA.1, mutations in the BA.2 S remodel its antigenic surfaces leading to strong resistance to neutralizing antibodies. These results suggest that both immune evasion and replicative advantage may contribute to the heightened transmissibility for the Omicron subvariants.

Dynamic three-dimensional sensing for specular surface with monoscopic fringe reflectometry.

Dynamic full-field three-dimensional sensing of specular reflective surfaces can be conveniently implemented with fringe reflection technique. A monoscopic fringe reflectometric system can be adopted as a simple measuring setup. With the assistance of the windowed Fourier ridges method as an advanced fringe demodulation technique, only one cross grating is needed to reconstruct the three-dimensional surface shape changes. A suitable calibration enables determination of the actual three-dimensional surface profile. Experimental results of water wave variations are shown to demonstrate the feasibility of the proposed approach.

Disposable flow cytometer with high efficiency in particle counting and sizing using an optofluidic lens.

Flow cytometers are widely applied to environmental monitoring, industrial testing, and biochemical studies. Integrating a flow cytometer into microfluidic networks helps to miniaturize the system and make it portable for field use. The integration of optical components, such as lenses, further improves the compactness and thus has been intensively studied recently. However, the current designs suffer from severe light scattering due to the roughness of the solid-based lens interface. In this Letter, we propose a flow cytometer using an optofluidic lens to focus the light beam. Benefiting from the smooth liquid-liquid lens interface and the refractive-index matching liquid as cladding streams, a light beam can be well focused without scattering. The variations of the signal peak values are reduced, owing to the small beam width at the beam waist. The device presents an efficient and accurate performance on both the counting and sizing of particles.

Tunable optofluidic aperture configured by a liquid-core/liquid-cladding structure.

Miniaturized and tunable optical components, such as the waveguide, lens, and prism, have been of great interest for lab-on-chip systems. This Letter reports an optofluidic aperture stop formed by the liquid-core/liquid-cladding flow. The aperture size can be tuned accordingly by adjusting the flow rates. Manipulation of the aperture size allows control of the amount of light passing through the corresponding optical system as well as the angular aperture on the image side. This optofluidic aperture enables lab-on-chip optical systems to have a greater flexibility and more functionalities.

Miro (Mitochondrial Rho GTPase), a key player of mitochondrial axonal transport and mitochondrial dynamics in neurodegenerative diseases.

Miro (mitochondrial Rho GTPases) a mitochondrial outer membrane protein, plays a vital role in the microtubule-based mitochondrial axonal transport, mitochondrial dynamics (fusion and fission) and Mito-Ca2+ homeostasis. It forms a major protein complex with Milton (an adaptor protein), kinesin and dynein (motor proteins), and facilitates bidirectional mitochondrial axonal transport such as anterograde and retrograde transport. By forming this protein complex, Miro facilitates the mitochondrial axonal transport and fulfills the neuronal energy demand, maintain the mitochondrial homeostasis and neuronal survival. It has been demonstrated that altered mitochondrial biogenesis, improper mitochondrial axonal transport, and mitochondrial dynamics are the early pathologies associated with most of the neurodegenerative diseases (NDs). Being the sole mitochondrial outer membrane protein associated with mitochondrial axonal transport-related processes, Miro proteins can be one of the key players in various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Thus, in the current review, we have discussed the evolutionarily conserved Miro proteins and its role in the pathogenesis of the various NDs. From this, we indicated that Miro proteins may act as a potential target for a novel therapeutic intervention for the treatment of various NDs.

Complications and Soft-Tissue Coverage After Complete Articular, Open Tibial Plafond Fractures.

OBJECTIVES: To evaluate the incidence of nonunion and wound complications after open, complete articular pilon fractures. Second, to study the effect that both timing of fixation and timing of flap coverage have on deep infection rates. DESIGN: Retrospective case series. SETTING: Three Academic Level 1 Trauma Centers. PATIENTS: One hundred sixty-one patients with open OTA/AO type 43C distal tibia fractures treated with open reduction internal fixation (ORIF) between 2002 and 2018. The mean (SD) age was 46 (14) years, 70% male, with median (interquartile range) follow-up of 2.1 (1.3-5.0) years (minimum 1 year). There were 133 (83%) type 3A and 28 (17%) type 3B open fractures. INTERVENTION: Fracture fixation: acute, primary (<24 hours) versus delayed, staged ORIF (>24 hours). Soft-tissue coverage: rotational or free flap. MAIN OUTCOME MEASUREMENT: Primary outcomes included deep infection and nonunion. Secondary outcomes included rates of soft-tissue coverage and reoperation. RESULTS: Acute fixation (<24 hours) was performed in 36 (22%) patients; 125 (78%) underwent delayed, staged fixation. Deep infection occurred in 27% patients and was associated with men (33% vs. 16%, P = 0.029), smoking (38% vs. 23%, P = 0.047), and type 3B fractures (39% vs. 25%, P = 0.046). Acute fixation of type 3A fractures demonstrated a higher rate of infection (38% vs. 20% P = 0.036) than delayed, staged fixation. In type 3B fractures, early flap coverage (<1 week) demonstrated a lower rate of infection (18% vs. 53%, P = 0.066) and 20% (vs. 43%) with a single-staged "fix and flap" procedure (P = 0.408). Nonunion occurred in 36 (22%) and was associated with deep infection (43% vs. 15%, P < 0.001). Fifteen (42%) were septic nonunions. Twenty-nine of the 36 (81%) nonunions achieved radiographic union after median (interquartile range) 27 (20-41) weeks and median (range) 1 (1-3) revision ORIF procedures. There was no difference in the rate of secondary union between septic and aseptic nonunions (85% vs. 86%, P = 1.00). There was a high rate of secondary procedures (47%): revision ORIF (17%), irrigation and debridement (15%), and removal of implants (11%). CONCLUSIONS: Complete articular, open pilon fractures are associated with a high rate of complications after ORIF. Early fixation carries a high risk of deep infection; however, early flap coverage for 3B fractures seems to play a protective role. We advocate for aggressive management including urgent surgical debridement and very early soft-tissue cover combined with definitive fixation during single procedure if possible. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.