Computational approaches such as genome and metabolome mining are becoming essential to natural products (NPs) research. Consequently, a need exists for an automated structure-type classification ...system to handle the massive amounts of data appearing for NP structures. An ideal semantic ontology for the classification of NPs should go beyond the simple presence/absence of chemical substructures, but also include the taxonomy of the producing organism, the nature of the biosynthetic pathway, and/or their biological properties. Thus, a holistic and automatic NP classification framework could have considerable value to comprehensively navigate the relatedness of NPs, and especially so when analyzing large numbers of NPs. Here, we introduce NPClassifier, a deep-learning tool for the automated structural classification of NPs from their counted Morgan fingerprints. NPClassifier is expected to accelerate and enhance NP discovery by linking NP structures to their underlying properties.
Introduction
L’Échelle de provisions sociales à 10 items (SPS-10) a été mise en oeuvre dans un certain nombre d’enquêtes nationales canadiennes pour évaluer le soutien social. L’objectif de notre ...étude était de réduire l’échelle SPS-10 à une échelle à 5 items (SPS-5) tout en conservant des propriétés de mesure adéquates.
Méthodologie
Nous avons analysé les données fournies par les personnes de 18 ans et plus ayant répondu aux questions du module utilisant l’Échelle de provisions sociales dans le cadre du cycle thématique sur la santé mentale de l’Enquête sur la santé dans les collectivités canadiennes de 2012 (ESCC-SM 2012) et du cycle annuel de l’Enquête sur la santé dans les collectivités canadiennes de 2017 (ESCC 2017). Pour choisir les items, nous avons effectué une analyse factorielle exploratoire et une corrélation item-total sur les données du cycle SM ESCC 2012. Nous avons utilisé une analyse de corrélation entre l’échelle SPS-5, l’échelle SPS-10 et les construits de santé mentale positive (SMP) correspondants pour évaluer la validité critérielle de l’échelle SPS-5 par rapport à l’échelle SPS-10. Nous avons effectué une analyse factorielle confirmatoire à partir des données du cycle ESCC 2017 afin de confirmer la structure des facteurs de l’échelle SPS‑5.
Résultats
L’échelle SPS-5 présente une cohérence interne élevée (indice alpha de Cronbach de 0,88) et des corrélations avec les construits de SMP correspondants semblables à celles de l’échelle SPS-10. Les échelles SPS-5 et SPS-10 se sont aussi avérées très fortement corrélées (r = 0,97). L’analyse factorielle confirmatoire indique que le modèle à un seul facteur par provision, c’est-à-dire la SPS-5, est bien ajusté aux données. Les échelles SPS-5 et SPS-10 produisent des estimations similaires d’un soutien social élevé, de respectivement 92,7 et 91,5 %.
Conclusion
La nouvelle échelle SPS-5 offre des propriétés de mesure adéquates et fonctionne de façon semblable à l’échelle SPS-10, étayant l’utilisation de cette version réduite. Elle constitue une solution de remplacement valide et utilisable de l’échelle SPS-10, ce qui pourrait alléger la tâche des participants aux enquêtes nationales sur la santé.
Organs-on-chips (OoCs) have attracted significant attention because they can be designed to mimic in vivo environments. Beyond constructing a single OoC, recent efforts have tried to integrate ...multiple OoCs to broaden potential applications such as disease modeling and drug discoveries. However, various challenges remain for integrating OoCs towards in vivo-like operation, such as incorporating various connections for integrating multiple OoCs. We review multiplexed OoCs and challenges they face: scaling, vascularization, and innervation. In our opinion, future OoCs will be constructed to have increased predictive power for in vivo phenomena and will ultimately become a mainstream tool for high quality biomedical and pharmaceutical research.
Major considerations for integrating organs-on-chips (OoCs) include scaling and interconnection via vascularization and innervation.Scaling rules are crucial for predicting events that occur in vivo, but so far, there are no optimal scaling rules for microsystems.To develop scaling rules for microsystems, data should be acquired using mesoscale approaches by using in vitro tissues fabricated by bioreactors or 3D printing.Beyond numerous OoC models of vascularization, organ-specific microvasculature and the main connections between each organ part should also be considered for mimicking the in vivo vascular system.There are still few examples of on-chip innervation, but innervated OoCs and neuronal connections between each part in vitro will give new insights into corresponding in vivo behavior.
Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), ...NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligands were formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing cellular cancer vaccines--termed STINGVAX--that demonstrated potent in vivo antitumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including one with an Rp,Rp dithio diastereomer and noncanonical cA(2',5')pA(3',5')p phosphate bridge structure, enhanced antitumor efficacy of STINGVAX in multiple aggressive therapeutic models of established cancer in mice. Antitumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen-specific CD8(+) T cells. Tumors from STINGVAX-treated mice demonstrated marked PD-L1 (programmed death ligand 1) up-regulation, which was associated with tumor-infiltrating CD8(+)IFNγ(+) T cells. When combined with PD-1 (programmed death 1) blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone.
To determine the characteristics of US medical schools associated with successful urology match applicants.
Using publicly available data, demographics and bibliometrics were collected for 1814 ...current urology residents who attend a US-based Accreditation Council for Graduate Medical Education (ACGME) Accredited program, reflecting matched applicants over a 6-year period from 2016-2021. A generated list of US feeder medical schools for urology was analyzed for correlative and predictive factors. Statistical analyses to characterize these factors included Pearson's Correlation Coefficient (PCC) and univariable and multivariable linear regression, respectively, as needed.
There were 516 (28.45%) female residents and 58 (3.20%) international medical graduates. The mean number of published papers and abstracts ± SD pre-residency was 5.54 ± 7.20 with a mean h-index of 1.97 ± 2.24. The Cleveland Clinic Lerner College of Medicine had the highest percentage of successful matches into urology (n = 7, 3.65%), while the State University of New York Downstate Medical Center College of Medicine produced the highest absolute number (n = 41, 3.30%). The presence of a home urology program and pre-residency h-index had the strongest correlation with producing urology residents (PCC = 0.5769 and 0.3709, respectively, P<.0001).
Understanding the characteristics of a successful urology match applicant and the medical schools that produce them will be vital as USMLE Step 1 exam becomes pass/fail. Further research into these schools’ curricula is required to better understand the effect of early exposure to urology on matching into urology.
Background
Femoral continuous peripheral nerve blocks (CPNBs) provide effective analgesia after TKA but have been associated with quadriceps weakness and delayed ambulation. A promising alternative ...is adductor canal CPNB that delivers a primarily sensory blockade; however, the differential effects of these two techniques on functional outcomes after TKA are not well established.
Questions/purposes
We determined whether, after TKA, patients with adductor canal CPNB versus patients with femoral CPNB demonstrated (1) greater total ambulation distance on Postoperative Day (POD) 1 and 2 and (2) decreased daily opioid consumption, pain scores, and hospital length of stay.
Methods
Between October 2011 and October 2012, 180 patients underwent primary TKA at our practice site, of whom 93% (n = 168) had CPNBs. In this sequential series, the first 102 patients had femoral CPNBs, and the next 66 had adductor canal CPNBs. The change resulted from a modification to our clinical pathway, which involved only a change to the block. An evaluator not involved in the patients’ care reviewed their medical records to record the parameters noted above.
Results
Ambulation distances were higher in the adductor canal group than in the femoral group on POD 1 (median 10
th
–90
th
percentiles: 37 m 0–90 m versus 6 m 0–51 m; p < 0.001) and POD 2 (60 m 0–120 m versus 21 m 0–78 m; p = 0.003). Adjusted linear regression confirmed the association between adductor canal catheter use and ambulation distance on POD 1 (
B
= 23; 95% CI = 14–33; p < 0.001) and POD 2 (
B
= 19; 95% CI = 5–33; p = 0.008). Pain scores, daily opioid consumption, and hospital length of stay were similar between groups.
Conclusions
Adductor canal CPNB may promote greater early postoperative ambulation compared to femoral CPNB after TKA without a reduction in analgesia. Future randomized studies are needed to validate our major findings.
Level of Evidence
Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.
Porous membranes used in co‐culture enable the in vitro partitioning of cellular microenvironments, while still permitting physical and biochemical crosstalk between cells. Thus, features of the ...co‐culture membrane are crucial for recapitulating the physiological functions of co‐cultured cells. This study presents elastic, porous, and ultrathin membranes (EPUMs), which enhance cell–cell interactions and control cell alignment with surface topology created by stretching the membranes. The EPUM is fabricated using poly(lactide‐co‐caprolactone) as the base material, and the porous feature is endowed by a vapor‐induced phase separation process induced by the presence of hygroscopic salt. Owing to its elastic property, the membrane can be stretched, and the deformed porous structures on the membrane surfaces act as nanostructured topographical cues, resulting in cell alignment. By co‐culturing human mesenchymal stem cells (hMSCs) and human umbilical vein endothelial cells (HUVECs) on the opposite sides of the membrane, rapid endothelialization occurs through the membranes, as compared to the commercial membranes. Furthermore, the stretched membranes induce the alignment of hMSCs and HUVECs and ultimately exhibit enhanced endothelial barrier function. The co‐culture membrane developed in this study may provide an effective tool for recapitulating endothelial basement membranes with a controllable endothelial barrier function.
Elastic, porous, and ultrathin membranes (EPUMs) are developed to control endothelial barrier function through cell alignment and co‐culture. EPUMs are easily prepared, transferable, stretchable, and ≈10‐fold thinner than conventional co‐culture membranes. This work demonstrates that the stretched membranes induce enhanced endothelial barrier function, which is confirmed by mesenchymal stem cell differentiation, endothelial intercellular junction formation, and paracellular permeability analysis.
Artificial vascular grafts consisting of ePTFE have been mainly used in clinics for the treatment of cardiovascular disease. However, artificial grafts can become clogged after a long time due to ...thrombosis, as graft maturation by endothelialization is limited. The strategy introduced in this study is to induce graft remodeling through interaction between the bioinert graft and the body. The Substance P (SP) and heparin were covalently conjugated with PLCL, an elastic biocompatible copolymer and the Substance P-conjugated PLCL (SP-PLCL) and/or heparin-conjugated PLCL (Hep-PLCL) were vacuum-coated onto ePTFE vascular grafts. To assess the effectiveness of the coating, coated samples were evaluated by implanting them subcutaneously into SD-Rats. Coatings allow grafts to be remodeled by creating a microenvironment where cells can grow by infiltrating into the grafts while also greatly enhancing angiogenesis. In particular, a double coating of Hep-PLCL and SP-PLCL (Hep/SP-PLCL) at four weeks showed markedly improved vascular remodeling through the recruitment of mesenchymal stem cells (MSCs), vascular cells (ECs, SMCs) and M2 macrophages. Based on these results, it is expected that when the Hep/SP-PLCL-coated ePTFE vascular grafts are implanted in situ, long-term patency will be assured due to the appropriate formation of an endothelial layer and smooth muscle cells in the grafts like native vessels.
Small RNAs direct RNA-induced silencing complexes (RISCs) to regulate stability and translation of mRNAs. RISCs associated with target mRNAs often accumulate in discrete cytoplasmic foci known as ...GW-bodies. However, RISC proteins can associate with membrane compartments such as the Golgi and endoplasmic reticulum. Here, we show that GW-bodies are associated with late endosomes (multivesicular bodies, MVBs). Blocking the maturation of MVBs into lysosomes by loss of the tethering factor HPS4 (ref. 5) enhances short interfering RNA (siRNA)- and micro RNA (miRNA)-mediated silencing in Drosophila melanogaster and humans. It also triggers over-accumulation of GW-bodies. Blocking MVB formation by ESCRT (endosomal sorting complex required for transport) depletion results in impaired miRNA silencing and loss of GW-bodies. These results indicate that active RISCs are physically and functionally coupled to MVBs. We further show that MVBs promote the competence of RISCs in loading small RNAs. We suggest that the recycling of RISCs is promoted by MVBs, resulting in RISCs more effectively engaging with small RNA effectors and possibly target RNAs. It may provide a means to enhance the dynamics of RNA silencing in the cytoplasm.
Immunoglobulin replacement therapy is a standard treatment for patients with antibody production deficiencies, which is of interest in patients with chronic obstructive pulmonary disease (COPD). This ...systematic review, registered with PROSPERO (CRD42021281118), assessed the current literature regarding immunoglobulin replacement therapy on COPD clinical outcomes in patients with low immunoglobulin G (IgG) serum concentrations.
Literature searches conducted from inception to August 23, 2021, in databases including MEDLINE, EMBASE, and CINAHL. Population (sex, age, comorbidities), baseline clinical characteristics (pulmonary function testing results, IgG levels), and outcome (hospitalizations, emergency department visits) were extracted after title/abstract and full text screening. The Cochrane risk of bias assessment form was used for risk of bias assessment of randomized controlled trials and the National Heart, Lung, and Blood Institute (NHLBI) assessment was used for pre and post studies.
A total of 1381 studies were identified in the preliminary search, and 874 records were screened after duplicates were removed. Screening 77 full texts yielded four studies that were included in the review.
It is unclear whether immune globulin replacement therapy reduces acute exacerbation frequency and severity in COPD. Current evidence suggests that it is worth considering, but better developed protocols for administration of immune globulin supplementation is required for future randomized controlled trials.
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