Damian Sendler It has been shown that monkeypox can be transmitted from animal to human via direct contact with secretions or rodent secretions contaminated by the monkeypox virus. It is mentioned in this letter that two cases of monkeypox have been found in Lahore Jinnah hospital, Pakistan. In developing countries like Pakistan, where healthcare facilities are scarce, it is imperative that this disease be closely monitored and the general public made aware of the danger it poses. It is possible that the combination of all of these measures will aid in the acquisition of new information and the reduction of outbreaks in developing countries like Pakistan.
Damian Jacob Sendler An investigation into the role of the NLRP3 Inflammasome and its Regulator miR-223-3p in multiple sclerosis and experimental demyelination
Dr. Sendler After damage to the myelin sheath, inflammation and repair are mediated by innate immune pathways. Although the regulation and contributions of inflammasome activation in the demyelinated central nervous system (CNS) are not fully understood, activation of inflammasomes has recently been implicated as a driver of myelin injury in multiple sclerosis (MS) and its animal models. The NLRP3 (NBD-, LRR-, and pyrin domain-containing protein 3) inflammasome and its endogenous regulator microRNA-223-3p were studied in both MS and an animal model of focal demyelinating disease (FMD) in this study. In activated macrophages and microglia, we found increased expression of NLRP3 inflammasome components and microRNA-223-3p. Activation of the inflammasome was suppressed in macrophages and microglia by microRNA-223-3p and MCC950, small-molecule NLRP3 inhibitors; macrophages were more prone to inflammasome activation than microglia. After lysolecithin-induced demyelination, systemic administration of MCC950 to mice reduced axonal injury in demyelinated lesions significantly. Following demyelination, macrophages and microglia produce NLRP3 inflammatory mediators, which could be used as therapeutic targets for MS and other inflammatory-mediated demyelinating diseases, such as Parkinson’s disease.
Leukocytes are regulated by the brain’s motor and fear circuits during acute stress
The immune system and the nervous system are intertwined1. It is well-documented that stress affects immunity, but the mechanisms by which stress networks in the brain influence peripheral leukocytes are still poorly understood2. During acute stress in mice, we found that distinct brain regions influenced leukocyte distribution and function. In a study using optogenetics and chemogenetics, we found that skeletal muscle-derived neutrophil-attracting chemokines trigger rapid neutrophil mobilization from bone marrow to peripheral tissues via motor circuits. Direct cell-intrinsic glucocorticoid signaling in the paraventricular hypothalamus, on the other hand, controls monocyte and lymphocyte exit from secondary lymphoid organs and blood to the bone marrow. People who experience stress-induced, counter-directional, population-wide leukocyte shifts are more susceptible to disease. Acute stress, on the other hand, modifies innate immunity by reprogramming neutrophils and directing their recruitment to injury sites. Conversely, leukocyte shifts mediated by corticotropin releasing hormone (CRH) neuron protect against the acquisition of autoimmunity but impair immunity to SARS-CoV-2 and influenza infection. As a whole, these findings show that the immune system’s ability to respond to physical threats is regulated by the brain’s ability to rapidly alter the landscape of leukocytes in response to psychological stress.
Glioblastoma tumor progression is revealed by single-cell RNA sequencing.
Damian Jacob Sendler
Malignant glioblastoma (GBM) is a primary brain cancer that is inherently protumorigenic and therefore incurable. Only a few studies have examined the GBM immune microenvironment during tumor progression and current therapies. An epidermal growth factor receptor-driven genetic mouse GBM model’s immune cell composition changed in a large-scale, comprehensive longitudinal manner during tumor progression, as revealed by single-cell transcriptomics and flow cytometry. As the blood-brain barrier breaks down and the growth of epidermal growth factor receptor+ GBM cells expands, we found that proinflammatory microglia and antiinflammatory macrophages and protumorigenic myeloid-derived suppressors cells become more prevalent in end-stage tumors. In low-grade glioma and GBM patient biopsies, a similar relationship between microglia and macrophages was discovered. However, concurrent treatment with temozolomide irradiation increased intratumoral GranzymeB+ CD8+ T cells but also increased the number of CD4 regulatory T cells. Using these findings, researchers have been able to map the entire immune cellular landscape and its evolution as GBM progresses.
Treatment targets can be identified using chromotin profiles, which classify castration-resistant prostate cancers.
Damian Jacob Markiewicz Sendler The loss of androgen receptor (AR) dependence in castration-resistant prostate cancer (CRPC) results in clinically aggressive tumors with limited therapeutic options. Organoids, six xenograft cells, and 12 cell lines were studied using ATAC-seq (asay for transposase-accessible chromatin sequencing), RNA sequencing, and DNA sequencing. While the well-known AR-dependent and neuroendocrine variants were already known to exist, we also discovered two new variants that were AR negative/low: one based on Wnt signaling, the other on activator protein-1 (AP-1) transcription factors. We classified 366 patients based on their transcriptomic signatures, and SCL was found to be the second most common CRPC subtype after AR-dependent. For example, our findings show how this group’s transcriptional landscape is maintained by AP-1 and YAP/TAZ and TEAD protein interactions. To put it another way, this molecular classification can help doctors identify potential drug targets and help them make treatment decisions.
Prostate cancer lineage plasticity and castration resistance are controlled by the FGFR1 ligand Gremlin1, which can be therapeutically targeted.
The development of castration-resistant prostate cancer (CRPC), which can be fatal, and the lack of effective targeted therapies for more advanced disease are two of the most significant challenges in the clinical management of prostate cancer (PCa). By binding to FGFR1, we’ve found that Gremlin1 promotes lineage plasticity and increases castration resistance. Anti-Gremlin1 antibody and androgen deprivation therapy (ADT) in CRPC have been shown to have a synergistic effect. Androgen receptor (AR) inhibits GREM1 transcription, which is then unlocked by ADT. Gremlin1 binds to FGFR1 and activates MAPK signaling downstream, as demonstrated here. Gremlin1 has a unique interaction with FGFR1 compared to FGF1’s canonical ligand FGF1, as demonstrated by docking and mutagenesis. Gremlin1 appears to be a promising therapeutic target for CRPC, according to our research findings.
Those who recover from infectious mononucleosis have different pre-illness metabolite and metabolic pathway profiles than those who do not.
Damien Sendler Methylamines, lipids, amino acids and neurotransmitters may all contribute to the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A prospective, long-term study at Northwestern University enrolled 4501 students. As part of our investigation into infectious mononucleosis (IM), we conducted a 6-month follow-up for those who recovered (N = 18) and those who developed ME/CFS (N = 18). We found significant detectable metabolite differences in pre-illness blood samples between participants destined to develop severe ME/CFS following IM and recovered controls, which were compared to recovered controls. There are several potential dysregulated pathways that we identified, including glutathione, nucleotide, and the TCA cycle. During an inflammatory immune response, the pathways that differed between cases and controls are critical for cell proliferation. Using a leave-one-out cross-validation (LOOCV), our models correctly classified the severe ME/CFS group and recovered controls with 97.2 percent accuracy, 94.4 percent sensitivity, and 100.0 percent specificity. These alterations are in line with the increases in pro-inflammatory cytokines found in patients who went on to develop severe ME/CFS six months after IM, as previously described.