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Fusobacterium sphaericum sp nov, Isolated From a Human Colon Tumor Adheres to Colonic Epithelial Cells and Induces Il-8 Secretion
Get PDFCancerous tissue is a largely unexplored microbial niche that provides a unique environment for the colonization and growth of specific bacterial communities, and with it, the opportunity to identify novel bacterial species. Here, we report distinct features of a novel Fusobacterium species, F. sphaericum sp. nov. (Fs), isolated from primary colon adenocarcinoma tissue. We acquire the complete closed genome and associated methylome of this organism and phylogenetically confirm its classification into the Fusobacterium genus, with F. perfoetens as its closest neighbor. Fs is phenotypically and genetically distinct, with morphological analysis revealing its coccoid shape, that while similar to F. perfoetens is rare for most Fusobacterium members. Fs displays a metabolic profile and antibiotic resistance repertoire consistent with other Fusobacterium species. In vitro, Fs has adherent and immunomodulatory capabilities, as it intimately associates with human colon cancer epithelial cells and promotes IL-8 secretion. An analysis of the prevalence and abundance of Fs in \u3e 20,000 human metagenomic samples shows that it is a rarely detected member within human stool with variable relative abundance, found in both healthy controls and patients with colorectal cancer (CRC). Our study sheds light on a novel bacterial species isolated directly from the human CRC tumor niche and given its in vitro interaction with cancer epithelial cells suggests that its role in human health and disease warrants further investigation
PSPC1 Exerts an Oncogenic Role in AML by Regulating a Leukemic Transcription Program in Cooperation With PU1
No full textAcute myeloid leukemia (AML) is an aggressive hematopoietic malignancy characterized by the blockage of myeloid cell differentiation and uncontrolled proliferation of immature myeloid cells. Here, we show that paraspeckle component 1 (PSPC1) is aberrantly overexpressed and associated with poor survival in AML patients. Using human AML cells and mouse models, we demonstrate that PSPC1 is not required for normal hematopoiesis, but it is critical and essential for AML cells to maintain their leukemic characteristics. PSPC1 loss induces robust differentiation, suppresses proliferation, and abolishes leukemogenesis in diverse AML cells. Mechanistically, PSPC1 exerts a pro-leukemia effect by regulating a unique leukemic transcription program via cooperative chromatin binding with PU.1 and activation of tumor-promoting genes, including NDC1, which is not previously implicated in AML. Our findings uncover a unique and crucial role of PSPC1 dependency in AML and highlight its potential as a promising therapeutic target for AML
Strategies for the Secondary Prevention of Atherosclerotic Cardiovascular Disease
No full textPatients with atherosclerotic cardiovascular disease (ASCVD), such as those with a history of MI or stroke, are at high risk for morbidity and mortality associated with future cardiovascular events. Ideal management of these patients requires a multifactorial strategy for risk factor mitigation and prevention of additional cardiovascular events. Traditional management of secondary prevention patients involves lipid-lowering with statins, blood pressure control, and anti-platelet treatment. Several additional targets have been identified to optimize the secondary prevention of ASCVD, such as further lipid control, inflammation management, lifestyle and weight optimization, strict diabetes control, use of β-blockers, use of renin-angiotensin-aldosterone system inhibitors, vaccinations, and additional considerations of anti-thrombotic therapies. This review will describe the interventions associated with these targets, as well as the relevant research and indications for these therapies
First Assembly of a Draft Genome of the Critically Endangered Northern Muriqui ( Brachyteles hypoxanthus , Primates, Atelidae) Including Non‐Invasive Genotyping Strategies for the Species
No full textGenomic resources, such as draft genomes, are vital for biodiversity monitoring and conservation. For endangered species, they enable the development of tools like organellar genomes and molecular markers, which are crucial for population genetics. Advances in sequencing technologies now allow high‐throughput genotyping with detailed amplicon sequences, enhancing genetic variation studies. The northern muriqui ( Brachyteles hypoxanthus ), a critically endangered primate endemic to Brazil\u27s Atlantic Forest, currently lacks both nuclear and mitochondrial genome data and species‐specific microsatellite markers for population genetic studies. We assembled a 2.52 Gb draft genome for B. hypoxanthus with 202,243 contigs (N50 = 29,134 bp), and BUSCO analyses indicated 52% completeness and 15.5% fragmented genes. The complete 16,635 bp mitochondrial genome retains the conserved mammalian structure with 22 tRNAs, 2 rRNAs, 13 CDS, and an origin of replication. Additionally, we designed 31 SSR primer pairs suitable for non‐invasive sampling and genotyping, alongside two mtDNA and two sex‐determination primers, configured into three multiplex PCR sets. These genomic resources, including the draft genome, complete mitochondrial genome, and microsatellite markers, provide essential tools for evolutionary analyses and the genetic monitoring of B. hypoxanthus populations, supporting its conservation
Optimal Head-of-Bed Positioning Before Thrombectomy in Large Vessel Occlusion Stroke: A Randomized Clinical Trial
No full textImportance: Small studies show that 0° head positioning of patients with large vessel occlusion (LVO) stroke improves penumbral blood flow and clinical stability. Understanding whether 0° head position maintains clinical stability would allow for optimal patient positioning before thrombectomy.
Objective: To determine superiority of 0° over 30° head positioning at maintaining clinical stability in patients with LVO before thrombectomy.
Design, setting, and participants: This was a prospective randomized clinical trial with blinding to study enrollment/end points conducted from May 2018 to November 2023. There were 3 planned interim analyses, and the study was conducted at certified thrombectomy hospitals in the US. Included in this analysis were consecutive consenting individuals with computed tomography (CT) angiography-positive anterior or posterior LVO who were candidates for thrombectomy (baseline mRS 0-1) and had viable penumbra (CT perfusion or Alberta Stroke Program Early Computed Tomography Score ≥6) within 24 hours of stroke onset. Enrollment of systemic thrombolysis more than 15 minutes from consent was discouraged to prevent confounding of head position effects; in addition, patients with disabilities who lacked a legal representative could not participate due to lack of consent.
Interventions: Randomization to 0° or 30° head positioning with monitoring every 10 minutes using the National Institutes of Health Stroke Scale (NIHSS) until movement to a catheterization table.
Main outcome and measures: The primary outcome was worsening of 2 or more NIHSS points before thrombectomy. Safety outcomes included severe neurologic deterioration (worsening ≥4 NIHSS points) before thrombectomy, hospital-acquired pneumonia (HAP) during hospitalization, and all-cause death within 3 months.
Results: Planned enrollment included 182 patients. Before data and safety monitoring board study closure, a total of 92 patients (mean [SD] age, 66.6 [14.4] years; 48 male [52.2%]) were randomized: 45 patients to the group with 0° head positioning and 47 patients to the group with 30° head positioning. Patient characteristics were similar between groups; however, patients with head position at 30° experienced worsening on the NIHSS of 2 points or more, whereas patients with head position at 0° showed score stability (hazard ratio [HR], 34.40; 95% CI, 4.65-254.37; P \u3c .001). One patient with 0° head positioning and 20 patients with 30° head positioning experienced worsening on the NIHSS of 4 points or more during positioning (HR, 23.57; 95% CI, 3.16-175.99; P = .002). No patients developed HAP; all-cause death occurred in 2 patients (4.4%) in the 0° group, compared with 10 patients (21.7%; P = .03) in the 30° group.
Conclusions and relevance: Results suggest that 0° head positioning for patients with acute LVO was a protective maneuver to maintain clinical stability in the prethrombectomy phase while awaiting definitive treatment
Integrating Endocannabinoid Signaling, CCK Interneurons, and Hippocampal Circuit Dynamics in Behaving Animals
No full textThe brain\u27s endocannabinoid signaling system modulates a diverse range of physiological phenomena and is also involved in various psychiatric and neurological disorders. The basic components of the molecular machinery underlying endocannabinoid-mediated synaptic signaling have been known for decades. However, limitations associated with the short-lived nature of endocannabinoid lipid signals had made it challenging to determine the spatiotemporal specificity and dynamics of endocannabinoid signaling in vivo. Here, we discuss how novel technologies have recently enabled unprecedented insights into endocannabinoid signaling taking place at specific synapses in behaving animals. In this review, we primarily focus on cannabinoid-sensitive inhibition in the hippocampus in relation to place cell properties to illustrate the potential of these novel methodologies. In addition, we highlight implications of these approaches and insights for the unraveling of cannabinoid regulation of synapses in vivo in other brain circuits in both health and disease
Pregnancy in Dystonia or Tourette\u27s Patients with DBS. Fourteen News Cases and a Review of the Literature
No full textBackground: Deep Brain Stimulation (DBS) has been demonstrated to improve quality of life in patients with refractory dystonia and Tourette\u27s syndrome (TS). Because of the young age at onset of these disorders, and the marked benefit from DBS, pregnancy in patients who have received DBS is becoming a more frequent clinical occurrence, although clear management guidelines are lacking.
Cases: We report 14 new pregnancies in patients with dystonia or TS and DBS.
Literature review: Upon review of the literature, 23 pregnancies in patients with dystonia or TS were previously reported in seven articles.
Conclusion: Based on the available data from a total of 37 pregnancies, DBS does not seem associated with worse pregnancy outcome. However, careful planning and communication between neurologist, anesthesiologist and obstetrician are key. A registry on pregnancy outcome in patients with DBS should be generated to facilitate the development of guidelines
Author Correction: Disruption of Neural Periodicity Predicts Clinical Response After Deep Brain Stimulation for Obsessive-Compulsive Disorder
No full textThe Synaptic Architecture of Layer 5 Thick Tufted Excitatory Neurons in Mouse Visual Cortex
No full textDespite significant progress in characterizing neocortical cell types, a complete understanding of the synaptic connections of individual excitatory cells remains elusive. This study investigates the connectivity of mouse visual cortex thick tufted layer 5 pyramidal cells, also known as extratelencephalic neurons (L5-ETns), using a 1 mm3 publicly available electron microscopy dataset. The analysis reveals that, in their immediate vicinity, L5-ETns primarily establish connections with a group of inhibitory cell types, which, in turn, specifically target the L5-ETns back. The most common excitatory targets of L5-ETns are layer 5 intertelencephalic neurons (L5-ITns) and layer 6 (L6) pyramidal cells, whereas synapses with other L5-ETns are less common. When L5-ETns extend their axons to other cortical regions, they tend to connect more with excitatory cells. Our results highlight a circuit motif where a subclass of excitatory cells forms a subcircuit with specific inhibitory cell types. This is achieved using a publicly available, automated approach for synapse recognition and automated cell typing, offering a framework for exploring the connectivity of other neuron types