Biology subjects

Mark, J.

Publications and source records attributed to Mark, J..

6 recordsLinked to original sources

bioRxiv2026

Rapid Detection and Initial Treatment of Life-Threatening Subdural Hematoma in a Sheep Model

Traumatic brain injury (TBI) is the leading cause of death and disability in people under 40 worldwide. There is an unmet need for detection and treatment of life-threatening TBI when computed tomography (CT) scanners and neurosurgeons are unavailable. We developed a new handheld frequency-domain multidetector infrared hemorrhage detection device. Using the new device, military pre-hospital medics required <4 minutes to detect life-threatening subdural hematoma in a sheep model. We developed a second device that allows non-neurosurgeons to safely create a burr hole and partially remove clotted subdural blood. In sheep, the treatment device reduced intracranial pressure within 20 minutes, and improved post-anesthesia blinded neurological outcomes. With human use adaptation, these devices could allow rapid detection and initial treatment of some life-threatening TBIs in challenging situations.

neuroscience↗

bioRxiv2024

ASO-mediated knockdown of GPNMB in mutant-GRN and Grn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses

BackgroundIncreases in GPNMB are detectable in FTD-GRN cerebrospinal fluid (CSF) and post-mortem brain, and brains of aged Grn-deficient mice. Although no upregulation of GPNMB is observed in the brains of young Grn-deficient mice, peripheral immune cells of these mice do exhibit this increase in GPNMB. Importantly, the functional significance of GPNMB upregulation in progranulin-deficient states is currently unknown. Given that GPNMB has been discussed as a potential therapeutic target in GRN-mediated neurodegeneration, it is vital for the field to determine what the normal function of GPNMB is in the immune system, and whether targeting GPNMB will elicit beneficial or deleterious effects. MethodsThe effects of GPNMB knock-down via antisense oligonucleotide (ASO) were assessed in peripheral blood mononuclear cells (PBMCs) from 25 neurologically healthy controls (NHCs) and age- and sex-matched FTD-GRN patients, as well as peritoneal macrophages (pMacs) from progranulin-deficient (Grn-/-) and B6 mice. Lysosomal function, antigen presentation and MHC-II processing and recycling were assessed, as well as cytokine release and transcription. ResultsWe demonstrate here that ASO-mediated knockdown of GPNMB increases lysosomal burden and cytokine secretion in FTD-GRN carrier and neurologically healthy controls (NHCs) monocytes. ASO-mediated knockdown of GPNMB in Grn-deficient macrophages decreased lysosomal pan-cathepsin activity and protein degradation. In addition, ASO-mediated knockdown of GPNMB increased MHC-II surface expression, which was driven by decreased MHC-II uptake and recycling, in macrophages from Grn-deficient females. Finally, ASO-mediated knockdown of GPNMB dysregulated IFN{gamma}-stimulated cytokine transcription and secretion by mouse macrophages due to the absence of regulatory actions of the GPNMB extracellular fragment (ECF). ConclusionsOur data herein reveals that GPNMB has a regulatory effect on multiple immune effector functions, including capping inflammation and immune responses in myeloid cells via secretion of its ECF. Therefore, in progranulin-deficient states, the drastic upregulation in GPNMB transcript and protein may represent a compensatory mechanism to preserve lysosomal function in myeloid cells. These novel findings indicate that targeted depletion in FTD-GRN would not be a rational therapeutic strategy because it is likely to dysregulate important immune cell effector functions.

immunology↗

bioRxiv2023

Totally tubular: ASO-mediated knock-down of G2019S-Lrrk2 modulates lysosomal tubule-associated antigen presentation in macrophages

Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinsons disease (PD). LRRK2 levels have become an appealing target for potential PD-therapeutics with LRRK2 antisense oligonucleotides (ASOs) now in clinical trials. However, LRRK2 has been suggested to play a fundamental role in peripheral immunity, and it is currently unknown if targeting increased LRRK2 levels in peripheral immune cells will be beneficial or deleterious. Furthermore, the precise role of LRRK2 in immune cells is currently unknown, although it has been suggested that LRRK2-mediated lysosomal function may be crucial to immune responses. Here, it was observed that G2019S macrophages exhibited increased stimulation-dependent lysosomal tubule formation (LTF) and MHC-II trafficking from the perinuclear lysosome to the plasma membrane in an mTOR dependent manner with concomitant increases in pro-inflammatory cytokine release. Both ASO-mediated knock down of mutant Lrrk2 and LRRK2 kinase inhibition ameliorated this phenotype and decreased these immune responses in control cells. Given the critical role of antigen presentation, lysosomal function, and cytokine release in macrophages, it is likely LRRK2-targetting therapies may have therapeutic value with regards to mutant LRRK2 but deleterious effects on the peripheral immune system, such as altered pathogen control and infection resolution.

neuroscience↗

bioRxiv2022

High dose dietary vitamin D allocates surplus calories to muscle and growth instead of fat via modulation of myostatin and leptin signaling.

Obesity is the leading proportional cause for diabetes, heart disease and cancer. Obesity occurs because the body stores surplus calories as fat. Fat cells secrete a hormone, leptin, that modulates energy balance at the brain. Changes in fat mass are mirrored by changes in serum leptin. Increases in leptin cause the brain to decrease appetite and increase energy expenditure. However in obesity, leptin sensitivity is decreased which mutes leptin mediated changes in appetite and energy expenditure. We have limited understanding of what controls leptin production by fat or how sensitive the brain is to leptin. Muscle produces a hormone, myostatin, that plays an analogous role to the role that leptin plays in fat. Absent myostatin leads to increased muscle mass and strength. We also do not know what controls myostatin production or sensitivity. Although fat mass and muscle mass are closely linked, the interplay between leptin and myostatin remains unexplored. Vitamin D improves lean mass via what are thought to be primarily trophic effects at the muscle. Here we show that high dose dietary vitamin D preferentially allocates excess calories to muscle and growth instead of storage as fat by decreasing myostatin production and increasing leptin production and sensitivity. That is, high dose vitamin D improves organismal energy sensing. Obesity, aging and other chronic inflammatory diseases are associated with decreased muscle function and mass. Our work provides a physiologic framework for how high-dose vitamin D would be effective in these pathologies to increase allocation of calories to muscle instead of fat and reveals novel interplay between the myostatin and leptin signaling whereby myostatin conveys energy needs to modulate leptin effects on calorie allocation. Furthermore, our work reveals how physiologic seasonal variation in vitamin D may be important in controlling season-specific metabolism and calorie allocation to fat in winter and muscle in summer.

physiology↗

bioRxiv2020

Areas of global importance for terrestrial biodiversity, carbon, and water

Summary paragraphTo meet the ambitious objectives of biodiversity and climate conventions, countries and the international community require clarity on how these objectives can be operationalized spatially, and multiple targets be pursued concurrently1. To support governments and political conventions, spatial guidance is needed to identify which areas should be managed for conservation to generate the greatest synergies between biodiversity and natures contribution to people (NCP). Here we present results from a joint optimization that maximizes improvements in species conservation status, carbon retention and water provisioning and rank terrestrial conservation priorities globally. We found that, selecting the top-ranked 30% (respectively 50%) of areas would conserve 62.4% (86.8%) of the estimated total carbon stock and 67.8% (90.7%) of all clean water provisioning, in addition to improving the conservation status for 69.7% (83.8%) of all species considered. If priority was given to biodiversity only, managing 30% of optimally located land area for conservation may be sufficient to improve the conservation status of 86.3% of plant and vertebrate species on Earth. Our results provide a global baseline on where land could be managed for conservation. We discuss how such a spatial prioritisation framework can support the implementation of the biodiversity and climate conventions.

ecology↗

bioRxiv2020

RNA editing enzyme APOBEC3A promotes pro-inflammatory (M1) macrophage polarization

Pro-inflammatory (M1) macrophage polarization is associated with microbicidal and antitumor responses. We recently described APOBEC3A-mediated cytosine-to-uracil (C>U) RNA editing during M1 polarization. However, the functional significance of this editing is unknown. Here, we find that APOBEC3A-mediated cellular RNA editing can also be induced by influenza or Maraba virus infections of normal human macrophages, and by interferons in tumor-associated macrophages. Gene knockdown and RNA_Seq analyses show that APOBEC3A mediates C>U RNA editing of 209 exonic/UTR sites in 203 genes during M1 polarization. The highest level of deleterious C>U RNA editing occurred in THOC5, encoding a nuclear mRNA export protein implicated in M-CSF-driven macrophage differentiation. Knockdown of APOBEC3A reduces pro-inflammatory M1 markers including IL6, IL23A and IL12B gene expression, CD86 surface protein expression, and TNF-, IL-1{beta} and IL-6 cytokine secretion, and increases glycolysis and glycolytic capacity. Thus, APOBEC3A cytidine deaminase plays an important role in transcriptomic and functional polarization of M1 macrophages.

immunology↗