Miracle-dz/UniFAR-FTUs huggingface dataset:
Enhancement of the oral bioavailability of isopropoxy benzene guanidine though complexation with hydroxypropyl-β-cyclodextrin

Abstract Isopropoxy benzene guanidine (IBG) is a novel substituted benzene guanidine analogue with antibacterial activity against multidrug-resistant bacteria. However, the bioavailability of IBG is not optimal due to its finite aqueous solubility, thus hampering its potential therapeutic exploitation. In this study, we prepared IBG/hydroxypropyl-β-CD (IBG/HP-β-CD) complex, and characterized it by differential scanning calorimetry, Fourier transform infrared spectroscopy, powder X-ray diffraction, and scanning electron microscopy. Physicochemical characterization indicated that the crystal morphology of IBG transformed into an amorphous state, thus forming IBG/HP-β-CD inclusion complexes. Complexation with HP-β-CD significantly improve the aqueous solubility, pharmaceutical properties, absorption, and bioavailability of IBG.
Validation of the NIH Toolbox-Cognition Battery against legacy neurocognitive measures in adults with cognitive impairments: An exploratory analysis

Abstract Objective: The purpose of this exploratory study was to describe associations between NIH Toolbox-Cognition Battery subtests and legacy measures of neurocognitive function in two samples with neurological conditions (stroke and sickle cell disease (SCD)). Method: This exploratory secondary analysis uses data from two studies that assessed cognition at one time point using the NIH Toolbox-Cognition Battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and subtests from the Delis-Kaplan Executive Functions System (DKEFS). People with stroke (n = 26) and SCD (n = 64) were included. Associations between the NIH Toolbox-Cognition Battery subtests and corresponding legacy measures were examined using linear correlations, Bland–Altman analysis, and Lin’s Concordance Correlation Coefficient. Results: Linear correlations and Lin’s Concordance Correlation Coefficient were poor to strong in both samples on NIH Toolbox-CB subtests: Flanker Inhibitory Control and Attention (r = .35 to .48, Lin CCC = .27 to .37), Pattern Comparison Processing Speed (r = .40 to .65, Lin CCC = .37 to .62), Picture Sequence Memory (r = .19 to .55, Lin CCC = .18 to .48), Dimensional Change Card Sort (r = .39 to .77, Lin CCC = .38 to .63), Fluid Cognition Composite (r = .88 to .90, Lin CCC = .60 to .79), and Total Cognition Composite (r = .64 to .83, Lin CCC = .60 to .78). Bland–Altman analyses demonstrated wide limits of agreement across all subtests (–3.17 to 3.78). Conclusions: The NIH Toolbox-Cognition Battery subtests may behave similarly to legacy measures as an overall assessment of cognition across samples at risk for neurological impairment. Findings should be replicated across additional clinical samples.
A Quantitative Study of Decision Thresholds for Initiation of Antibiotics in Suspected Sepsis

Background Clinicians’ decision thresholds for initiating antibiotics in patients with suspected sepsis have not been quantified. We aimed to define an average threshold of infection likelihood at which clinicians initiate antibiotics when treating a patient with suspected infection and to evaluate the influence of severity of illness and clinician-related factors on the threshold. Design This was a prospective survey of 153 clinicians responding to 8 clinical vignettes constructed from real-world data from 3 health care systems in the United States. We treated each hour in the vignette as a decision to treat or not treat with antibiotics and assigned an infection probability to each hour using a previously developed infection prediction model. We then estimated decision thresholds using regression models based on the timing of antibiotic initiation. We compared thresholds across categories of severity of illness and clinician-related factors. Results Overall, the treatment threshold occurred at a 69% probability of infection, but the threshold varied significantly across severity of illness categories—when patients had high severity of illness, the treatment threshold occurred at a 55% probability of infection; when patients had intermediate severity, the threshold for antibiotic initiation occurred at an infection probability of 69%, and the threshold was 84% when patients had low severity of illness (P < 0.001 for group differences). Thresholds differed significantly across specialty, highest among infectious disease and lowest among emergency medicine clinicians and across years of experience, decreasing with increasing years of experience. Conclusions The threshold infection probability above which physicians choose to initiate antibiotics in suspected sepsis depends on illness severity as well as clinician factors. Implications Incorporating these context-dependent thresholds into discriminating and well-calibrated models will inform the development of future sepsis clinical decision support systems. Clinician-related differences in treatment thresholds suggests potential unwarranted variation and opportunities for performance improvement. Highlights Decision making about antibiotic initiation in suspected sepsis occurs under uncertainty, and little is known about clinicians’ thresholds for treatment. In this prospective study, 153 clinicians from 3 health care systems reviewed 8 real-world clinical vignettes representing patients with sepsis and indicated the time that they would initiate antibiotics. Using a model-based approach, we estimated decision thresholds and found that thresholds differed significantly across illness severity categories and by clinician specialty and years of experience.
Different modes of synaptic and extrasynaptic NMDA receptor alteration in the hippocampus of P301S tau transgenic mice

N‐methyl‐d‐aspartate receptors (NMDARs) are pivotal players in the synaptic transmission and synaptic plasticity underlying learning and memory. Accordingly, dysfunction of NMDARs has been implicated in the pathophysiology of Alzheimer disease (AD). Here, we used histoblot and sodium dodecylsulphate‐digested freeze‐fracture replica labelling (SDS‐FRL) techniques to investigate the expression and subcellular localisation of GluN1, the obligatory subunit of NMDARs, in the hippocampus of P301S mice. Histoblots showed that GluN1 expression was significantly reduced in the hippocampus of P301S mice in a laminar‐specific manner at 10 months of age but was unaltered at 3 months. Using the SDS‐FRL technique, excitatory synapses and extrasynaptic sites on spines of pyramidal cells and interneuron dendrites were analysed throughout all dendritic layers in the CA1 field. Our ultrastructural approach revealed a high density of GluN1 in synaptic sites and a substantially lower density at extrasynaptic sites. Labelling density for GluN1 in excitatory synapses established on spines was significantly reduced in P301S mice, compared with age‐matched wild‐type mice, in the stratum oriens (so), stratum radiatum (sr) and stratum lacunosum‐moleculare (slm). Density for synaptic GluN1 on interneuron dendrites was significantly reduced in P301S mice in the so and sr but unaltered in the slm. Labelling density for GluN1 at extrasynaptic sites showed no significant differences in pyramidal cells, and only increased density in the interneuron dendrites of the sr. This differential alteration of synaptic versus extrasynaptic NMDARs supports the notion that the progressive accumulation of phospho‐tau is associated with changes in NMDARs, in the absence of amyloid‐β pathology, and may be involved in the mechanisms causing abnormal network activity of the hippocampal circuit.
Geographical similarity and differences in the burden and genetic predisposition of NAFLD

NAFLD has become a major public health problem for more than 2 decades with a growing prevalence in parallel with the epidemic of obesity and type 2 diabetes (T2D). The disease burden of NAFLD differs across geographical regions and ethnicities. Variations in prevalence of metabolic diseases, extent of urban–rural divide, dietary habits, lifestyles, and the prevalence of NAFLD risk and protective alleles can contribute to such differences. The rise in NAFLD has led to a remarkable increase in the number of cases of cirrhosis, hepatocellular carcinoma, hepatic decompensation, and liver‐related mortality related to NAFLD. Moreover, NAFLD is associated with multiple extrahepatic manifestations. Most of them are risk factors for the progression of liver fibrosis and thus worsen the prognosis of NAFLD. All these comorbidities and complications affect the quality of life in subjects with NAFLD. Given the huge and growing size of the population with NAFLD, it is expected that patients, healthcare systems, and the economy will suffer from the ongoing burden related to NAFLD. In this review, we examine the disease burden of NAFLD across geographical areas and ethnicities, together with the distribution of some well‐known genetic variants for NAFLD. We also describe some special populations including patients with T2D, lean patients, the pediatric population, and patients with concomitant liver diseases. We discuss extrahepatic outcomes, patient‐reported outcomes, and economic burden related to NAFLD.
Quantum dots in the biomedical world: A smart advanced nanocarrier for multiple venues application

Quantum dots (QDs) are semiconducting nanoparticles having different optical and electrical properties when compared to larger particles. They exhibit photoluminescence when irradiated with ultraviolet light, which is due to the transition of an excited electron from the valence band to the conductance band followed by the return of the exciting electron back into the valence band. The size and material of QDs can affect their optical and other properties too. The QDs possess special attributes like high brightness, protection from photobleaching, photostability, color tunability, low toxicity, low production cost, a multiplexing limit, and a high surface‐to‐volume proportion, which make them a promising tool for biomedical applications. Here, in this study, we summarize the utilization of QDs in different applications including bioimaging, diagnostics, immunostaining, single‐cell analysis, drug delivery, and protein detection. Moreover, we discuss the advantages and challenges of using QDs in biomedical applications when compared with other conventional tools.
Influence of inflammatory plasma biomarkers on choroidal thickness in type 2 diabetes mellitus

Purpose To assess the influence of inflammatory plasma biomarkers on choroidal thickness (CT) in patients with type 2 diabetes (T2D). Methods Cross-sectional study enrolling T2D patients and age-matched healthy controls (>55 years of age, Caucasian, axial length <26 mm, no macular edema, and naïve). Patients were examined with swept-source OCT Triton, obtaining automatic measurements. CT was analyzed using the ETDRS grid and the recently proposed choroidal division. A blood analysis was commanded: general biochemical profile, liver status, T2D status, thyroid and parathyroid activity, coagulation, general immunological profile, and inflammatory biomarkers. Results 124 eyes of 124 patients with a mean age between 66 and 68 years were examined. The new choroidal division showed differences between groups (p < 0.05) in more sectors than the ETDRS grid, and more biomarkers influenced these new sectors. T2D patients had higher levels of IL-8, TNF-α, MCP1, adiponectin and L-selectin. CT was influenced by TNF-α, IL-17, leukocytes and erythrocyte sedimentation rate, as well as by HDL cholesterol, albumin, liver function biomarkers, and TSH. HbA1c showed little influence on CT. Conclusions T2D patients present increased plasma inflammatory biomarkers, exhibiting an influence on CT. IL-17 is related to a thicker choroid but TNF-α is related to a thinner choroid. HbA1c has little influence on CT. The recently proposed choroidal division is more sensitive to CT changes than the ETDRS grid. Some sectors are more sensitive to plasma biomarkers.
Nasal Staphylococcus aureus and S. pseudintermedius carriage in healthy dogs and cats: a systematic review of their antibiotic resistance, virulence and genetic lineages of zoonotic relevance

The molecular ecology of Staphylococcus aureus, Staphylococcus pseudintermedius and their methicillin‐resistant strains in healthy dogs and cats could serve as good models to understand the concept of bacterial zoonosis due to animal companionship. This study aims to provide insights into pooled prevalence, genetic lineages, virulence and antimicrobial resistance (AMR) among healthy dogs and cats. Original research and brief communication articles published from 2001 to 2021 that reported the nasal detection of S. aureus and S. pseudintermedius in healthy dogs and cats in the community, homes and outside veterinary clinics were examined and analysed. Forty‐nine studies were eligible and included in this systematic review. The pooled prevalence of nasal carriage of S. aureus/methicillin‐resistant S. aureus (MRSA) in healthy dogs and cats were 10.9% (95% CI: 10.1–11.9)/2.8% (95% CI: 2.4–3.2) and 3.2% (95% CI: 1.9–4.8)/0.5% (95% CI: 0.0–1.1), respectively. Conversely, the pooled prevalence of S. pseudintermedius/methicillin‐resistant S. pseudintermedius (MRSP) in healthy dogs and cats were 18.3% (95% CI: 17.1–19.7)/3.1% (95% CI: 2.5–3.7) and 1.3% (95% CI: 0.6–2.4)/1.2% (95% CI: 0.6–2.3), respectively. Although highly diverse genetic lineages of S. aureus were detected in healthy dogs and cats, MSSA‐CC1/CC5/CC22/CC45/CC121/CC398 and MRSA‐CC5/CC93/CC22/CC30 were mostly reported in dogs; and MSSA‐CC5/CC8/CC15/CC48 and MRSA‐CC22/CC30/CC80 in cats. Of note, MSSA‐CC398 isolates (spa‐types t034 and t5883) were detected in dogs. Genetic lineages often associated with MSSP/MRSP were ST20/ST71, highlighting the frequent detection of the epidemic European MRSP‐ST71 clone in dogs. S. aureus isolates carrying the luk‐S/F‐PV, tst, eta, etb and etd genes were seldomly detected in dogs, and luk‐S/F‐PV was the unique virulence factor reported in isolates of cats. S. pseudintermedius isolates harbouring the luk‐S/F‐I, seint and expA genes were frequently found, especially in dogs. High and diverse rates of AMR were noted, especially among MRSA/MRSP isolates. There is a need for additional studies on the molecular characterization of isolates from countries with under‐studied nasal staphylococci isolates.
Longitudinal change in serial position scores in older adults with entorhinal and hippocampal neuropathologies

Abstract Objective: Serial position scores on verbal memory tests are sensitive to early Alzheimer’s disease (AD)-related neuropathological changes that occur in the entorhinal cortex and hippocampus. The current study examines longitudinal change in serial position scores as markers of subtle cognitive decline in older adults who may be in preclinical or at-risk states for AD. Methods: This study uses longitudinal data from the Religious Orders Study and the Rush Memory and Aging Project. Participants (n = 141) were included if they did not have dementia at enrollment, completed follow-up assessments, and died and were classified as Braak stage I or II. Memory tests were used to calculate serial position (primacy, recency), total recall, and episodic memory composite scores. A neuropathological evaluation quantified AD, vascular, and Lewy body pathologies. Mixed effects models were used to examine change in memory scores. Neuropathologies and covariates (age, sex, education, APOE e4) were examined as moderators. Results: Primacy scores declined (β = −.032, p < .001), whereas recency scores increased (β = .021, p = .012). No change was observed in standard memory measures. Greater neurofibrillary tangle density and atherosclerosis explained 10.4% of the variance in primacy decline. Neuropathologies were not associated with recency change. Conclusions: In older adults with hippocampal neuropathologies, primacy score decline may be a sensitive marker of early AD-related changes. Tangle density and atherosclerosis had additive effects on decline. Recency improvement may reflect a compensatory mechanism. Monitoring for changes in serial position scores may be a useful in vivo method of tracking incipient AD.
The Role of Extracellular Vesicles in Senescence

Cells can communicate in a variety of ways, such as by contacting each other or by secreting certain factors. Recently, extracellular vesicles (EVs) have been proposed to be mediators of cell communication. EVs are small vesicles with a lipid bilayer membrane that are secreted by cells and contain DNA, RNAs, lipids, and proteins. These EVs are secreted from various cell types and can migrate and be internalized by recipient cells that are the same or different than those that secrete them. EVs harboring various components are involved in regulating gene expression in recipient cells. These EVs may also play important roles in the senescence of cells and the accumulation of senescent cells in the body. Studies on the function of EVs in senescent cells and the mechanisms through which nonsenescent and senescent cells communicate through EVs are being actively conducted. Here, we summarize studies suggesting that EVs secreted from senescent cells can promote the senescence of other cells and that EVs secreted from nonsenescent cells can rejuvenate senescent cells. In addition, we discuss the functional components (proteins, RNAs, and other molecules) enclosed in EVs that enter recipient cells.
Investigation of the structure and thermodynamics of star-polymers in semi-dilute solution

In this work, we consider a semi-dilute solution of identical star-polymers, made of attached flexible long polymer chains of the same polymerization degree N. We first compute the effective pair-potential between star-polymers. Such a potential results from the excluded volume forces between monomers. We show that this potential is logarithmic, below some known characteristic distance, σ, depending on the number of attached chains per star-polymer, f, and volume fraction of polymers, φ0 . Beyond σ, the potential fails exponentially. Second, we investigate the structure and thermodynamics of these star-polymers. To this end, we use the integral equation method with the hybridized-mean spherical approximation. The numerical resolution of this equation gives the structure factor of the star-polymers, for various particle densities. Finally, the standard relationships between thermodynamics and structure enable us to deduce three physical quantities, namely the isotherm compressibility, pressure and internal energy, as functions of density.
Progressive stages of dysmetabolism are associated with impaired biological features of human cardiac stromal cells mediated by the oxidative state and autophagy

Cardiac stromal cells (CSCs) are the main players in fibrosis. Dysmetabolic conditions (metabolic syndrome—MetS, and type 2 diabetes mellitus—DM2) are strong pathogenetic contributors to cardiac fibrosis. Moreover, modulation of the oxidative state (OxSt) and autophagy is a fundamental function affecting the fibrotic commitment of CSCs, that are adversely modulated in MetS/DM2. We aimed to characterize CSCs from dysmetabolic patients, and to obtain a beneficial phenotypic setback from such fibrotic commitment by modulation of OxSt and autophagy. CSCs were isolated from 38 patients, stratified as MetS, DM2, or controls. Pharmacological modulation of OxSt and autophagy was obtained by treatment with trehalose and NOX4/NOX5 inhibitors (TREiNOX). Flow‐cytometry and real‐time quantitative polymerase chain reaction (RT‐qPCR) analyses showed significantly increased expression of myofibroblasts markers in MetS‐CSCs at baseline (GATA4, ACTA2, THY1/CD90) and after starvation (COL1A1, COL3A1). MetS‐ and DM2‐CSCs displayed a paracrine profile distinct from control cells, as evidenced by screening of 30 secreted cytokines, with a significant reduction in vascular endothelial growth factor (VEGF) and endoglin confirmed by enzyme‐linked immunoassay (ELISA). DM2‐CSCs showed significantly reduced support for endothelial cells in angiogenic assays, and significantly increased H2O2 release and NOX4/5 expression levels. Autophagy impairment after starvation (reduced ATG7 and LC3‐II proteins) was also detectable in DM2‐CSCs. TREiNOX treatment significantly reduced ACTA2, COL1A1, COL3A1, and NOX4 expression in both DM2‐ and MetS‐CSCs, as well as GATA4 and THY1/CD90 in DM2, all versus control cells. Moreover, TREiNOX significantly increased VEGF release by DM2‐CSCs, and VEGF and endoglin release by both MetS‐ and DM2‐CSCs, also recovering the angiogenic support to endothelial cells by DM2‐CSCs. In conclusion, DM2 and MetS worsen microenvironmental conditioning by CSCs. Appropriate modulation of autophagy and OxSt in human CSCs appears to restore these features, mostly in DM2‐CSCs, suggesting a novel strategy against cardiac fibrosis in dysmetabolic patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
OHP2 is not required for psbA translation in Chlamydomonas

In land plants and cyanobacteria, co-translational association of chlorophyll (Chl) to the nascent D1 polypeptide, a reaction center protein of photosystem II (PSII), requires a Chl binding complex consisting of a short-chain dehydrogenase (HCF244/Ycf39) and One-Helix Proteins of the LHC superfamily (OHP1 and OHP2 in chloroplasts). Here, we show that an ohp2 mutant of the green alga Chlamydomonas reinhardtii fails to accumulate core PSII subunits, in particular D1. Extragenic suppressors arise at high frequency, suggesting the existence of another route for Chl association to PSII. The ohp2 mutant can be complemented by the Arabidopsis ortholog. In contrast to land plants, where psbA translation is prevented in the absence of OHP2, ribosome profiling experiments show that the Chlamydomonas mutant translates the psbA transcript over its full length. Pulse labelling suggests that D1 is degraded during or immediately after translation. The translation of other PSII subunits is affected by assembly-controlled translational regulation (the CES process). Proteomics show that HCF244, a translation factor which associates with and is stabilized by OHP2 in land plants, still partly accumulates in the Chlamydomonas ohp2 mutant, explaining the persistence of psbA translation. Several Chl biosynthesis enzymes overaccumulate in the mutant membranes. Partial inactivation of the D1-degrading FtsH protease restores a low level of PSII activity in an ohp2 background, but not photoautotrophy. Taken together, our data suggest that OHP2 is not required for psbAD1 translation in Chlamydomonas, but necessary for its stabilization.
Predicting anti-cancer drug synergy using extended drug similarity profiles

Combination therapy is a promising strategy for confronting the complexity of cancer. However, experimental exploration of the vast space of potential drug combinations is costly and unfeasible. Therefore, computational methods for predicting drug synergy are much-needed for narrowing down this space, especially when examining new cellular contexts. Here, we thus introduce CCSynergy, a flexible, context-aware and integrative deep learning framework that we have established to unleash the potential of the Chemical Checker extended drug similarity profiles for the purpose of drug synergy prediction. We have shown that CCSynergy enables predictions of superior accuracy, remarkable robustness and improved context-generalizability as compared to the state-of-the-art methods in the field. Having established the potential of CCSynergy for generating experimentally validated predictions, we exhaustively explored the untested drug combination space. This resulted in a compendium of potentially synergistic drug combinations on hundreds of cancer cell lines, which can guide future experimental screens.