Background
Learning assistants (LAs) increase accessibility to instructor–student interactions in large STEM lecture classes. In this research, we used the Formative Assessment Enactment Model ...developed for K-12 science teachers to characterize LA facilitation practices. The Formative Assessment Enactment Model describes instructor actions as eliciting or advancing student thinking, guided by their purposes and the perspective they center as well as by what they notice about and how they interpret student thinking. Thus, it describes facilitation practices in a holistic way, capturing the way purposes, perspectives, noticing, interpreting, and actions are intertwined and working together to characterize different LA actions. In terms of how perspectives influence actions, eliciting and advancing moves can be enacted either in authoritative ways, driven by one perspective that has authority, or in dialogic ways, driven by multiple perspectives. Dialogic practices are of particular interest because of their potential to empower students and center student thinking.
Results
Our analysis of video recordings of LA–student interactions and stimulated recall interviews with 37 introductory physical science lectures’ LAs demonstrates that instead of as a dichotomy between authoritative and dialogic, LA actions exist along a spectrum of authoritative to dialogic based on the perspectives centered. Between the very authoritative perspective that centers on canonically correct science and the very dialogic perspective that centers the perspectives of the students involved in the discussion, we find two intermediary categories. The two new categories encompass a moderately authoritative perspective focused on the LA’s perspective without the claim of being correct and a moderately dialogic perspective focused on ideas from outside the current train of thought such as from students in the class that are not part of the current discussion.
Conclusions
This spectrum further adds to theory around authoritative and dialogic practices as it reconsiders what perspectives can drive LA enactment of facilitation other than the perspective of canonically correct science and the perspectives of the students involved in the discussion. This emerging characterization may be used to give LAs and possibly other instructors a tool to intentionally shift between authoritative and dialogic practices. It may also be used to transition towards more student-centered practices.
Among a variety of inorganic-based nanomaterials, mesoporous silica nanoparticles (MSNs) have several attractive features for application as a delivery system, due to their high surface areas, large ...pore volumes, uniform and tunable pore sizes, high mechanical stability, and a great diversity of surface functionalization options. We developed novel hybrid MSNs composed of a mesoporous silica nanostructure core and a pH-responsive polymer shell. The polymer shell was prepared by RAFT polymerization of 2-(diisopropylamino)ethyl methacrylate (pKa ~6.5), using a hybrid grafting approach. The hybrid nanoparticles have diameters of ca. 100 nm at pH < 6.5 and ca. 60 nm at pH > 6.5. An excellent control of cargo release is achieved by the combined effect of electrostatic interaction of the cargo with the charged silica and the extended cationic polymer chains at low pH, and the reduction of electrostatic attraction with a simultaneous collapse of the polymer chains to a globular conformation at higher pH. The system presents a very low (almost null) release rate at acidic pH values and a large release rate at basic pH, resulting from the squeezing-out effect of the coil-to-globule transition in the polymer shell.
The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches ...have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence.
We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an
search strategy -performed in a large and diverse chemolibrary- complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (
) and prospective (experimentally confirmed) screening.
The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46
hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC
≤ 25 μM): two analogues of
hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC
= 0.12-20 μM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC
7-45 μM).
Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known "garbage in, garbage out" machine learning principle.
Gastrointestinal (GI) dysfunction is frequent in the critically ill but can be overlooked as a result of the lack of standardization of the diagnostic and therapeutic approaches. We aimed to develop ...a research agenda for GI dysfunction for future research. We systematically reviewed the current knowledge on a broad range of subtopics from a specific viewpoint of GI dysfunction, highlighting the remaining areas of uncertainty and suggesting future studies.
This systematic scoping review and research agenda was conducted following successive steps: (1) identify clinically important subtopics within the field of GI function which warrant further research; (2) systematically review the literature for each subtopic using PubMed, CENTRAL and Cochrane Database of Systematic Reviews; (3) summarize evidence for each subtopic; (4) identify areas of uncertainty; (5) formulate and refine study proposals that address these subtopics; and (6) prioritize study proposals via sequential voting rounds.
Five major themes were identified: (1) monitoring, (2) associations between GI function and outcome, (3) GI function and nutrition, (4) management of GI dysfunction and (5) pathophysiological mechanisms. Searches on 17 subtopics were performed and evidence summarized. Several areas of uncertainty were identified, six of them needing consensus process. Study proposals ranked among the first ten included: prevention and management of diarrhoea; management of upper and lower feeding intolerance, including indications for post-pyloric feeding and opioid antagonists; acute gastrointestinal injury grading as a bedside tool; the role of intra-abdominal hypertension in the development and monitoring of GI dysfunction and in the development of non-occlusive mesenteric ischaemia; and the effect of proton pump inhibitors on the microbiome in critical illness.
Current evidence on GI dysfunction is scarce, partially due to the lack of precise definitions. The use of core sets of monitoring and outcomes are required to improve the consistency of future studies. We propose several areas for consensus process and outline future study projects.
Abstract
This international guideline proposes improving clozapine package inserts
worldwide by using ancestry-based dosing and titration. Adverse drug reaction
(ADR) databases suggest that clozapine ...is the third most toxic drug in the
United States (US), and it produces four times higher worldwide pneumonia
mortality than that by agranulocytosis or myocarditis. For trough steady-state
clozapine serum concentrations, the therapeutic reference range is narrow, from
350 to 600 ng/mL with the potential for toxicity and ADRs as
concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female
non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer
status through phenotypic conversion is associated with co-prescription of
inhibitors (including oral contraceptives and valproate), obesity, or
inflammation with C-reactive protein (CRP) elevations. The Asian population
(Pakistan to Japan) or the Americas’ original inhabitants have lower
CYP1A2 activity and require lower clozapine doses to reach concentrations of
350 ng/mL. In the US, daily doses of
300–600 mg/day are recommended. Slow personalized
titration may prevent early ADRs (including syncope, myocarditis, and
pneumonia). This guideline defines six personalized titration schedules for
inpatients: 1) ancestry from Asia or the original people from the Americas with
lower metabolism (obesity or valproate) needing minimum therapeutic dosages of
75–150 mg/day, 2) ancestry from Asia or the original
people from the Americas with average metabolism needing
175–300 mg/day, 3) European/Western Asian
ancestry with lower metabolism (obesity or valproate) needing
100–200 mg/day, 4) European/Western Asian
ancestry with average metabolism needing 250–400 mg/day,
5) in the US with ancestries other than from Asia or the original people from
the Americas with lower clozapine metabolism (obesity or valproate) needing
150–300 mg/day, and 6) in the US with ancestries other
than from Asia or the original people from the Americas with average clozapine
metabolism needing 300–600 mg/day. Baseline and weekly
CRP monitoring for at least four weeks is required to identify any inflammation,
including inflammation secondary to clozapine rapid titration.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical ...management or therapeutic development. Here, we construct a high-resolution molecular landscape of the cellular subtypes and spatial communities that compose PDAC using single-nucleus RNA sequencing and whole-transcriptome digital spatial profiling (DSP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment naive. We uncovered recurrent expression programs across malignant cells and fibroblasts, including a newly identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities with distinct contributions from malignant, fibroblast and immune subtypes: classical, squamoid-basaloid and treatment enriched. Our refined molecular and cellular taxonomy can provide a framework for stratification in clinical trials and serve as a roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aurantiochytrium
sp. is an emerging alternative source of polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA), and squalene, playing an important role in the phasing out of traditional ...fish sources for these compounds. Novel lipid extraction techniques with a focus on sustainability and low environmental footprint are being developed for this organism, but the exploration of other added-value compounds within it is still very limited. In this work, a combination of novel green extraction techniques (high hydrostatic pressure extraction (HPE) and supercritical fluid extraction (SFE)) and traditional techniques (organic solvent Soxhlet extraction and hydrodistillation (HD)) was used to obtain lipophilic extracts of
Aurantiochytrium
sp., which were then screened for antioxidant (DPPH radical reduction capacity and ferric-reducing antioxidant potential (FRAP) assays), lipid oxidation protection, antimicrobial, anti-aging enzyme inhibition (collagenase, elastase and hyaluronidase), and anti-inflammatory (inhibition of NO production) activities. The screening revealed promising extracts in nearly all categories of biological activity tested, with only the enzymatic inhibition being low in all extracts. Powerful lipid oxidation protection and anti-inflammatory activity were observed in most SFE samples. Ethanolic HPEs inhibited both lipid oxidation reactions and microbial growth. The HD extract demonstrated high antioxidant, antimicrobial, and anti-inflammatory activities making, it a major contender for further studies aiming at the valorization of
Aurantiochytrium
sp. Taken together, this study presents compelling evidence of the bioactive potential of
Aurantiochytrium
sp. and encourages further exploration of its composition and application.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The evolving classification of rhabdomyosarcoma (RMS) now includes spindle cell RMS (SRMS). Bone/soft tissue SRMS often harbor TFCP2, or less often MEIS1 rearrangements. We studied 25 fusion-driven ...SRMS involving bone (n = 19) and soft tissue (n = 6).
Osseous SRMS occurred in 13 women and 6 men (median age: 41 years) and involved the pelvis (5), sacrum (2), spine (4), maxilla (4), mandible (1), skull (1), and femur (2). Follow-up (median: 5 months) demonstrated local recurrence in 2/16 and distant metastases in 8/17 patients (median time to metastasis: 1 month). Eight patients died of disease; 9 were alive with disease. Soft tissue SRMS occurred in 4 men and 2 women (median: 50 years). Follow-up (median: 10 months) revealed distant metastasis at diagnosis (1), alive with unresected tumor (1), and no evidence of disease (4). Next-generation sequencing demonstrated FUS::TFCP2 (12), EWSR1::TFCP2 (3) and MEIS1::NCOA2 (2); FISH identified EWSR1 (2) rearrangements. Most TFCP2-rearranged SRMS (13/17) showed spindled/epithelioid morphology, rarely with rhabdomyoblasts. The bone tumors were diffusely desmin and MyoD1 positive with limited myogenin; 10/13 were ALK -positive and 6/15 were keratin positive. Soft tissue SRMS harbored EWSR1::TFCP2, MEIS1::NCOA2, ZFP64::NCOA2, MEIS1::FOXO1, TCF12::VGLL3 and DCTN1::ALK, and displayed spindled/epithelioid, leiomyomatous, and myxofibrosarcoma-like morphologies. Immunohistochemistry (IHC) was positive for MyoD1 (6/6), focal desmin (5/6), myogenin (3/6), and keratin (1/6).
We conclude that TFCP2-rearranged SRMS of bone and soft tissue show consistent morphologic and IHC features, likely representing a distinct subset of RMS. Non-TFCP2 fusion-positive SRMS could represent a single RMS subset, multiple subtypes of RMS, or “fusion-defined” sarcomas with rhabdomyoblastic differentiation.
Abstract
A perimetastatic capsule is a strong positive prognostic factor in liver metastases, but its origin remains unclear. Here, we systematically quantify the capsule’s extent and cellular ...composition in 263 patients with colorectal cancer liver metastases to investigate its clinical significance and origin. We show that survival improves proportionally with increasing encapsulation and decreasing tumor-hepatocyte contact. Immunostaining reveals the gradual zonation of the capsule, transitioning from benign-like NGFR
high
stroma at the liver edge to FAP
high
stroma towards the tumor. Encapsulation correlates with decreased tumor viability and preoperative chemotherapy. In mice, chemotherapy and tumor cell ablation induce capsule formation. Our results suggest that encapsulation develops where tumor invasion into the liver plates stalls, representing a reparative process rather than tumor-induced desmoplasia. We propose a model of metastases growth, where the efficient tumor colonization of the liver parenchyma and a reparative liver injury reaction are opposing determinants of metastasis aggressiveness.
•PDAC cells in the duodenal epithelium mimic intestinal cells and co-opt the basement membrane.•Intramucosal PDAC location is strongly coupled to the classical phenotype and to intestinal ...traits.•Intratumoral heterogeneity is linked to specific tissue compartments, which shape phenotype plasticity of PDAC cells.
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors. Based on transcriptomic classifiers, basal-like and classical PDAC subtypes have been defined that differ in prognosis. Cells of both subtypes can coexist in individual tumors; however, the contribution of either clonal heterogeneity or microenvironmental cues to subtype heterogeneity is unclear. Here, we report the spatial tumor phenotype dynamics in a cohort of patients in whom PDAC infiltrated the duodenal wall, and identify the duodenal epithelium as a distinct PDAC microniche. Materials and methods: We used serial multiplex quantitative immunohistochemistry (smq-IHC) for 24 proteins to phenotypically chart PDAC tumor cells in patients whose tumors infiltrated the duodenal epithelium. Additionally, we used a genetically engineered mouse model to study the PDAC cell phenotype in the small intestinal epithelium in a controlled genetic background. Result: We show that pancreatic cancer cells revert to non-destructive growth upon integration into the duodenal epithelium, where they adopt traits of intestinal cell differentiation, associated with phenotypical stabilization of the classical subtype. The integrated tumor cells replace epithelial cells in an adenoma-like manner, as opposed to invasive growth in the submucosa. Finally, we show that this phenomenon is shared between species, by confirming duodenal integration and phenotypic switching in a genetic PDAC mouse model. Discussion: Our results identify the duodenal epithelium as a distinct PDAC microniche and tightly link microenvironmental cue to cancer transcriptional subtypes. The phenomenon of “intestinal mimicry” provides a unique opportunity for the systematic investigation of microenvironmental influences on pancreatic cancer plasticity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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