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Case summary: A 1-year-old male neutered domestic shorthair cat presented on an emergency basis with clinical signs suspected to be secondary to organophosphate (OP) toxicity. The control of clinical abnormalities (bradycardia, obtundation, tachypnea, anorexia) was achieved using high-dose continuous rate intravenous infusion (CRI) of atropine sulfate (maximum rate 0.1 mg/kg/h). After 5 days of hospitalization, the patient made a full clinical recovery without the development of atropine toxicity, intermediate syndrome or delayed polyneuropathy at 4 weeks after discharge. Relevance and novel information: Treatment of OP toxicity in cats is sparsely reported in veterinary literature. Current standards of treatment and published protocols recommend the use of atropine sulfate as intermittent boluses for the treatment of muscarinic signs of toxicity; however, there is a paucity of information regarding the safety and efficacy of atropine sulfate as a CRI for severe toxicosis as described in humans. This report includes the first published case using such a treatment protocol in a cat.
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Viral fusion proteins facilitate cellular infection by fusing viral and cellular membranes, which involves dramatic transitions from their pre- to postfusion conformations. These proteins are among the most protective viral immunogens, but they are metastable which often makes them intractable as subunit vaccine targets. Adapting a natural enzymatic reaction, we harness the structural rigidity that targeted dityrosine crosslinks impart to covalently stabilize fusion proteins in their native conformations. We show that the prefusion conformation of respiratory syncytial virus fusion protein can be stabilized with two engineered dityrosine crosslinks (DT-preF), markedly improving its stability and shelf-life. Furthermore, it has 11X greater potency as compared with the DS-Cav1 stabilized prefusion F protein in immunogenicity studies and overcomes immunosenescence in mice with simply a high-dose formulation on alum.
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Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Tirosina/análogos & derivados , Animales , Ratones , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Tirosina/metabolismo , Proteínas Virales de Fusión , Infecciones por Virus Sincitial Respiratorio/prevención & controlRESUMEN
OBJECTIVE: We examined the associations between coping strategies in response to racism and distress symptoms. SAMPLE: One hundred forty-four racially minoritized students at a northeastern university completed an online survey. METHODS: Participants completed self-report active and emotion-focused coping and distress symptom (i.e., depression and anxiety) measures. Hierarchical regressions were conducted to test: 1) correlations between coping strategies in response to racism and distress symptoms, and 2) whether emotional acceptance moderates the association between active coping in response to racism and distress symptoms. RESULTS: Students' self-compassionate responses to their emotional reactions to discrimination uniquely predicted less distress. In contrast, reports of using resistance and education in response to discrimination were positively correlated with distress symptoms; however, these associations were no longer significant when accounting for emotional acceptance. CONCLUSIONS: Our findings suggest that emotional acceptance coping may be associated with lower distress symptoms. Active coping was associated with increased distress symptoms, except when accounting for emotional acceptance coping.
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In 2021, overdose deaths surpassed the 100,000 mark for the first time in the United States' history, and alcohol-related deaths continue to surpass 140,000 each year. Regulatory and societal barriers to effective treatment and prevention of substance use disorder (SUD) persist. Innovative strategies and approaches to support long-term recovery can help re-duce morbidity and mortality associated with SUD. Improving access to quality treatment and the availability of a broad range of policies and programs to support recovery and address social determinants of health, including employment supports, are key to curbing the overdose epidemic and rebuilding stronger communities. This article outlines the role Recovery Ready Workplaces can play in reducing overdoses and helping individuals sustain recovery from SUD, as well as in strengthening communities. This article describes how congressional and state legisla-tive action, Americans with Disabilities Act (ADA) enforcement and expansion, and other programmatic and fiscal policy changes at the state and federal levels will accelerate the adoption of Recovery Ready Workplaces as an element of a comprehensive response to SUD. The article also identifies existing state models and proposes specific federal- and state-level solutions to address some of the current limitations. Recovery Ready Workplaces benefit employees, employers, and the nation's economy. Recovery Ready Workplaces are a supportive tool and policy strategy to help those with SUD thrive in recovery and to bolster communities and the econ-omy as a whole.
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BACKGROUND: Development of precision medicine requires the identification of easily detectable and druggable biomarkers. Despite recent targeted drug approvals, prognosis of acute myeloid leukemia (AML) patients needs to be greatly improved, as relapse and refractory disease are still difficult to manage. Thus, new therapeutic approaches are needed. Based on in silico-generated preliminary data and the literature, the role of the prolactin (PRL)-mediated signaling was interrogated in AML. METHODS: Protein expression and cell viability were determined by flow cytometry. Repopulation capacity was studied in murine xenotransplantation assays. Gene expression was measured by qPCR and luciferase-reporters. SA-ß-Gal staining was used as a senescence marker. RESULTS: The prolactin receptor (PRLR) was upregulated in AML cells, as compared to their healthy counterpart. The genetic and molecular inhibition of this receptor reduced the colony-forming potential. Disruption of the PRLR signaling, either using a mutant PRL or a dominant-negative isoform of PRLR, reduced the leukemia burden in vivo, in xenotransplantation assays. The expression levels of PRLR directly correlated with resistance to cytarabine. Indeed, acquired cytarabine resistance was accompanied with the induction of PRLR surface expression. The signaling associated to PRLR in AML was mainly mediated by Stat5, in contrast to the residual function of Stat3. In concordance, Stat5 mRNA was significantly overexpressed at mRNA levels in relapse AML samples. A senescence-like phenotype, measured by SA-ß-gal staining, was induced upon enforced expression of PRLR in AML cells, partially dependent on ATR. Similar to the previously described chemoresistance-induced senescence in AML, no cell cycle arrest was observed. Additionally, the therapeutic potential of PRLR in AML was genetically validated. CONCLUSIONS: These results support the role of PRLR as a therapeutic target for AML and the further development of drug discovery programs searching for specific PRLR inhibitors.
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Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the basis of previous results, in silico drug discovery screening was used to identify a new family of lysosome-/mitochondria-targeting compounds. These novel tetracyclic hits, with a cationic amphiphilic structure, specifically eradicate leukemic cells by inducing both mitochondrial damage and apoptosis, and simultaneous lysosomal membrane leakiness. Lysosomal leakiness does not only elicit canonical lysosome-dependent cell death, but also activates the terminal differentiation of AML cells through the Ca2+-TFEB-MYC signaling axis. In addition to being an effective monotherapy, its combination with the chemotherapeutic arsenic trioxide (ATO) used in other types of leukemia is highly synergistic in AML cells, widening the therapeutic window of the treatment. Moreover, the compounds are effective in a wide panel of cancer cell lines and possess adequate pharmacological properties rendering them promising drug candidates for the treatment of AML and other neoplasias.
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BACKGROUND: Mindfulness-based interventions have been shown to improve psychological outcomes including stress, anxiety, and depression in general population studies. However, effectiveness has not been sufficiently examined in racially and ethnically diverse community-based settings. We will evaluate the effectiveness and implementation of a mindfulness-based intervention on depressive symptoms among predominantly Black women at a Federally Qualified Health Center in a metropolitan city. METHODS: In this 2-armed, stratified, individually randomized group-treated controlled trial, 274 English-speaking participants with depressive symptoms ages 18-65 years old will be randomly assigned to (1) eight weekly, 90-min group sessions of a mindfulness-based intervention (M-Body), or (2) enhanced usual care. Exclusion criteria include suicidal ideation in 30 days prior to enrollment and regular (>4x/week) meditation practice. Study metrics will be assessed at baseline and 2, 4, and 6 months after baseline, through clinical interviews, self-report surveys, and stress biomarker data including blood pressure, heart rate, and stress related biomarkers. The primary study outcome is depressive symptom score after 6 months. DISCUSSION: If M-Body is found to be an effective intervention for adults with depressive symptoms, this accessible, scalable treatment will widely increase access to mental health treatment in underserved, racial/ethnic minority communities. TRIAL REGISTRATION: ClinicalTrials.gov NCT03620721. Registered on 8 August 2018.
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Depresión , Atención Plena , Adulto , Humanos , Femenino , Adolescente , Adulto Joven , Persona de Mediana Edad , Anciano , Depresión/diagnóstico , Depresión/terapia , Depresión/psicología , Atención Plena/métodos , Etnicidad , Grupos Minoritarios , Encuestas y Cuestionarios , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Lipid imaging mass spectrometry (LIMS) has been tested in several pathological contexts, demonstrating its ability to segregate and isolate lipid signatures in complex tissues, thanks to the technique's spatial resolution. However, it cannot yet compete with the superior identification power of high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS), and therefore, very often, the latter is used to refine the assignment of the species detected by LIMS. Also, it is not clear if the differences in sensitivity and spatial resolution between the two techniques lead to a similar panel of biomarkers for a given disease. Here, we explore the capabilities of LIMS and HPLC-MS to produce a panel of lipid biomarkers to screen nephrectomy samples from 40 clear cell renal cell carcinoma patients. The same set of samples was explored by both techniques, and despite the important differences between them in terms of the number of detected and identified species (148 by LIMS and 344 by HPLC-MS in negative-ion mode) and the presence/absence of image capabilities, similar conclusions were reached: using the lipid fingerprint, it is possible to set up classifiers that correctly identify the samples as either healthy or tumor samples. The spatial resolution of LIMS enables extraction of additional information, such as the existence of necrotic areas or the existence of different tumor cell populations, but such information does not seem determinant for the correct classification of the samples, or it may be somehow compensated by the higher analytical power of HPLC-MS. Similar conclusions were reached with two very different techniques, validating their use for the discovery of lipid biomarkers.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Cromatografía Líquida de Alta Presión/métodos , Lipidómica/métodos , Carcinoma de Células Renales/diagnóstico , Neoplasias Renales/diagnóstico , Lípidos/análisisRESUMEN
Biofilms are aggregates of bacteria, in most cases, which are resistant usually to broad-spectrum antibiotics in their typical concentrations or even in higher doses. A trend of increasing multi-drug resistance in biofilms, which are responsible for emerging life-threatening nosocomial infections, is becoming a serious problem. Biofilms, however, are at various sensitivity levels to environmental factors and are versatile in infectivity depending on virulence factors. This review presents the fundamental information about biofilms: formation, antibiotic resistance, impacts on public health and alternatives to conventional approaches. Novel developments in micro-biosystems that help reveal the new treatment tools by sensing and characterization of biofilms will also be discussed. Understanding the formation, structure, physiology and properties of biofilms better helps eliminate them by the usage of appropriate antibiotics or their control by novel therapy approaches, such as anti-biofilm molecules, effective gene editing, drug-delivery systems and probiotics.
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We defined the mechanisms by which the chaperone ATPase inhibitor AR12 and the multi-kinase inhibitor neratinib interacted to reduce expression of Tau and amyloid-precursor protein (APP) in microglia and neuronal cells. AR12 and neratinib interacted to increase the phosphorylation of eIF2A S51 and the expression of BAG3, Beclin1 and ATG5, and in parallel, enhanced autophagosome formation and autophagic flux. Knock down of BAG3, Beclin1 or ATG5 abolished autophagosome formation and significantly reduced degradation of p62, LAMP2, Tau, APP, and GRP78 (total and plasma membrane). Knock down of Rubicon, a key component of LC3-associated phagocytosis (LAP), significantly reduced autophagosome formation but not autophagic flux and prevented degradation of Tau, APP, and cell surface GRP78, but not ER-localized GRP78. Knock down of Beclin1, ATG5 or Rubicon or over-expression of GRP78 prevented the significant increase in eIF2A phosphorylation. Knock down of eIF2A prevented the increase in BAG3 expression and significantly reduced autophagosome formation, autophagic flux, and it prevented Tau and APP degradation. We conclude that AR12 has the potential to reduce Tau and APP levels in neurons and microglia via the actions of LAP, endoplasmic reticulum stress signaling and macroautophagy. We hypothesize that the initial inactivation of GRP78 catalytic function by AR12 facilitates an initial increase in eIF2A phosphorylation which in turn is essential for greater levels of eIF2A phosphorylation, greater levels of BAG3 and macroautophagy and eventually leading to significant amounts of APP/Tau degradation.
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Autofagia , Macroautofagia , Beclina-1 , Autofagia/fisiología , Fagocitosis , Fosforilación , Precursor de Proteína beta-AmiloideRESUMEN
We report innovative scalable, vertical, ultra-sharp nanowire arrays that are individually addressable to enable long-term, native recordings of intracellular potentials. Stable amplitudes of intracellular potentials from 3D tissue-like networks of neurons and cardiomyocytes are obtained. Individual electrical addressability is necessary for high-fidelity intracellular electrophysiological recordings. This study paves the way toward predictive, high-throughput, and low-cost electrophysiological drug screening platforms.
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Despite the outstanding advances in understanding the biology underlying the pathophysiology of acute myeloid leukemia (AML) and the promising preclinical data published lastly, AML treatment still relies on a classic chemotherapy regimen largely unchanged for the past five decades. Recently, new drugs have been approved for AML, but the real clinical benefit is still under evaluation. Nevertheless, primary refractory and relapse AML continue to represent the main clinical challenge, as the majority of AML patients will succumb to the disease despite achieving a complete remission during the induction phase. As such, treatments for chemoresistant AML represent an unmet need in this disease. Although great efforts have been made to decipher the biological basis for leukemogenesis, the mechanism by which AML cells become resistant to chemotherapy is largely unknown. The identification of the signaling pathways involved in resistance may lead to new combinatory therapies or new therapeutic approaches suitable for this subset of patients. Several mechanisms of chemoresistance have been identified, including drug transporters, key secondary messengers, and metabolic regulators. However, no therapeutic approach targeting chemoresistance has succeeded in clinical trials, especially due to broad secondary effects in healthy cells. Recent research has highlighted the importance of lysosomes in this phenomenon. Lysosomes' key role in resistance to chemotherapy includes the potential to sequester drugs, central metabolic signaling role, and gene expression regulation. These results provide further evidence to support the development of new therapeutic approaches that target lysosomes in AML.
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Photodynamic therapy (PDT) has been explored as a therapeutic strategy to clear toxic amyloid aggregates involved in neurodegenerative disorders such as Alzheimer's disease. A major limitation of PDT is off-target oxidation, which can be lethal for the surrounding cells. We have shown that a novel class of oligo-p-phenylene ethynylenes (OPEs) exhibit selective binding and fluorescence turn-on in the presence of prefibrillar and fibrillar aggregates of disease-relevant proteins such as amyloid-ß (Aß) and α-synuclein. Concomitant with fluorescence turn-on, OPE also photosensitizes singlet oxygen under illumination through the generation of a triplet state, pointing to the potential application of OPEs as photosensitizers in PDT. Herein, we investigated the photosensitizing activity of an anionic OPE for the photo-oxidation of Aß fibrils and compared its efficacy to the well-known but nonselective photosensitizer methylene blue (MB). Our results show that, while MB photo-oxidized both monomeric and fibrillar conformers of Aß40, OPE oxidized only Aß40 fibrils, targeting two histidine residues on the fibril surface and a methionine residue located in the fibril core. Oxidized fibrils were shorter and more dispersed but retained the characteristic ß-sheet rich fibrillar structure and the ability to seed further fibril growth. Importantly, the oxidized fibrils displayed low toxicity. We have thus discovered a class of novel theranostics for the simultaneous detection and oxidization of amyloid aggregates. Importantly, the selectivity of OPE's photosensitizing activity overcomes the limitation of off-target oxidation of traditional photosensitizers and represents an advancement of PDT as a viable strategy to treat neurodegenerative disorders.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Enfermedad de Alzheimer/metabolismo , Amiloide/química , Péptidos beta-Amiloides/metabolismo , Proteínas Amiloidogénicas , Humanos , Fragmentos de Péptidos/química , Conformación Proteica en Lámina betaRESUMEN
The LDL receptor-related protein 1 (LRP1) partakes in metabolic and signaling events regulated in a tissue-specific manner. The function of LRP1 in airways has not been studied. We aimed to study the function of LRP1 in smoke-induced disease. We found that bronchial epithelium of patients with chronic obstructive pulmonary disease and airway epithelium of mice exposed to smoke had increased LRP1 expression. We then knocked out LRP1 in human bronchial epithelial cells in vitro and in airway epithelial club cells in mice. In vitro, LRP1 knockdown decreased cell migration and increased transforming growth factor ß activation. Tamoxifen-inducible airway-specific LRP1 knockout mice (club Lrp1-/-) induced after complete lung development had increased inflammation in the bronchoalveolar space and lung parenchyma at baseline. After 6 months of smoke exposure, club Lrp1-/- mice showed a combined restrictive and obstructive phenotype, with lower compliance, inspiratory capacity, and forced expiratory volume0.05/forced vital capacity than WT smoke-exposed mice. This was associated with increased values of Ashcroft fibrotic index. Proteomic analysis of room air exposed-club Lrp1-/- mice showed significantly decreased levels of proteins involved in cytoskeleton signaling and xenobiotic detoxification as well as decreased levels of glutathione. The proteome fingerprint created by smoke eclipsed many of the original differences, but club Lrp1-/- mice continued to have decreased lung glutathione levels and increased protein oxidative damage and airway cell proliferation. Therefore, LRP1 deficiency leads to greater lung inflammation and damage and exacerbates smoke-induced lung disease.
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Remodelación de las Vías Aéreas (Respiratorias) , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Estrés Oxidativo , Humo , Animales , Epitelio/metabolismo , Glutatión/metabolismo , Humanos , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Pulmón/metabolismo , Ratones , Proteómica , Humo/efectos adversosRESUMEN
INTRODUCTION: Orthodontic tooth movement (OTM) relies on bone remodeling and controlled aseptic inflammation. Autophagy, a conserved homeostatic pathway, has been shown to play a role in bone turnover. We hypothesize that autophagy participates in regulating bone remodeling during OTM in a force-dependent and cell type-specific manner. METHODS: A split-mouth design was used to load molars with 1 of 3 force levels (15, 30, or 45 g of force) in mice carrying a green fluorescent protein-LC3 transgene to detect cellular autophagy. Fluorescent microscopy and quantitative polymerase chain reaction analyses were used to evaluate autophagy activation and its correlation with force level. Cell type-specific antibodies were used to identify cells with green fluorescent protein-positive puncta (autophagosomes) in periodontal tissues. RESULTS: Autophagic activity increased shortly after loading with moderate force and was associated with the expression of bone turnover, inflammatory, and autophagy markers. Different load levels resulted in altered degrees of autophagic activation, gene expression, and osteoclast recruitment. Autophagy was specifically induced by loading in macrophages and osteoclasts found in the periodontal ligament and alveolar bone. Data suggest autophagy participates in regulating bone turnover during OTM. CONCLUSIONS: Autophagy is induced in macrophage lineage cells by orthodontic loading in a force-dependent manner and plays a role during OTM, possibly through modulation of osteoclast bone resorption. Exploring the roles of autophagy in OTM is medically relevant, given that autophagy is associated with oral and systemic inflammatory conditions.
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Osteoclastos , Técnicas de Movimiento Dental , Animales , Autofagia , Remodelación Ósea/fisiología , Ratones , Ligamento PeriodontalRESUMEN
Objectives: Racism-related stress is associated with significant mental health costs, necessitating the development of coping strategies to mitigate the negative sequelae. Mindfulness and valued living (MVL)-based strategies may be uniquely beneficial in addressing the negative effects of racism-related stress for people of color (POC) by decreasing internalized messages, while increasing self-compassion, coping flexibility, and engagement in values-based actions. It is imperative that clinicians applying or recommending MVL strategies to POC for coping with racism-related stress understand the complex nature of racism and, given that complexity, consider how MVL may need to be adapted to be effective. This paper offers guidance to clinicians seeking to use MVL strategies with clients of color to cope with racism-related stress. Methods: We provide a brief contextual literature review on the nature of racism, mental health impacts of racism-related stress for POC, and selected models of coping with racism-related stress. We also review existing mindfulness literature in relation to coping with racism-related stress, while offering considerations for adapting MVL strategies specifically for coping with racism-related stress. Results: Altogether, the research points to the promise of MVL strategies as beneficial interventions for coping with racism-related stress, although more research is warranted. We recommend that clinicians consider the suggestions outlined to present MVL strategies to clients in culturally responsive, validating ways. Conclusions: Further research is needed to evaluate links between MVL strategies and mental health, and to evaluate whether discrimination-specific adaptations are beneficial in mitigating the mental health impacts of racism-related stress.