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JOURNAL/nrgr/04.03/01300535-202504000-00033/figure1/v/2024-07-06T104127Z/r/image-tiff Behavioral recovery using (viable) peripheral nerve allografts to repair ablation-type (segmental-loss) peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal regeneration. Furthermore, such peripheral nerve allografts undergo immunological rejection by the host immune system. In contrast, peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks, reduced immune responses, and many axons do not undergo Wallerian degeneration. The relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this study. We hypothesized that polyethylene glycol might have some immune-protective effects, but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral recovery. We examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal fusion. Ablation-type sciatic nerve injuries in outbred Sprague-Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts, but peripheral nerve allografts were loose-sutured (loose-sutured polyethylene glycol) with an intentional gap of 1-2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host axons. Similar to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts, animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days postoperatively. Other morphological signs of rejection, such as collapsed Schwann cell basal lamina tubes, were absent in polyethylene glycol-fused peripheral nerve allografts but commonly observed in negative control and loose-sutured polyethylene glycol peripheral nerve allografts at 21 days postoperatively. Loose-sutured polyethylene glycol peripheral nerve allografts had more pro-inflammatory and less anti-inflammatory macrophages than negative control peripheral nerve allografts. While T cell counts were similarly high in loose-sutured-polyethylene glycol and negative control peripheral nerve allografts, loose-sutured polyethylene glycol peripheral nerve allografts expressed some cytokines/chemokines important for T cell activation at much lower levels at 14 days postoperatively. MHCI expression was elevated in loose-sutured polyethylene glycol peripheral nerve allografts, but MHCII expression was modestly lower compared to negative control at 21 days postoperatively. We conclude that, while polyethylene glycol per se reduces some immune responses of peripheral nerve allografts, successful polyethylene glycol-fusion repair of some axons is necessary to prevent Wallerian degeneration of those axons and immune rejection of peripheral nerve allografts, and produce recovery of sensory/motor functions and voluntary behaviors. Translation of polyethylene glycol-fusion technologies would produce a paradigm shift from the current clinical practice of waiting days to months to repair ablation peripheral nerve injuries.
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While the centrality of posttranscriptional modifications to RNA biology has long been acknowledged, the function of the vast majority of modified sites remains to be discovered. Illustrative of this, there is not yet a discrete biological role assigned for one of the most highly conserved modifications, 5-methyluridine at position 54 in tRNAs (m5U54). Here, we uncover contributions of m5U54 to both tRNA maturation and protein synthesis. Our mass spectrometry analyses demonstrate that cells lacking the enzyme that installs m5U in the T-loop (TrmA in Escherichia coli, Trm2 in Saccharomyces cerevisiae) exhibit altered tRNA modification patterns. Furthermore, m5U54-deficient tRNAs are desensitized to small molecules that prevent translocation in vitro. This finding is consistent with our observations that relative to wild-type cells, trm2Δ cell growth and transcriptome-wide gene expression are less perturbed by translocation inhibitors. Together our data suggest a model in which m5U54 acts as an important modulator of tRNA maturation and translocation of the ribosome during protein synthesis.
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Escherichia coli , RNA de Transferência , Ribossomos , Saccharomyces cerevisiae , Uridina , RNA de Transferência/metabolismo , RNA de Transferência/genética , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Ribossomos/metabolismo , Uridina/metabolismo , Escherichia coli/metabolismo , Escherichia coli/genética , Processamento Pós-Transcricional do RNA , Biossíntese de Proteínas , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , tRNA Metiltransferases/metabolismo , tRNA Metiltransferases/genéticaRESUMO
INTRODUCTION: The Control Network Neuromodulation to Enhance Cognitive Training in Complex Traumatic Brain Injury (CONNECT-TBI) study is an ongoing randomized, double-blinded, sham-controlled multisite clinical trial to determine the enhancing effects of noninvasive neuromodulation when paired with cognitive training in military participants (Veterans and active duty) with mild TBI. Attention Process Training-III (APT-III) was selected for its strong evidence base, manualized procedures, and computerized program. However, many aspects of APT-III that make it ideal for personalization make it less ideal for reliable implementation across participants, clinicians/technicians, and sites. The purpose of this feature article is to highlight APT-III procedures that require additional standardization for reliable administration across participants and sites. MATERIALS AND METHODS: Ten studies using APT-III were reviewed for methodology of APT-III administration. The manual was also scrutinized; aspects of administration that involved clinical decision-making, subjectivity, flexibility, and/or that were identified by the APT-III developers as areas in need of "empirical evaluation" were flagged by clinicians. Literature and manual review findings were presented to the team for discussion and solution-finding. The authors created and refined a standardized process that would allow participants to move through APT-III training, including task movement algorithms and new materials drafts. Refining of algorithms and drafts continued until there was a consensus from team members. RESULTS: Many gray areas were identified, but we will limit our reporting to focus on (1) dosage, (2) adaptation, (3) metacognitive strategy instruction, and (4) goal attainment scaling. We present APT-III manual details, literature review findings, and CONNECT-TBI decisions and materials for each of these areas of focus. CONCLUSIONS: We have highlighted some of the major gray areas of APT-III administration so that fellow researchers can understand the need to take similar steps in clinical trials using APT-III. We provide examples of our standardization process and resultant rules and materials. Our algorithm, based on prior studies using the APT-III and our own iterative adjustments, allows for adjustment of the difficulty and speed of the training tasks (but within certain parameters) in order to achieve the best balance between individualization and consistency across participants and sites. We provide an example of a workflow and reporting process for future studies.
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Atenção , Humanos , Atenção/fisiologia , Método Duplo-Cego , Lesões Encefálicas Traumáticas/terapiaRESUMO
Prior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5-year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere-winter (December-February); spring (March-May); summer (June-August); autumn (September-November) and Southern Hemisphere-winter (June-August); spring (September-November); summer (December-February); autumn (March-May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%-31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization.
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Apicomplexan parasites balance proliferation, persistence, and spread in their metazoan hosts. AGC kinases, such as PKG, PKA, and the PDK1 ortholog SPARK, integrate environmental signals to toggle parasites between replicative and motile life stages. Recent studies have cataloged pathways downstream of apicomplexan PKG and PKA; however, less is known about the global integration of AGC kinase signaling cascades. Here, conditional genetics coupled to unbiased proteomics demonstrates that SPARK complexes with an elongin-like protein to regulate the stability of PKA and PKG in the model apicomplexan Toxoplasma gondii. Defects attributed to SPARK depletion develop after PKG and PKA are down-regulated. Parasites lacking SPARK differentiate into the chronic form of infection, which may arise from reduced activity of a coccidian-specific PKA ortholog. This work delineates the signaling topology of AGC kinases that together control transitions within the asexual cycle of this important family of parasites.
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Proteínas de Protozoários , Toxoplasma , Toxoplasma/genética , Toxoplasma/enzimologia , Toxoplasma/fisiologia , Toxoplasma/crescimento & desenvolvimento , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/genética , Animais , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/genética , Transdução de Sinais , Reprodução AssexuadaRESUMO
Background: The univoltine leaf beetle Psylliodesattenuata (Koch, 1803) is a pest of Cannabis and Humulus (Cannabaceae) and native to the Palaearctic Region, known from eastern Asia to western Europe. New information: First North American records are presented for P.attenuata from Canada: Ontario and Québec. Adult beetle feeding damage to hops Humuluslupulus L. (Cannabacaea) plants is recorded from Québec. Diagnostic information is presented to distinguish P.attenuata from other North American Chrysomelidae and a preliminary assessment of its potential to spread in North America is presented. While our climate analysis is limited by a lack of data, it appears P.attenuata is physiologically capable of persisting throughout the range of Humulus in North America.The United States of America and Canada are now known to be home to 71 or more species of adventive Chrysomelidae.
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BACKGROUND AND AIMS: Dysregulated cholesterol metabolism is a hallmark of atherosclerotic cardiovascular diseases, yet our understanding of how endogenous cholesterol synthesis affects atherosclerosis is not clear. The energy sensor AMP-activated protein kinase (AMPK) phosphorylates and inhibits the rate-limiting enzyme in the mevalonate pathway HMG-CoA reductase (HMGCR). Recent work demonstrated that when AMPK-HMGCR signaling was compromised in an Apoe-/- model of hypercholesterolemia, atherosclerosis was exacerbated due to elevated hematopoietic stem and progenitor cell mobilization and myelopoiesis. We sought to validate the significance of the AMPK-HMGCR signaling axis in atherosclerosis using a non-germline hypercholesterolemia model with functional ApoE. METHODS: Male and female HMGCR S871A knock-in (KI) mice and wild-type (WT) littermate controls were made atherosclerotic by intravenous injection of a gain-of-function Pcsk9D374Y-adeno-associated virus followed by high-fat and high-cholesterol atherogenic western diet feeding for 16 weeks. RESULTS: AMPK activation suppressed endogenous cholesterol synthesis in primary bone marrow-derived macrophages from WT but not HMGCR KI mice, without changing other parameters of cholesterol regulation. Atherosclerotic plaque area was unchanged between WT and HMGCR KI mice, independent of sex. Correspondingly, there were no phenotypic differences observed in hematopoietic progenitors or differentiated immune cells in the bone marrow, blood, or spleen, and no significant changes in systemic markers of inflammation. When lethally irradiated female mice were transplanted with KI bone marrow, there was similar plaque content relative to WT. CONCLUSIONS: Given previous work, our study demonstrates the importance of preclinical atherosclerosis model comparison and brings into question the importance of AMPK-mediated control of cholesterol synthesis in atherosclerosis.
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In this study we have identified POLθ-S6K-p62 as a novel druggable regulator of radiation response in prostate cancer. Despite significant advances in delivery, radiotherapy continues to negatively affect treatment outcomes and quality of life due to resistance and late toxic effects to the surrounding normal tissues such as bladder and rectum. It is essential to develop new and effective strategies to achieve better control of tumor. We found that ribosomal protein S6K (RPS6KB1) is elevated in human prostate tumors, and contributes to resistance to radiation. As a downstream effector of mTOR signaling, S6K is known to be involved in growth regulation. However, the impact of S6K signaling on radiation response has not been fully explored. Here we show that loss of S6K led to formation of smaller tumors with less metastatic ability in mice. Mechanistically we found that S6K depletion reduced NFκB and SQSTM1 (p62) reporter activity and DNA polymerase θ (POLθ) that is involved in alternate end-joining repair. We further show that the natural compound berberine interacts with S6K in a in a hitherto unreported novel mode and that pharmacological inhibition of S6K with berberine reduces Polθ and downregulates p62 transcriptional activity via NFκB. Loss of S6K or pre-treatment with berberine improved response to radiation in prostate cancer cells and prevented radiation-mediated resurgence of PSA in animals implanted with prostate cancer cells. Notably, silencing POLQ in S6K overexpressing cells enhanced response to radiation suggesting S6K sensitizes prostate cancer cells to radiation via POLQ. Additionally, inhibition of autophagy with CQ potentiated growth inhibition induced by berberine plus radiation. These observations suggest that pharmacological inhibition of S6K with berberine not only downregulates NFκB/p62 signaling to disrupt autophagic flux but also decreases Polθ. Therefore, combination treatment with radiation and berberine inhibits autophagy and alternate end-joining DNA repair, two processes associated with radioresistance leading to increased radiation sensitivity.
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NF-kappa B , Neoplasias da Próstata , Tolerância a Radiação , Proteína Sequestossoma-1 , Transdução de Sinais , Masculino , Animais , Humanos , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/tratamento farmacológico , Proteína Sequestossoma-1/metabolismo , Proteína Sequestossoma-1/genética , NF-kappa B/metabolismo , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos , Camundongos , Tolerância a Radiação/efeitos dos fármacos , Linhagem Celular Tumoral , DNA Polimerase Dirigida por DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genéticaAssuntos
Ecocardiografia Doppler , Artéria Pulmonar , Insuficiência da Valva Tricúspide , Humanos , Insuficiência da Valva Tricúspide/fisiopatologia , Insuficiência da Valva Tricúspide/complicações , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Ecocardiografia Doppler/métodos , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Feminino , Masculino , Índice de Gravidade de Doença , Reprodutibilidade dos Testes , Pessoa de Meia-Idade , Sístole , Sensibilidade e Especificidade , IdosoRESUMO
Metabolic programming underpins inflammation and liver macrophage activation in the setting of chronic liver disease. Here, we sought to identify the role of an important metabolic regulator, AMP-activated protein kinase (AMPK), specifically within myeloid cells during the progression of non-alcoholic steatohepatitis (NASH) and whether treatment with metformin, a firstline therapy for diabetes and activator of AMPK could stem disease progression. Male and female Prkaa1fl/fl/Prkaa2fl/fl (Flox) control and Flox-LysM-Cre+ (MacKO) mice were fed a low-fat control or a choline-deficient, amino acid defined 45% Kcal high-fat diet (CDAHFD) for 8 weeks, where metformin was introduced in the drinking water (50 or 250 mg/kg/day) for the last 4 weeks. Hepatic steatosis and fibrosis were dramatically increased in response to CDAHFD-feeding compared to low-fat control. While myeloid AMPK signaling had no effect on markers of hepatic steatosis or circulating markers, fibrosis as measured by total liver collagen was significantly elevated in livers from MacKO mice, independent of sex. Although treatment with 50 mg/kg/day metformin had no effect on any parameter, intervention with 250 mg/kg/day metformin completely ameliorated hepatic steatosis and fibrosis in both male and female mice. While the protective effect of metformin was associated with lower final body weight, and decreased expression of lipogenic and Col1a1 transcripts, it was independent of myeloid AMPK signaling. These results suggest that endogenous AMPK signaling in myeloid cells, both liver-resident and infiltrating, acts to restrict fibrogenesis during CDAHFD-induced NASH progression but is not the mechanism by which metformin improves markers of NASH.
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Proteínas Quinases Ativadas por AMP , Dieta Hiperlipídica , Metformina , Hepatopatia Gordurosa não Alcoólica , Transdução de Sinais , Animais , Metformina/farmacologia , Metformina/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Camundongos , Dieta Hiperlipídica/efeitos adversos , Proteínas Quinases Ativadas por AMP/metabolismo , Masculino , Feminino , Transdução de Sinais/efeitos dos fármacos , Células Mieloides/metabolismo , Células Mieloides/efeitos dos fármacos , Cirrose Hepática/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Cirrose Hepática/induzido quimicamente , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologiaRESUMO
Realizing topological superconductivity by integrating high-transition-temperature (TC) superconductors with topological insulators can open new paths for quantum computing applications. Here, a new approach is reported for increasing the superconducting transition temperature ( T C onset ) $( {T_{\mathrm{C}}^{{\mathrm{onset}}}} )$ by interfacing the unconventional superconductor Fe(Te,Se) with the topological insulator Bi-Te system in the low-Se doping regime, near where superconductivity vanishes in the bulk. The critical finding is that the T C onset $T_{\mathrm{C}}^{{\mathrm{onset}}}$ of Fe(Te,Se) increases from nominally non-superconducting to as high as 12.5 K when Bi2Te3 is replaced with the topological phase Bi4Te3. Interfacing Fe(Te,Se) with Bi4Te3 is also found to be critical for stabilizing superconductivity in monolayer films where T C onset $T_{\mathrm{C}}^{{\mathrm{onset}}}$ can be as high as 6 K. Measurements of the electronic and crystalline structure of the Bi4Te3 layer reveal that a large electron transfer, epitaxial strain, and novel chemical reduction processes are critical factors for the enhancement of superconductivity. This novel route for enhancing TC in an important epitaxial system provides new insight on the nature of interfacial superconductivity and a platform to identify and utilize new electronic phases.
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Stent migration is a rare but significant complication following endovascular procedures. Techniques for managing dislodged stents have included surgical, endovascular, and conservative approaches. This case details a patient who had a covered stent placed within the left renal vein which later migrated to the pulmonary artery causing damage to the tricuspid valve. The migrated stent was successfully removed using a percutaneous endovascular approach utilizing fluoroscopy and transesophageal echocardiogram guidance.
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Background: Thinner anterior hip capsules are associated with hip laxity, but there is little known about the impact of capsular thickness on the development of instability after primary hip arthroscopic surgery. Purpose: To investigate the relationship between hip capsular thickness as measured on preoperative magnetic resonance imaging (MRI) and the development of hip instability after hip arthroscopic surgery for femoroacetabular impingement. Study Design: Case-control study; Level of evidence, 3. Methods: We reviewed revision hip arthroscopic procedures performed between January 1, 2019, and May 1, 2021, at a single institution. Inclusion criteria were preoperative MRI/magnetic resonance arthrography, completion of the study traction protocol, and asymmetric distraction between the hips of ≥3 mm on examination under anesthesia. A comparison group of patients treated for femoroacetabular impingement with primary hip arthroscopic surgery who did not develop capsular instability were matched 1:1 to the patients with instability. Superolateral hip capsular thickness was measured on MRI before index surgery. Analysis was conducted using independent-samples t tests and multivariable linear regression. Results: A total of 44 patients were included, with 22 patients each in the instability and no-instability groups. The mean capsular thickness was lower in the patients with hip instability than in those without (1.9 ± 0.6 vs 3.4 ± 1.1 mm, respectively; P < .001). Decreased capsular thickness was significantly associated with hips with instability versus no-instability (ß = -1.468 [95% CI, -2.049 to -0.887]; P < .001). Conclusion: Thinner preoperative hip capsules in the region of the iliofemoral ligament were seen in patients who subsequently underwent revision arthroscopic surgery for hip instability compared to patients who underwent primary hip arthroscopic surgery without subsequent revision. Patients at a higher risk for the development of postoperative hip instability had a superolateral hip capsular thickness of <2 mm.
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The function and stability of mesophotic coral ecosystems (MCEs) have been extensively studied in recent years. These deep reefs are characterized by local physical processes, particularly the steep gradient in irradiance with increasing depth, and their impact on trophic resources. Mesophotic reefs exhibit distinct zonation patterns that segregate shallow reef biodiversity from ecologically unique deeper communities of endemic species. While mesophotic reefs are hypothesized as relatively stable refuges from anthropogenic stressors and a potential seed bank for degraded shallow reefs, these are site-specific features, if they occur at all. Mesophotic reefs are now known to be susceptible to many of the same stressors that are degrading shallow reefs, suggesting that they require their own specific conservation and management strategies.
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Antozoários , Biodiversidade , Conservação dos Recursos Naturais , Recifes de Corais , Animais , Antozoários/fisiologia , EcossistemaRESUMO
Importance: Current interventions for posttraumatic stress disorder (PTSD) are efficacious, yet effectiveness may be limited by adverse effects and high withdrawal rates. Acupuncture is an emerging intervention with positive preliminary data for PTSD. Objective: To compare verum acupuncture with sham acupuncture (minimal needling) on clinical and physiological outcomes. Design, Setting, and Participants: This was a 2-arm, parallel-group, prospective blinded randomized clinical trial hypothesizing superiority of verum to sham acupuncture. The study was conducted at a single outpatient-based site, the Tibor Rubin VA Medical Center in Long Beach, California, with recruitment from April 2018 to May 2022, followed by a 15-week treatment period. Following exclusion for characteristics that are known PTSD treatment confounds, might affect biological assessment, indicate past nonadherence or treatment resistance, or indicate risk of harm, 93 treatment-seeking combat veterans with PTSD aged 18 to 55 years were allocated to group by adaptive randomization and 71 participants completed the intervention protocols. Interventions: Verum and sham were provided as 1-hour sessions, twice weekly, and participants were given 15 weeks to complete up to 24 sessions. Main Outcomes and Measures: The primary outcome was pretreatment to posttreatment change in PTSD symptom severity on the Clinician-Administered PTSD Scale-5 (CAPS-5). The secondary outcome was pretreatment to posttreatment change in fear-conditioned extinction, assessed by fear-potentiated startle response. Outcomes were assessed at pretreatment, midtreatment, and posttreatment. General linear models comparing within- and between-group were analyzed in both intention-to-treat (ITT) and treatment-completed models. Results: A total of 85 male and 8 female veterans (mean [SD] age, 39.2 [8.5] years) were randomized. There was a large treatment effect of verum (Cohen d, 1.17), a moderate effect of sham (d, 0.67), and a moderate between-group effect favoring verum (mean [SD] Δ, 7.1 [11.8]; t90 = 2.87, d, 0.63; P = .005) in the intention-to-treat analysis. The effect pattern was similar in the treatment-completed analysis: verum d, 1.53; sham d, 0.86; between-group mean (SD) Δ, 7.4 (11.7); t69 = 2.64; d, 0.63; P = .01). There was a significant pretreatment to posttreatment reduction of fear-potentiated startle during extinction (ie, better fear extinction) in the verum but not the sham group and a significant correlation (r = 0.31) between symptom reduction and fear extinction. Withdrawal rates were low. Conclusions and Relevance: The acupuncture intervention used in this study was clinically efficacious and favorably affected the psychobiology of PTSD in combat veterans. These data build on extant literature and suggest that clinical implementation of acupuncture for PTSD, along with further research about comparative efficacy, durability, and mechanisms of effects, is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02869646.
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Distúrbios de Guerra , Transtornos de Estresse Pós-Traumáticos , Veteranos , Humanos , Adulto , Masculino , Transtornos de Estresse Pós-Traumáticos/terapia , Feminino , Pessoa de Meia-Idade , Distúrbios de Guerra/terapia , Distúrbios de Guerra/psicologia , Veteranos/psicologia , Adulto Jovem , Resultado do Tratamento , Terapia por Acupuntura/métodos , Reflexo de Sobressalto/fisiologia , Estudos Prospectivos , Acupuntura Auricular/métodosRESUMO
Ciguatera Poisoning (CP) is a widespread and complex poisoning syndrome caused by the consumption of fish or invertebrates contaminated with a suite of potent neurotoxins collectively known as ciguatoxins (CTXs), which are produced by certain benthic dinoflagellates species in the genera Gambierdiscus and Fukuyoa. Due to the complex nature of this HAB problem, along with a poor understanding of toxin production and entry in the coral reef food web, the development of monitoring, management, and forecasting approaches for CP has lagged behind those available for other HAB syndromes. Over the past two decades, renewed research on the taxonomy, physiology, and toxicology of CP-causing dinoflagellates has advanced our understanding of the species diversity that exists within these genera, including identification of highly toxic species (so called "superbugs") that likely contribute disproportionately to ciguatoxins entering coral reef food webs. The recent development of approaches for molecular analysis of field samples now provide the means to investigate in situ community composition, enabling characterization of spatio-temporal species dynamics, linkages between toxic species abundance and toxin flux, and the risk of ciguatoxin prevalence in fish. In this study we used species-specific fluorescent in situ hybridization (FISH) probes to investigate Gambierdiscus species composition and dynamics in St. Thomas (USVI) and the Florida Keys (USA) over multiple years (2018-2020). Within each location, samples were collected seasonally from several sites comprising varying depths, habitats, and algal substrates to characterize community structure over small spatial scales and across different host macrophytes. This approach enabled the quantitative determination of communities over spatiotemporal gradients, as well as the selective enumeration of species known to exhibit high toxicity, such as Gambierdiscus silvae. The investigation found differing community structure between St. Thomas and Florida Keys sites, driven in part by differences in the distribution of toxin-producing species G. silvae and G. belizeanus, which were present throughout sampling sites in St. Thomas but scarce or absent in the Florida Keys. This finding is significant given the high toxicity of G. silvae, and may help explain differences in fish toxicity and CP incidence between St. Thomas and Florida. Intrasite comparisons along a depth gradient found higher concentrations of Gambierdiscus spp. at deeper locations. Among the macrophytes sampled, Dictyota may be a likely vector for toxin transfer based on their widespread distribution, apparent colonization by G. silvae, and palatability to at least some herbivore grazers. Given its ubiquity throughout both study regions and sites, this taxa may also serve as a refuge, accumulating high concentrations of Gambierdiscus and other benthic dinoflagellates, which in turn can serve as source populations for highly palatable and ephemeral habitats nearby, such as turf algae. These studies further demonstrate the successful application of FISH probes in examining biogeographic structuring of Gambierdiscus communities, targeting individual toxin-producing species, and characterizing species-level dynamics that are needed to describe and model ecological drivers of species abundance and toxicity.
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Ciguatera , Ciguatoxinas , Dinoflagellida , Ciguatoxinas/toxicidade , Florida , Hibridização in Situ Fluorescente , Ilhas Virgens AmericanasRESUMO
Ciguatera poisoning (CP) is the most common form of phycotoxin-borne seafood poisoning globally, affecting thousands of people on an annual basis. It most commonly occurs in residential fish of coral reefs, which consume toxin-laden algae, detritus, and reef animals. The class of toxins that cause CP, ciguatoxins (CTXs), originate in benthic, epiphytic dinoflagellates of the genera, Gambierdiscus and Fukuyoa, which are consumed by herbivores and detritivores that facilitate food web transfer. A number of factors have hindered adequate environmental monitoring and seafood surveillance for ciguatera including the low concentrations in which the toxins are found in seafood causing illness (sub-ppb), a lack of knowledge on the toxicity equivalence of other CTXs and contribution of other benthic algal toxins to the disease, and the limited availability of quantified toxin standards and reference materials. While progress has been made on the identification of the dinoflagellate taxa and toxins responsible for CP, more effort is needed to better understand the dynamics of toxin transfer into reef food webs in order to implement a practical monitoring program for CP. Here, we present a conceptual model that utilizes empirical field data (temperature, Gambierdiscus cell densities, macrophyte cover) in concert with other published studies (grazing rates and preference) to produce modeling outputs that suggest approaches that may be beneficial to developing monitoring programs: 1) targeting specific macrophytes for Gambierdiscus and toxin measurements to monitor toxin levels at the base of the food web (i.e., toxin loading); and 2) adjusting these targets across sites and over seasons. Coupling this approach with other methodologies being incorporated into monitoring programs (artificial substrates; FISH probes; toxin screening) may provide an "early warning" system to develop strategic responses to potential CP flare ups in the future.
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Ciguatera , Ciguatoxinas , Dinoflagellida , Humanos , Animais , Ciguatoxinas/toxicidade , Região do Caribe , Monitoramento Ambiental/métodosRESUMO
ABSTRACT: Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor (CAR) T-cell platforms to treat T-cell malignancies often requires additional gene modifications to overcome fratricide because of shared T-cell antigens on normal and malignant T cells. We developed a CD5-directed CAR that produces minimal fratricide by downmodulating CD5 protein levels in transduced T cells while retaining strong cytotoxicity against CD5+ malignant cells. In our first-in-human phase 1 study (NCT0308190), second-generation autologous CD5.CAR T cells were manufactured from patients with r/r T-cell malignancies. Here, we report safety and efficacy data from a cohort of patients with mature T-cell lymphoma (TCL). Among the 17 patients with TCL enrolled, CD5 CAR T cells were successfully manufactured for 13 out of 14 attempted lines (93%) and administered to 9 (69%) patients. The overall response rate (complete remission or partial response) was 44%, with complete responses observed in 2 patients. The most common grade 3 or higher adverse events were cytopenias. No grade 3 or higher cytokine release syndrome or neurologic events occurred. Two patients died during the immediate toxicity evaluation period due to rapidly progressive disease. These results demonstrated that CD5.CAR T cells are safe and can induce clinical responses in patients with r/r CD5-expressing TCLs without eliminating endogenous T cells or increasing infectious complications. More patients and longer follow-up are needed for validation. This trial was registered at www.clinicaltrials.gov as #NCT0308190.
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Imunoterapia Adotiva , Linfoma de Células T , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Recidiva Local de Neoplasia/tratamento farmacológico , Linfócitos T , Doença Crônica , Linfoma de Células T/tratamento farmacológico , Antígenos CD19RESUMO
The self-organization of cells during development is essential for the formation of healthy tissues and requires the coordination of cell activities at local scales. Cytonemes, or signaling filopodia, are dynamic actin-based cellular protrusions that allow cells to engage in contact mediated signaling at a distance. While signaling filopodia have been shown to support several signaling paradigms during development, less is understood about how these protrusions are regulated. We investigated the role of the plus-end directed, unconventional MyTH4-FERM myosins in regulating signaling filopodia during sensory bristle patterning on the dorsal thorax of the fruit fly Drosophila melanogaster. We found that Myosin XV is required for regulating signaling filopodia dynamics and, as a consequence, lateral inhibition more broadly throughout the patterning epithelium. We found that Myosin XV is required for limiting the length and number of signaling filopodia generated by bristle precursor cells. Cells with additional and longer signaling filopodia due to loss of Myosin XV are not signaling competent, due to altered levels of Delta ligand and Notch receptor along their lengths. We conclude that Myosin XV acts to negatively regulate signaling filopodia, as well as promote the ability of signaling filopodia to engage in long-range Notch signaling. Since Myosin XV isoforms are present across several vertebrate and invertebrate systems, this may have significance for other long-range signaling mechanisms.
Assuntos
Drosophila melanogaster , Pseudópodes , Animais , Pseudópodes/metabolismo , Drosophila melanogaster/metabolismo , Miosinas , Drosophila/metabolismo , Transdução de SinaisRESUMO
In 2017, retail sales of herbal dietary supplements in the United States surpassed $8 billion for the first time, reaching an estimated total of $8.085 billion. Consumer spending increased by approximately $633 million, or 8.5%, from 2016 the strongest US sales growth for herbal supplements in more than 15 years. Total US retail sales have increased every year since 2004, and since then, consumer spending on herbal supplements has nearly doubled.