Biology subjects

Joseph, N.

Publications and source records attributed to Joseph, N..

10 recordsLinked to original sources

bioRxiv2025

Macrophage migration inhibitory factor is a potential therapeutic target for cisplatin induced peripheral neuropathy in breast cancer

BackgroundCisplatin (CP) is an effective chemotherapy drug for several cancers. However, the use of CP is associated with peripheral neuropathy, a painful nerve disorder. Unfortunately, no therapies are available for CP-induced peripheral neuropathy (CisIPN). This study explored the role of a cytokine, the macrophage migration inhibitory factor (MIF), as a potential therapeutic target for CisIPN. MethodsThe role of neuroinflammation and MIF in CisIPN was evaluated in mice models of CisIPN, with and without breast cancer, after treatment with the anti-inflammatory drug Dexamethasone (Dex). Circulating MIF levels in animals were examined using ELISA. Pharmacological inhibition of MIF was achieved using the small molecule inhibitors, CPSI-1306 and ISO-1. Mechanical and thermal sensitivities of animals were assessed using von frey filament and cold acetone assays. Macrophage infiltration in peripheral nerve tissues was examined using CD68 and Iba-1 staining. ResultsOur results showed that Dex suppressed mechanical hyperalgesia in CisIPN animals, which was accompanied by downregulation of MIF. We also found that circulating MIF levels were increased in CisIPN animals. Furthermore, direct inhibition of MIF using CPSI-1306 and ISO-1 led to suppression of mechanical hyperalgesia, without compromising the anti-tumor efficacy of CP, in CisIPN animals. We did not find any significant change in macrophage infiltration in the peripheral nerve tissues of CisIPN animals. Immunostaining results indicated that sensory neurons in the DRGs and Schwann Cells in the sciatic nerves are potential sources for increased MIF in CisIPN. InterpretationOverall, our results strongly suggest that MIF is a promising therapeutic target for CisIPN.

neuroscience↗

bioRxiv2025

Molecular and cellular features of nerve-invaded cancer cells using a newly characterized experimental model

Perineural invasion (PNI) is the invasion of cancer cells into nerves. Although PNI is a risk factor for cancer recurrence and metastasis, the lack of in vitro experimental models representing natural PNI challenges basic studies and therapeutic screening. In this work, we fully characterized a dorsal root ganglia (DRG)-nerve explant model for PNI and demonstrated the characteristic cellular and molecular features of cancer cells undergoing natural PNI. Briefly, thoracic and lumbar DRGs intactly connected to nerves were co-cultured with breast and prostate cancer cells in a 3D matrix for two weeks. Time-dependent brightfield and fluorescence imaging captured the complex interactions of cancer cells, neurons, axons, and Schwann cells within nerves in the DRG-nerve explant, demonstrating the natural invasion of cancer cells. Fundamental investigations showed that the autonomic neurotransmitters norepinephrine and acetylcholine significantly promote PNI. We also demonstrated increased survival of PNI cells against the cytotoxic drug cisplatin. Additionally, we characterized the proteomics profile of PNI cells for future theranostics applications and validated the results using patient breast tumor samples. Overall, this work characterized and established a clinically relevant model for PNI and revealed the cellular crosstalk of PNI cells within nerves. The established model is suitable for fundamental studies and therapeutic screening pertaining to PNI.

cancer biology↗

bioRxiv2025

Schwann cells modified to secrete MANF is a potential cellular therapy for peripheral nerve regeneration

Despite several decades of research, an effective therapy for peripheral nerve regeneration is still lacking. The lack of knowledge of molecular candidates that equally promote axon regeneration and glial cell dynamics essential for regeneration poses challenges in developing effective therapies. Improper optimization of potential therapies leading to failures in ensuring their local availability in nerves also poses additional challenges. Here, we showed that the neurotrophic factor, the mesencephalic astrocyte-derived neurotrophic factor (MANF), equally promotes axon regeneration and glial cell dynamics favorable for nerve regeneration. We showed that while endogenous expression of MANF is primarily restricted to non-peptidergic sensory neurons in adult rats, exogenous MANF promotes the growth of all subtypes of adult rat sensory neurons. We also demonstrated that exogenous MANF promotes the proliferation and migration of adult rat primary Schwann Cells (SCs). Further, we found that local and repeated administration of exogenous MANF to injured mouse nerve promote axon regeneration. Finally, we devised a therapeutic approach by programming nerve resident SCs to locally and continuously deliver MANF to injured rat nerves and showed that this approach improved nerve regeneration indices. Overall, this work developed a therapeutic approach by harnessing the power of SCs as a local delivery system of MANF for improving nerve regeneration.

neuroscience↗

bioRxiv2025

Discoloration of the Cephalothorax in Pandalus borealis and its Correlation with Internal Cadmium Concentration

This study investigates the correlation between discoloration of the cephalothorax in Pandalus borealis (P. borealis) shrimp and cadmium concentration. The data, obtained through Atomic Absorption Spectroscopy (AAS), was converted into weight-based cadmium concentrations and analyzed using both parametric and non-parametric statistical tests. Despite assumptions of normal distribution not being met, a two-sample Students t-test and Mann-Whitney test were performed to examine the differences in cadmium concentrations between pink and discolored shrimp. Results indicated no statistically significant differences between the two groups. Experimental analysis revealed considerable overlap in cadmium concentration ranges for both groups, with high standard deviations. Factors such as the period of exposure to cadmium and potential influences from other contaminants or microorganisms were also considered. Previous studies have linked discoloration in shrimp to heavy metals and infections, but this study found no correlation between cadmium concentration and discoloration in P. borealis. The conclusion suggests that cadmium may not be a sole factor in shrimp discoloration, and other variables should be explored. Recommendations for future research include examining other trace metals, microbial infections, shrimp age, and extent of exposure to provide a comprehensive understanding of cephalothorax discoloration in shrimp.

pathology↗

bioRxiv2024

Creating anatomically-derived, standardized, customizable, and three-dimensional printable head caps for functional neuroimaging

AbstractO_ST_ABSSignificanceC_ST_ABSConsistent and accurate probe placement is a crucial step towards enhancing the reproducibility of longitudinal and group-based functional neuroimaging studies. While the selection of headgear is central to these efforts, there does not currently exist a standardized design that can accommodate diverse probe configurations and experimental procedures. AimWe aim to provide the community with an open-source software pipeline for conveniently creating low-cost, 3-D printable neuroimaging head caps with anatomically significant landmarks integrated into the structure of the cap. ApproachWe utilize our advanced 3-D head mesh generation toolbox and 10-20 head landmark calculations to quickly convert a subjects anatomical scan or an atlas into a 3-D printable head cap model. The 3-D modeling environment of the open-source Blender platform permits advanced mesh processing features to customize the cap. The design process is streamlined into a Blender add-on named "NeuroCaptain". ResultsUsing the intuitive user interface, we create various head cap models using brain atlases, and share those with the community. The resulting mesh-based head cap designs are readily 3-D printable using off-the-shelf printers and filaments while accurately preserving the head topology and landmarks. ConclusionsThe methods developed in this work result in a widely accessible tool for community members to design, customize and fabricate caps that incorporate anatomically derived landmarks. This not only permits person-alized head cap designs to achieve improved accuracy, but also offers an open platform for the community to propose standardizable head caps to facilitate multi-centered data collection and sharing.

neuroscience↗

bioRxiv2024

A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer

Neuroendocrine prostate cancer (NEPC) presents a formidable clinical challenge owing to its aggressive progression and resistance to conventional therapies. A key driver of NEPC is the overexpression of MYCN, a well-established oncogene associated with neuroendocrine tumors. However, efforts to directly inhibit the N-Myc protein encoded by this gene have resulted in limited success, thereby hindering therapeutic advancements. To overcome this obstacle, we conducted unbiased genome-wide screening using isogenic prostate cancer cell lines to identify the synthetic vulnerabilities of MYCN. Among the identified candidates, NEUROG2 emerged as a significant candidate. Neurog2 is a proneural transcription factor (PTF) known for its role in developmental processes and trans-differentiation of adult cells. Our findings demonstrate that Neurog2 depletion does not affect non-malignant cells, but significantly suppresses the growth of MYCN-overexpressing cells and tumors in orthotopic NEPC models. Furthermore, our observations indicate that the Neurog2-mediated regulation of PTFs can facilitate NEPC development. Thus, targeting Neurog2 holds promise as an effective therapeutic strategy for MYCN-overexpressing NEPC.

cancer biology↗

bioRxiv2022

Novavax NVX-COV2373 triggers potent neutralization of Omicron sub-lineages

The SARS-CoV-2 Omicron (B.1.1.529) Variant of Concern (VOC) and its sub-lineages (including BA.2, BA.4/5, BA.2.12.1) contain spike mutations that confer high level resistance to neutralizing antibodies. The NVX-CoV2373 vaccine, a protein nanoparticle vaccine, has value in countries with constrained cold-chain requirements. Here we report neutralizing titers following two or three doses of NVX-CoV2373. We show that after two doses, Omicron sub-lineages BA.1 and BA.4 were resistant to neutralization by 72% (21/29) and 59% (17/29) of samples. However, after a third dose of NVX-CoV2373, we observed high titers against Omicron BA.1 (GMT: 1,197) and BA.4 (GMT: 582), with responses similar in magnitude to those triggered by three doses of an mRNA vaccine. These data are of particular relevance as BA.4 is emerging to become the dominant strain in many locations, and highlight the potential utility of the NVX-CoV2373 vaccine as a booster in resource-limited environments.

immunology↗

bioRxiv2021

Inhibition of the SHP-1 activity by PKC-θ regulates NK cell activation threshold and cytotoxicity

Natural Killer (NK) cells play a crucial role in immunity, killing virally infected and cancerous cells. The balance of signals initiated upon engagement of activating and inhibitory NK receptors with cognate ligands determines killing or tolerance. Nevertheless, the molecular mechanisms regulating rapid NK cell discrimination between healthy and malignant cells in a heterogeneous tissue environment are incompletely understood. The SHP-1 tyrosine phosphatase is the central negative NK cell regulator, which dephosphorylates key activating signaling proteins. Though the mechanism by which SHP-1 mediates NK cell inhibition has been partially elucidated, the pathways by which SHP-1 is itself regulated remain unclear. Here, we show that phosphorylation of SHP-1 in NK cells on the S591 residue by PKC-{theta} promotes the inhibited SHP-1 "folded" state. Silencing PKC-{theta} maintains SHP-1 in the active conformation, reduces NK cell activation and cytotoxicity, and promotes tumor progression in-vivo. This study reveals a molecular pathway that sustains the NK cell activation threshold through suppression of SHP-1 activity.

immunology↗

bioRxiv2020

Multimodal magnetic resonance imaging predicts regional amyloid-β burden in the brain

Alzheimers disease (AD) is the most common cause of dementia and identifying early markers of this disease is important for prevention and treatment strategies. Amyloid - {beta} protein deposition is one of the earliest detectable pathological changes in AD. But in-vivo detection of amyloid - {beta} using positron emission tomography (PET) is hampered by high cost and limited geographical accessibility. These factors can become limiting when PET is used to screen large numbers of subjects into prevention trials when only a minority are expected to be amyloid- {beta} - positive. Structural MRI is advantageous; as it is relatively inexpensive and more accessible. Thus it could be widely used in large studies, even when frequent or repetitive imaging is necessary. We used a machine learning, pattern recognition, approach using intensity-based features from individual and combination of MR modalities (T1 weighted, T2 weighted, T2 fluid attenuated inversion recovery [FLAIR], susceptibility weighted imaging) to predict voxel-level amyloid- {beta} in the brain. The MR- amyloid {beta} relation was learned within each subject and generalized across subjects using subject-specific features (demographic, clinical, and summary MR features). When compared to other modalities, combination of T1-weighted, T2-weighted FLAIR, and SWI performed best in predicting the amyloid- {beta} status as positive or negative. T2- weighted performed the best in predicting change in amyloid- {beta} over two timepoints. Overall, our results show feasibility of amyloid- {beta} prediction by MRI.

bioengineering↗

bioRxiv2019

De-novo discovery of tumoricidal aptamers in a DNA sequencing chip

We describe a technique for the rapid ab-initio discovery of target-tailored tumoricidal DNA oligonucleotides inside an Illumina sequencing chip. By sequencing oligonucleotide pools we generate a physical microfluidic map of hundreds of millions of potential oligo clusters, in which every cluster is mapped to a specific set of spatial coordinates. Tumor cells, pre-loaded with a fluorogenic reporter of apoptosis, are then injected into the chip and monitored over time. Apoptotic tumor cells are identified and analyzed across the entire map, automatically revealing the coordinates of oligos that induced this effect. We demonstrate this method by identifying, within just a few hours, new oligos capable of directly and selectively inducing apoptosis in primary human tumor cells. Such a major capability could lead to a new paradigm of personalized cancer therapy.

synthetic biology↗