Immunometabolic characteristics of Dendritic Cells and its significant modulation by mitochondria-associated signaling in the tumor microenvironment influence cancer progression.

Dendritic cells (DCs) mediated T-cell responses is critical to anti-tumor immunity. This study explores immunometabolic attributes of DC, emphasizing on mitochondrial association, in Tumor Microenvironment (TME) that regulate cancer progression. Conventional DC subtypes cross-present tumor-associated antigens to activate lymphocytes. However, plasmacytoid DCs participate in both pro- and anti-tumor signaling where mitochondrial reactive oxygen species (mtROS) play crucial role. CTLA-4, CD-47 and other surface-receptors of DC negatively regulates T-cell. Increased glycolysis-mediated mitochondrial citrate buildup and translocation to cytosol with augmented NADPH, enhances mitochondrial fatty acid synthesis fueling DCs. Different DC subtypes and stages, exhibit variable mitochondrial content, membrane potential, structural dynamics and bioenergetic metabolism regulated by various cytokine stimulation, e.g., GM-CSF, IL-4, etc. CD8α+ cDC1s augmented oxidative phosphorylation (OXPHOS) which diminishes at advance effector stages. Glutaminolysis in mitochondria supplement energy in DCs but production of kynurenine and other oncometabolites leads to immunosuppression. Mitochondria-associated DAMPs cause activation of cGAS-STING pathway and inflammasome oligomerization stimulating DC and T cells. In this study, through a comprehensive survey and critical analysis of the latest literature, the potential of DC metabolism for more effective tumor therapy is highlighted. This underscores the need for future research to explore specific therapeutic targets and potential drug candidates.

A Comprehensive Pan-Cancer Analysis of Cytochrome C Oxidase Assembly Factor 1 (COA1) Reveals Instrumental Role of Mitochondrial Protein Assembly in Cancer that Modulates Disease Progression and Prognostic Outcome.

Cytochrome c oxidase assembly factor 1 (COA1), a mitochondrial respiratory chain complex assembly factor protein of inner mitochondrial membrane (IMM), is involved in translating many mitochondrial components and assembling nuclear-encoded components within mitochondria. Given the lack of extensive research on COA1 in cancer, this study undertakes a comprehensive pan-cancer analysis of COA1, which is overexpressed across various cancer types, shedding light on its multifaceted role in tumorigenesis, prognosis, and tumor microenvironment (TME) modulation. Leveraging bioinformatics tools and public databases, we elucidated its potential as a diagnostic cancer biomarker as well as a target for novel anti-cancer therapeutics. Gene expression analysis using "TIMER2.0", "UALCAN" and "GEPIA2" platforms, supported by protein expression data, revealed a significant correlation between COA1 upregulation and poor prognosis in Kaplan-Meir analysis, underscoring its clinical relevance. Additionally, genetic mutation analysis of COA1 with the help of "cBioPortal" warrants further exploration into its functional significance. Moreover, our investigation of the tumor microenvironment unveiled the interplay of COA1 with fibroblast and T cell infiltration implicating the role of COA1 in the tumor immune microenvironment. Furthermore, COA1-related gene enrichment study in "GeneMANIA" and pathway cross-talk analysis with Gene Ontology (GO) gene sets established comprehensive clarifications about the molecular pathways and protein networks associated with COA1 deregulation. Overall, this study lays a sturdy foundation to support future research endeavors targeting COA1, unraveling the molecular mechanisms underlying COA1 deregulation, and exploring its therapeutic potential in cancer.

Primary Pituitary Abscess: Two Case Reports.

Introduction Pituitary abscess is a rare disorder that represents a small fraction of all pituitary lesions. In this report, we present two additional cases with unique features to promote awareness and prompt surgical intervention. Case Presentations A 42-year-old male presented with headache, photophobia, subjective fever, dizziness, imbalance, nausea, and vomiting. A pituitary hormone panel confirmed hypothyroidism and suggested central hypogonadism and secondary adrenal insufficiency. Magnetic resonance imaging (MRI) showed a large sellar mass measuring 2.5 cm × 1.8 cm × 1.6 cm (CC × XT × AP). A 76-year-old woman presented with several months of headaches and unsteady gait in the setting of a known previously asymptomatic sellar lesion, measuring 1.8 cm × 1.2 cm × 1.5 cm (XT × CC × AP). Repeat MRI demonstrated possible hemorrhage within the lesion. In both cases, a preliminary diagnosis of pituitary macroadenoma was made, but transsphenoidal surgery revealed an encapsulated abscess; cultures obtained from the abscesses stained for gram-positive bacteria. Conclusion Pituitary abscess is a rare, potentially life-threatening disorder that may be easily mistaken for other sellar lesions. In this review, we contribute two additional cases of pituitary abscesses to increase awareness and emphasize the importance of proper diagnosis and management.

A case of pituitary apoplexy mimicking viral meningitis.

Pituitary apoplexy (PA) is a clinical syndrome caused by ischemia or hemorrhage of the pituitary gland, typically in the context of an adenoma. It typically presents with a thunderclap headache and sterile cerebral spinal fluid (CSF). The authors identify a case of PA, which initially presented with the signs and symptoms of viral meningitis. Presentation of Case: A 44-year-old man presented to the emergency department with headache, nuchal rigidity, fever, and delirium. The patient reported a 10-year history of chronic that were partially responsive to acetaminophen. Four days after admission, the patient developed right-sided cranial nerve III, IV, and VI palsies. Labs revealed anemia and hyponatremia. The CSF was leukocytic, lymphocyte-predominant, and had elevated protein. In addition to these results, negative CSF bacterial cultures led the care team to believe this case was viral meningoencephalitis. Routine MRI of the brain at presentation revealed a 3.1×2.5×3.2 (craniocaudal×anterior posterior×transverse) expansile mass centered within the sella turcica. An endocrine workup revealed hypopituitarism. The diagnosis of PA was then made. A microscopic transsphenoidal resection of the sellar mass was performed, and histopathologic analysis confirmed necrotic pituitary adenoma tissue. Following an uncomplicated procedure, the patient recovered fully from his cranial nerve palsies and continues to do well. Discussion: Because life-threatening hypotension from acute adrenal insufficiency can be caused by PA, timely diagnosis is crucial. When a patient presents with meningism, PA should be included in the differential diagnosis. Conclusion: This report illustrates a case of PA presenting with symptoms and a CSF profile classically associated with viral meningitis.

Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight.

SARS-CoV-2 is a positive-strand RNA virus that infects humans through the nasopharyngeal and oral route causing COVID-19. Scientists left no stone unturned to explore a targetable key player in COVID-19 pathogenesis against which therapeutic interventions can be initiated. This article has attempted to review, coordinate and accumulate the most recent observations in support of the hypothesis predicting the altered state of mitochondria concerning mitochondrial redox homeostasis, inflammatory regulations, morphology, bioenergetics and antiviral signalling in SARS-CoV-2 infection. Mitochondria is extremely susceptible to physiological as well as pathological stimuli, including viral infections. Recent studies suggest that SARS-CoV-2 pathogeneses alter mitochondrial integrity, in turn mitochondria modulate cellular response against the infection. SARS-CoV-2 M protein inhibited mitochondrial antiviral signalling (MAVS) protein aggregation in turn hinders innate antiviral response. Viral open reading frames (ORFs) also play an instrumental role in altering mitochondrial regulation of immune response. Notably, ORF-9b and ORF-6 impair MAVS activation. In aged persons, the NLRP3 inflammasome is over-activated due to impaired mitochondrial function, increased mitochondrial reactive oxygen species (mtROS), and/or circulating free mitochondrial DNA, resulting in a hyper-response of classically activated macrophages. This article also tries to understand how mitochondrial fission-fusion dynamics is affected by the virus. This review comprehends the overall mitochondrial attribute in pathogenesis as well as prognosis in patients infected with COVID-19 taking into account pertinent in vitro, pre-clinical and clinical data encompassing subjects with a broad range of severity and morbidity. This endeavour may help in exploring novel non-canonical therapeutic strategies to COVID-19 disease and associated complications.

Immunometabolic attributes and mitochondria-associated signaling of Tumor-Associated Macrophages in tumor microenvironment modulate cancer progression.

Macrophages are specialized immune cells, which have the capacity to phagocytize and destroy the target cells, including tumor cells. Some macrophages, however on their way to devour the cancer cells undergo a change due to a complex set of signaling pathways. They are induced to change into a polarized state known as M2. The M2 macrophages help in metastasis, tumor suppression, and angiogenesis. The macrophage which gets associated with this TME, are referred to as tumor-associated macrophages (TAMs). TAMS undergo a metabolic reprogramming toward oxidative metabolism for bioenergetic purposes (OXPHOS), fatty acid oxidation (FAO), decreased glycolysis, decreased metabolism via the PPP, and upregulation of arginase 1 (ARG1) which triggers immunosuppressive pro-tumor signaling in the tumor microenvironment (TME) in which mitochondria plays an instrumental role. Reports have suggested that a complex series of interactions and exchange of materials, such as cytokines, metabolic intermediates and sometimes even transfer of mitochondria take place between TAMS and other TME components most importantly cancer cells that reprogram their metabolism to encourage cell growth, division, epithelial to mesenchymal transition, that ultimately play an important role in tumor progression. This review will try to focus on the crosstalk between the TAMs with several other components of TME, what instrumental role mitochondria play in that and also try to explore some of the therapeutic options available in cancer patients.

Elastocaloric determination of the phase diagram of Sr2RuO4.

One of the main developments in unconventional superconductivity in the past two decades has been the discovery that most unconventional superconductors form phase diagrams that also contain other strongly correlated states. Many systems of interest are therefore close to more than one instability, and tuning between the resultant ordered phases is the subject of intense research1. In recent years, uniaxial pressure applied using piezoelectric-based devices has been shown to be a particularly versatile new method of tuning2,3, leading to experiments that have advanced our understanding of the fascinating unconventional superconductor Sr2RuO4 (refs. 4-9). Here we map out its phase diagram using high-precision measurements of the elastocaloric effect in what we believe to be the first such study including both the normal and the superconducting states. We observe a strong entropy quench on entering the superconducting state, in excellent agreement with a model calculation for pairing at the Van Hove point, and obtain a quantitative estimate of the entropy change associated with entry to a magnetic state that is observed in proximity to the superconductivity. The phase diagram is intriguing both for its similarity to those seen in other families of unconventional superconductors and for extra features unique, so far, to Sr2RuO4.

Balanced cytokine upregulation by diluted ethanolic extract of Bryonia alba in Delta SARS-CoV-2 Spike protein RBD-induced pathogenesis in Gallus gallus embryo.

Background: Bryonia alba extract is a well-known drug which is being utilized as phytomedicines and homoeopathic preparations since more than two centuries. This medicine is frequently used in clinical practice for flu-like conditions, respiratory tract infections, and gastrointestinal diseases, as evidenced by old literature and historical records. The plant contains Bryonicin, Bryonolic acid, Bryodin, Cucurbitacin, etc. The alkaloids in Bryonia alba have been discovered to be a powerful heme-oxygenase-1 inhibitor, which could help reduce oxidative stress during SARS-CoV-2 pathogenesis. During three waves of SARS-CoV-2, extracts of Bryonia alba were used; however, the actual scientific explanation for its mechanism of action is still unknown. In this experiment, we studied cytokine changes by diluted Bryonia alba extract in Delta SARS-CoV-2 spike protein RBD-induced pathogenesis, in fertilized chick (Gallus gallus domesticus) embryos. Results: The recombinant Delta SARS-CoV-2 spike RBD protein was inoculated in 14-day-old chick (Gallus gallus domesticus) embryos along with control, pre-, and post-treatment sets with diluted Bryonia extract. After 48 h, allantoic fluids were collected and stored at - 20 °C for study of different cytokines. Histological changes of the liver were also studied in each animal. Diluted Bryonia extract upregulated IFN-α and IL-10 markedly. In pre-treatment set, IFN-α, IL-8, IL-10, and IL-1ß were markedly decreased, while in the post-treatment set IL-6, IL-10, IL-8, and TGFß1 were significantly decreased, with a tendency of more anti-inflammatory surge than pro-inflammatory cytokines. Conclusions: This experiment indicated an immunomodulatory role of diluted ethanolic extract of Bryonia particularly in the post-treatment set, decreasing pro-inflammatory cytokines with beneficial effect.

Biomolecular Modeling and Simulation: A Prospering Multidisciplinary Field.

We reassess progress in the field of biomolecular modeling and simulation, following up on our perspective published in 2011. By reviewing metrics for the field's productivity and providing examples of success, we underscore the productive phase of the field, whose short-term expectations were overestimated and long-term effects underestimated. Such successes include prediction of structures and mechanisms; generation of new insights into biomolecular activity; and thriving collaborations between modeling and experimentation, including experiments driven by modeling. We also discuss the impact of field exercises and web games on the field's progress. Overall, we note tremendous success by the biomolecular modeling community in utilization of computer power; improvement in force fields; and development and application of new algorithms, notably machine learning and artificial intelligence. The combined advances are enhancing the accuracy andscope of modeling and simulation, establishing an exemplary discipline where experiment and theory or simulations are full partners.

One-component order parameter in URu2Si2 uncovered by resonant ultrasound spectroscopy and machine learning.

The unusual correlated state that emerges in URu2Si2 below T HO = 17.5 K is known as "hidden order" because even basic characteristics of the order parameter, such as its dimensionality (whether it has one component or two), are "hidden." We use resonant ultrasound spectroscopy to measure the symmetry-resolved elastic anomalies across T HO. We observe no anomalies in the shear elastic moduli, providing strong thermodynamic evidence for a one-component order parameter. We develop a machine learning framework that reaches this conclusion directly from the raw data, even in a crystal that is too small for traditional resonant ultrasound. Our result rules out a broad class of theories of hidden order based on two-component order parameters, and constrains the nature of the fluctuations from which unconventional superconductivity emerges at lower temperature. Our machine learning framework is a powerful new tool for classifying the ubiquitous competing orders in correlated electron systems.

Spatial control of heavy-fermion superconductivity in CeIrIn5.

Although crystals of strongly correlated metals exhibit a diverse set of electronic ground states, few approaches exist for spatially modulating their properties. In this study, we demonstrate disorder-free control, on the micrometer scale, over the superconducting state in samples of the heavy-fermion superconductor CeIrIn5 We pattern crystals by focused ion beam milling to tailor the boundary conditions for the elastic deformation upon thermal contraction during cooling. The resulting nonuniform strain fields induce complex patterns of superconductivity, owing to the strong dependence of the transition temperature on the strength and direction of strain. These results showcase a generic approach to manipulating electronic order on micrometer length scales in strongly correlated matter without compromising the cleanliness, stoichiometry, or mean free path.

Simple quadratic magneto-optic Kerr effect measurement system using permanent magnets.

In recent times, quadratic magneto-optic Kerr effect (QMOKE) is emerging as an important experimental tool to investigate higher-order spin-orbit interactions in magnetic thin films and heterostructures. We have designed and constructed a simple, cost-effective QMOKE measurement system using permanent magnets. The permanent magnets are mounted on the inner surface of a cylindrical ferromagnetic yoke which can be rotated about its axis. Our system is sensitive to both the quadratic and linear MOKE signals. We use rotating field method to extract the QMOKE components in saturation. This system is capable of extracting the QMOKE signal from single crystals and thin film samples. Here we present the construction and working of the QMOKE measurement system using permanent magnets and report, for the first time, the QMOKE signal from Fe3O4 single crystal.