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Sigma-1 receptor regulates HIV-1 and methamphetamine-induced endothelial/pericyte barrier impairment via strain-specific inflammatory responses and mitochondrial dysregulation
No full textBackgroundMethamphetamine (METH) use disorder (MUD) is a frequent comorbidity among people with HIV-1 (PWH). While both METH and HIV-1 independently disrupt the brain microvascular system and promote neuroinflammation, the molecular mechanisms underlying their synergistic neurotoxicity remain unclear. The sigma-1 receptor (Sigma-1R) signaling pathway has been suggested as a potential target in METH misuse; however, its involvement in the impact of METH and/or HIV-1 infection on brain pericytes remains unknown.MethodsTranswell co-cultures of human brain microvascular endothelial cells (HBMECs) and human brain vascular pericytes (HBVPs) were employed to assess the impact of combined METH exposure and infection with HIV-1 on barrier integrity. Moreover, mitochondrial functions, inflammatory mediators, oxidative stress markers, and the expression of interferon-stimulated genes were analyzed.ResultsHBVP infection with the CXCR4-tropic HIV-1 strain NL4-3, but not the CCR5-tropic JR-CSF strain, disrupted endothelial/pericyte barrier permeability, reduced transendothelial electrical resistance (TEER), and lowered claudin-5 expression, effects alleviated by pretreatment with Sigma-1R antagonist S1RA (10 µM). S1RA suppressed interleukin-6 (IL-6) release without affecting increased ROS levels and mitigated HIV-1 NL4-3 and METH co–induced proton leak and mitochondrial network fragmentation in a DRP1 phosphorylation–dependent manner. Importantly, METH enhanced replication of HIV-1 NL4-3, a process modulated by the CXCR4/CCL2 signaling pathway rather than Sigma-1R.ConclusionsThe obtained results identify Sigma-1R antagonism as a potential therapeutic strategy to protect microvascular integrity in the context of HIV-1 infection and METH misuse. In addition, they reveal distinct mechanisms that may underly microvascular dysfunction in PWH who experience MUD
Data associated with the publication: Whole-body in vivo MPI cytometry reveals injection route-, dose-, cell size- and disease-dependent differences in organ biodistribution
No full textThe datasets within correspond to the Science Advances article titled “Whole-Body in Vivo MPI Cytometry Reveals Injection Route-, Dose-, Cell Size- and Disease-Dependent Differences in Organ Biodistribution”. The data are organized in terms of the corresponding Figure number within the paper: https://www.biorxiv.org/content/10.1101/2025.09.11.675624v2.abstrac
ALSUntangled #82: N-acetylcysteine
No full textN-acetylcysteine is a thiol-containing compound and a precursor of glutathione, with mechanistic plausibility for ALS, including reducing oxidative stress, regulating neuroinflammation, and mitigating mitochondrial dysfunction. Preclinical studies have yielded conflicting results on whether N-acetylcysteine can delay the onset of motor impairment and prolong survival in ALS mouse models. Several case studies of oral or subcutaneous administration of N-acetylcysteine in patients with ALS did not demonstrate convincing benefits. Clinical trials to date have also failed to demonstrate efficacy in slowing ALS progression. While N-acetylcysteine shows theoretical promise, further research is needed to clarify its therapeutic role in ALS. At present, ALSUntangled does not support the use of N-acetylcysteine as a treatment to slow ALS progression
Unique pore architecture underlies constitutive gating of human retinal TRPM1
No full textTransient receptor potential melastatin 1 (TRPM1), a Ca ²⁺ -permeable nonselective cation channel essential for retinal ON bipolar cell signaling and night vision, and implicated in congenital night blindness, has remained structurally and functionally poorly characterized. Here we report the first cryo-electron microscopy structure of human TRPM1 in conducting state. Although the channel assembles as a tetramer, it adopts an unexpected clockwise domain-swapped pore module with rotational geometry inverse to that observed in previously characterized 6-TM tetrameric channels. This inverted topology is accompanied by extensive remodeling of the S5-P-S6 module, dilation of the selectivity filter, expansion of the central cavity, and splaying of S6 to form a wide intracellular gate. Single-channel recordings reveal constitutive activity consistent with the conductive state captured. Together, these findings uncover a new 6-TM fold in tetrameric channel and provide a framework for understanding TRPM1 gating and disease-associated dysfunction.Transient receptor potential melastatin 1 (TRPM1), a Ca ²⁺ -permeable nonselective cation channel essential for retinal ON bipolar cell signaling and night vision, and implicated in congenital night blindness, has remained structurally and functionally poorly characterized. Here we report the first cryo-electron microscopy structure of human TRPM1 in conducting state. Although the channel assembles as a tetramer, it adopts an unexpected clockwise domain-swapped pore module with rotational geometry inverse to that observed in previously characterized 6-TM tetrameric channels. This inverted topology is accompanied by extensive remodeling of the S5-P-S6 module, dilation of the selectivity filter, expansion of the central cavity, and splaying of S6 to form a wide intracellular gate. Single-channel recordings reveal constitutive activity consistent with the conductive state captured. Together, these findings uncover a new 6-TM fold in tetrameric channel and provide a framework for understanding TRPM1 gating and disease-associated dysfunction
International Society of Urological Pathology Consensus Meeting 2024 Working Group 2 Preneoplastic and Precursor Lesions of the Urinary Bladder
No full textPreneoplastic and precursor lesions are important to recognize and report, as they can influence clinical management decisions. The International Society of Urological Pathology (ISUP) organized a consensus meeting in Florence, Italy, in September 2024 focused on preneoplastic and precursor lesions of the genitourinary organs. Working group 2 was assigned the topic of bladder and a group of pathologists and clinicians was convened. They developed a 46 question premeeting survey for the ISUP membership assessing flat, papillary, squamous, and glandular entities and clinical issues to determine use of terminology, reporting practices, and areas that needed to be addressed at the consensus meeting. The premeeting survey results showed consistency in the terminology used by pathologists, similarities in reporting practices, and highlighted areas of uncertainty with respect to whether certain entities could be classified as precursors/preneoplastic. The results enabled the working group to conduct focused literature reviews and to develop a presentation and set of in-meeting polling questions to address the problematic topics from the survey results. Overall, 14/18 in-meeting polling questions achieved consensus. The surveys and in-person voting demonstrated a strong preference to use existing terminology such as dysplasia, verrucous squamous, and papillary hyperplasia, to grade glandular and squamous dysplasia and to judiciously use immunohistochemistry to classify lesions. Pathologists expressed highly variable opinions with respect to questions about quantification, management recommendations, and inclusion of newer entities as precursors/preneoplastic lesions
Desiring the Disabled Body How disabled women are represented in visual journalism
No full textThis chapter explores how journalists visually construct disabled women at the intersection of disability and sex. The authors draw from disability studies to examine two cases that featured disabled women in news media representations that interpellate them as sexual beings: the appearance of Gigi Robinson, an American influencer with chronic illnesses, in the 2022 Sports Illustrated Swimsuit Issue and English-language news coverage of Inclov, an Indian matchmaking app for people with disabilities founded in 2016. The findings elucidate how these images both challenged stereotypes associated with people with disabilities in the news media as well as reinforced ableist assumptions about the relationship between disability and sexuality. Ultimately, the coverage of Inclov suggested the potential of effectively integrating images of disabled people into visual imaginings of romantic life, while the framing of the Sports Illustrated photo shoot suggested that disabled bodies must conform to normative notions of sexiness
Uncertainty Quantification in Hyperelastic Materials - A Nonintrusive Spectral Stochastic Smoothed Finite Element Method
No full textThis study presents a novel nonintrusive stochastic approach to model the large deformation behavior of quasi-incompressible hyperelastic materials with inherent uncertainty in the material properties and geometric parameters. In addition, the mesh distortion parameter is also considered a random parameter. The input and output uncertainties are represented by Polynomial Chaos Expansion (PCE). The domain is discretized with three-noded triangular elements and the edge-based smoothed finite element method is used to compute the corresponding bilinear/linear forms. The robustness and the efficacy of the framework are elucidated with a few standard benchmark problems considering the bulk modulus as the uncertain parameter by comparing with the brute-force Monte Carlo simulations. For identifying critical influencing parameters, a sensitivity analysis based on Sobol' indices is adopted
A Modernism of One's Own: Speculative Sexuality in Radclyffe Hall, Djuna Barnes, and Virginia Woolf
No full textLiterary critics have established the importance of 1914 for the formation of modernism as a movement whose precepts would lead to the dominant aesthetic of the twenties. As artists grappled with the consequences of the First World War, the questioning of institutions achieved a greater priority than ever before. With respect to this cultural upheaval, of no small importance is the questioning of traditional sex and gender politics that led to women receiving British suffrage in 1918, with America following two years later. This unprecedented period of freedom for women allowed for the exploration of speculative sexuality: fiction that upends sex and gender conventions to present alternative narratives which challenge the normative and prescriptive models of the day. These attitudes coalesce in 1928 with the publication of three works of fiction: Radclyffe Hall’s The Well of Loneliness, Djuna Barnes’ Ladies’ Almanack, and Virgina Woolf’s Orlando. Examining the relationship between speculative and science fiction, I argue for the generative potential of reading Hall, Barnes, and Woolf as science fiction, when science fiction is broadly interpreted as literature engaged with the “science” of emerging late nineteenth- and early twentieth-century sexological discourse.</p
Alterations in Gene Expression and Mitochondrial Mutation Levels Associated with Carcinogenesis in Damselfish Neurofibromatosis
No full textDamselfish neurofibromatosis (DNF) found in bicolor damselfish, Stegastes partitus, is caused by an etiologic agent infecting and replicating within mitochondria of host cells. This pathogen, termed the damselfish virus-like agent (DVLA), initiates the development of chromatophoromas and neurofibromas ultimately resulting in the death of the host. Previous studies have demonstrated significantly reduced mitochondrial DNA and oxidative phosphorylation levels associated with DVLA infected cell lines. However, these studies have not examined how DVLA infection results in carcinogenic transformation necessary for DNF formation. To investigate how DVLA alters the mitochondria and the cell causing cellular transformation, RNA sequences were used to examine mutation, differential expression (DE), and co-expression of healthy and tumor samples. The RNA sequence analyses revealed significant impairment of the mitochondrial genome and mitochondrial associated functions, supporting previous studies. Additionally, qPCR analyses highlighted competition between the mitochondrial and viral genome occurred only for replication machinery. Furthermore, DE and co-expression analyses identified upregulation of pathways identified in cancer development and survival. Taken together the results of this study indicate DVLA infection causes severe depression of mitochondrial related pathways and functions, causing overall cellular stress promoting tumor formation.</p
Innate Immune Responses and Iron Dysregulation in Intracortical Neural Implants
No full textThere are over 5 million individuals in the U.S. alone with neurological disorders who could benefit from neuroprosthetics, such as brain-computer interfaces (BCIs), to improve their mobility and ability to perform daily activities. Microelectrodes interface with the central nervous system (CNS) and play a crucial role in these technologies, enabling the recording of large assemblies of neurons to treat conditions like spinal cord injury, stroke, and neurodegenerative diseases. Intracortical microelectrode arrays (MEAs)—neural implants placed in the cortex that directly interact with brain tissue—are promising because they enable precise recording of neuronal signals, offering refined control of external devices to assist in restoring movement. However, intracortical MEAs have a limitation in that they create a robust, local foreign body response at the implantation site. This biological reaction includes inflammation, oxidative stress, blood-brain barrier disruption, and tissue encapsulation around the electrode, which diminishes the device's long-term function. This study reveals unique pathways that are activated and disrupted by device implantation, contributing to a decline in MEA performance over time. When a MEA is implanted, disruption of the blood-brain barrier leads to neurovascular damage and the release of iron, as well as triggers the innate immune system as a first line of defense against the foreign body. This dissertation includes investigating the effects of iron dysregulation from neurovascular damage, identifying the activation of the inflammasome pathway in the immune response at the electrode-tissue interface, and exploring iron chelation as a pharmacological, neuroprotective strategy to mitigate the foreign body response. Findings of this research provide evidence of mechanisms previously undefined in the context of intracortical MEAs and offer valuable insights for enhancing the long-term performance and stability of neural implants for clinical applications.</p