Rivers are a major source of microplastic particles (<5 mm) to oceans, but empirical measurements of microplastic movement in freshwater ecosystems are rare. The hard, buoyant surface of microplastic ...is a novel habitat that selects for unique microbial assemblages in rivers, especially downstream of wastewater treatment plant (WWTP) point sources. We measured microplastic in surface water and benthic habitats 50 m upstream and 50, 305, 1115, and 1900 m downstream of the effluent outfall from a large WWTP in an urban river. We used high-throughput sequencing to measure bacterial assemblages on microplastic from surface and benthic habitats and compared them to bacterial assemblages from seston, water, and sediment. Concentrations of total microplastic and microplastic types (fragment, pellet) in surface water did not change with distance downstream of the WWTP. Thus, microplastic transport showed no net deposition or resuspension. Microplastic concentrations were much higher in the benthic zone than surface water. Benthic deposition appears to be a plastic sink over longer time scales, but subsequent studies are needed to resolve microplastic transport dynamics by particle type, size, and habitat. Composition of microplastic-attached bacterial assemblages differed from that of assemblages in water, seston, and sediment and supports domestic wastewater as a point source of microplastic (e.g., gastrointestinal taxa). Shifts in microplastic assemblages with distance from the WWTP suggest succession toward a ‘stream-like’ bacterial assemblage. Future studies are required to quantify the metabolic capacity of microplastic-associated bacteria. Estimates of transport distance, microplastic storage, and microbial interactions are critical to include lotic ecosystems in accountings of global plastic budgets.
Purpose
Vertical sleeve gastrectomy (VSG) evolved in the early 2000s into the standalone weight loss procedure we see today. While numerous studies highlight VSG’s durability for weight loss, and ...improvements co-morbidities such as type 2 diabetes mellitus and cardiovascular disease, patients with gastroesophageal reflux disease (GERD) have been counseled against VSG due to the concern for worsening reflux symptoms. When considering anti-reflux procedures, VSG patients are unable to undergo traditional fundoplication due to lack of gastric cardia redundancy. Magnetic sphincter augmentation lacks long-term safety data and endoscopic approaches have undetermined longitudinal benefits. Until recently, the only option for patients with a history of VSG with medically refractory GERD has been conversion to roux en Y gastric bypass (RNYGB), however, this poses other risks including marginal ulcers, internal hernias, hypoglycemia, dumping syndrome, and nutritional deficiencies. Given the risks associated with conversion to RNYGB, we have adopted the ligamentum teres cardiopexy as an option for patients with intractable GERD following VSG.
Methods
A retrospective chart review was conducted of patients who had prior laparoscopic or robotic VSG and subsequently GERD symptoms refectory to pharmacological management who underwent ligamentum teres cardiopexy between 2017 and 2022. Pre-operative GERD disease burden, intraoperative cardiopexy characteristics, post-operative GERD symptomatology and changes in H2 blocker or PPI requirements were reviewed.
Results
Of the study’s 60 patients the median age was 50 years old, and 86% were female. All patients had a diagnosis of GERD through pre-operative assessments and were taking antisecretory medication. Of the 36 patients who have completed their one year follow up, 81% of patients had either a decrease in dosage or cessation of the antisecretory medication at one year following ligamentum teres cardiopexy.
Conclusion
Ligamentum teres cardiopexy is a viable alternative to RNYGB in patients with a prior vertical sleeve gastrectomy with medical refractory GERD.
Macrophages play an important role in structural cardiac remodeling and the transition to heart failure following myocardial infarction (MI). Previous research has focused on the impact of ...blood-derived monocytes on cardiac repair. Here we examined the contribution of resident cavity macrophages located in the pericardial space adjacent to the site of injury. We found that disruption of the pericardial cavity accelerated maladaptive post-MI cardiac remodeling. Gata6+ macrophages in mouse pericardial fluid contributed to the reparative immune response. Following experimental MI, these macrophages invaded the epicardium and lost Gata6 expression but continued to perform anti-fibrotic functions. Loss of this specialized macrophage population enhanced interstitial fibrosis after ischemic injury. Gata6+ macrophages were present in human pericardial fluid, supporting the notion that this reparative function is relevant in human disease. Our findings uncover an immune cardioprotective role for the pericardial tissue compartment and argue for the reevaluation of surgical procedures that remove the pericardium.
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•Pericardial cavity in mouse and human serves as a reservoir for GPCMs•GPCMs are transcriptionally distinct from neighboring cardiac macrophages•GPCMs relocate rapidly to the ischemic heart and undergo phenotypic alterations•Absence of GPCMs in Lyz2cre;Gata6fl/fl mice promotes post-injury cardiac fibrosis
Deniset et al. describe the pericardial cavity as an important source of resident macrophages that migrate into the heart following ischemic injury and prevent detrimental repair caused by excessive fibrosis.
Accumulation of plastic litter is accelerating worldwide. Rivers are a source of microplastic (i.e., particles <5 mm) to oceans, but few measurements of microplastic retention in rivers exist. We ...adapted spiraling metrics used to measure particulate organic matter transport to quantify microplastic deposition using an outdoor experimental stream. We conducted replicated pulse releases of three common microplastics: polypropylene pellets, polystyrene fragments, and acrylic fibers, repeating measurements using particles with and without biofilms. Depositional velocity (v
; mm/s) patterns followed expectations based on density and biofilm 'stickiness', where v
was highest for fragments, intermediate for fibers, and lowest for pellets, with biofilm colonization generally increasing v
. Comparing microplastic v
to values for natural particles (e.g., fine and coarse particulate organic matter) showed that particle diameter was positively related to v
and negatively related to the ratio of v
to settling velocity (i.e., sinking rate in standing water). Thus, microplastic v
in rivers can be quantified with the same methods and follows the same patterns as natural particles. These data are the first measurements of microplastic deposition in rivers, and directly inform models of microplastic transport at the landscape scale, making a key contribution to research on the global ecology of plastic waste.
Triclosan (TCS) is a broad-spectrum antimicrobial compound that is incorporated into numerous consumer products. TCS has been detected in aquatic ecosystems across the U.S., raising concern about its ...potential ecological effects. We conducted a field survey and an artificial stream experiment to assess effects of TCS on benthic bacterial communities. Field sampling indicated that TCS concentrations in stream sediments increased with degree of urbanization. There was significant correlation between sediment TCS concentration and the proportion of cultivable benthic bacteria that were resistant to TCS, demonstrating that the levels of TCS present in these streams was affecting the native communities. An artificial stream experiment confirmed that TCS exposure could trigger increases in TCS resistance within cultivable benthic bacteria, and pyrosequencing analysis indicated that TCS resulted in decreased benthic bacterial diversity and shifts in bacterial community composition. One notable change was a 6-fold increase in the relative abundance of cyanobacterial sequences and a dramatic die-off of algae within the artificial streams. Selection of cyanobacteria over algae could have significant implications for higher trophic levels within streams. Finally, there were no observed effects of TCS on bacterial abundance or respiration rates, suggesting that bacterial density and function were highly resilient to TCS exposure.
The mitogen-activated protein kinase (MAPK) pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. MEK inhibitors are being explored as a treatment option for ...patients with KRAS-mutant colorectal cancer who are not candidates for EGFR-directed therapies. Initial clinical results of MEK inhibitors have yielded limited single-agent activity in colorectal cancer, indicating that rational combination strategies are needed.
In this study, we conducted unbiased gene set enrichment analysis and synthetic lethality screens with selumetinib, which identified the noncanonical Wnt/Ca++ signaling pathway as a potential mediator of resistance to the MEK1/2 inhibitor selumetinib. To test this, we used shRNA constructs against relevant WNT receptors and ligands resulting in increased responsiveness to selumetinib in colorectal cancer cell lines. Further, we evaluated the rational combination of selumetinib and WNT pathway modulators and showed synergistic antiproliferative effects in in vitro and in vivo models of colorectal cancer.
Importantly, this combination not only showed tumor growth inhibition but also tumor regression in the more clinically relevant patient-derived tumor explant (PDTX) models of colorectal cancer. In mechanistic studies, we observed a trend toward increased markers of apoptosis in response to the combination of MEK and WntCa(++) inhibitors, which may explain the observed synergistic antitumor effects.
These results strengthen the hypothesis that targeting both the MEK and Wnt pathways may be a clinically effective rational combination strategy for patients with metastatic colorectal cancer.
The integrity of a cell's proteome depends on correct folding of polypeptides by chaperonins. The chaperonin TCP-1 ring complex (TRiC) acts as obligate folder for >10% of cytosolic proteins, ...including he cytoskeletal proteins actin and tubulin. Although its architecture and how it recognizes folding substrates are emerging from structural studies, the subsequent fate of substrates inside the TRiC chamber is not defined. We trapped endogenous human TRiC with substrates (actin, tubulin) and cochaperone (PhLP2A) at different folding stages, for structure determination by cryo-EM. The already-folded regions of client proteins are anchored at the chamber wall, positioning unstructured regions toward the central space to achieve their native fold. Substrates engage with different sections of the chamber during the folding cycle, coupled to TRiC open-and-close transitions. Further, the cochaperone PhLP2A modulates folding, acting as a molecular strut between substrate and TRiC chamber. Our structural snapshots piece together an emerging model of client protein folding within TRiC.
Graft versus host disease (GvHD) is a life-threating complication of allogeneic hematopoietic stem cell transplantation, which is initially treated with high dose corticosteroids. Approximately 50% ...of acute GvHD cases are resistant to steroid treatment, and two-year mortality rates in those steroid-resistant patients exceed 80%. Chronic GvHD necessitates prolonged corticosteroid use, which is typically associated with limited efficacy and troublesome adverse effects. No agent has yet been established as an optimal second line therapy for either acute or chronic GvHD, but mesenchymal stromal cells (MSCs) have shown substantial promise. MSCs promote an immunosuppressive and immunoregulatory environment
multifactorial mechanisms, including: secretion of proteins/peptides/hormones; transfer of mitochondria; and transfer of exosomes or microvesicles containing RNA and other molecules. A large number of clinical studies have investigated MSCs from various sources as a treatment for acute and/or chronic GvHD. MSCs are generally safe and well tolerated, and most clinical studies have generated encouraging efficacy results, but response rates have varied. Confounding factors include variability in MSC donor types, production methodology and dose regimens, as well as variations in study design. It is well-established that extensive culture expansion of primary donor-derived MSCs leads to marked changes in functionality, and that there is a high level of inter-donor variability in MSC properties. However, recent manufacturing innovations may be capable of overcoming these problems. Further adequately powered prospective studies are required to confirm efficacy and establish the place of MSC therapy in the treatment of this condition.
Glioblastomas (GBMs) are aggressive brain tumors characterized by extensive inter- and intratumor heterogeneity. Patient-derived models, such as organoids and explants, have recently emerged as ...useful models to study such heterogeneity, although the extent to which they can recapitulate GBM genomic features remains unclear. Here, we analyze bulk exome and single-cell genome and transcriptome profiles of 12 IDH wild-type GBMs, including two recurrent tumors, and of patient-derived explants (PDEs) and gliomasphere (GS) lines derived from these tumors. We find that PDEs are genetically similar to, and variably retain gene expression characteristics of, their parent tumors. Notably, PDEs appear to exhibit similar levels of transcriptional heterogeneity compared with their parent tumors, whereas GS lines tend to be enriched for cells in a more uniform transcriptional state. The approaches and datasets introduced here will provide a valuable resource to help guide experiments using GBM-derived models, especially in the context of studying cellular heterogeneity.
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•Genomic profiling reveals cellular variability of glioblastoma (GBM) model systems•Samples profiled include matched GBM tissues, explants, and gliomaspheres•Patient-derived explants (PDEs) can be generated from primary and recurrent tumors•PDEs retain parent tumors' genetic and transcriptomic heterogeneity across passages
LeBlanc et al. use bulk and single-cell genomic profiling approaches to characterize genetic and transcriptomic heterogeneity in primary glioblastomas and in matched patient-derived explants and gliomasphere cell lines. They show that explant models retain much of the genetic and transcriptomic heterogeneity observed in primary tissues.
Abstract
Background
The role of surgery for incidentally discovered diffuse incidental low-grade gliomas (iLGGs) is debatable and poorly documented in current literature.
Objective
The aim was to ...identify factors that influence survival for patients that underwent surgical resection of iLGGs in a large multicenter population.
Methods
Clinical, radiological, and surgical data were retrospectively analyzed in 267 patients operated for iLGG from 4 neurosurgical Centers. Univariate and multivariate analyses were performed to identify predictors of overall survival (OS) and tumor recurrence (TR).
Results
The OS rate was 92.41%. The 5- and 10-year estimated OS rates were 98.09% and 93.2%, respectively. OS was significantly longer for patients with a lower preoperative tumor volume (P = .001) and higher extent of resection (EOR) (P = .037), regardless the WHO-defined molecular class (P = .2). In the final model, OS was influenced only by the preoperative tumor volume (P = .006), while TR by early surgery (P = .028). A negative association was found between preoperative tumor volumes and EOR (rs = −0.44, P < .001). The median preoperative tumor volume was 15 cm3. The median EOR was 95%. Total or supratotal resection of T2-FLAIR abnormality was achieved in 61.62% of cases. Second surgery was performed in 26.22%. The median time between surgeries was 5.5 years. Histological evolution to high-grade glioma was detected in 22.85% of cases (16/70). Permanent mild deficits were observed in 3.08% of cases.
Conclusions
This multicenter study confirms the results of previous studies investigating surgical management of iLGGs and thereby strengthens the evidence in favor of early surgery for these lesions.
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