Miracle-dz/UniFAR-FTUs huggingface dataset:
Scaffold Effects on Halogen Bonding Strength

Halogen bonds have become increasingly popular interactions in molecular design and drug discovery. One of the key features is the strong dependence of the size and magnitude of the halogen's σ-hole on the chemical environment of the ligand. The term σ-hole refers to a region of lower electronic density opposite to a covalent bond, e.g., the C-X bond. It is typically (but not always) associated with a positive electrostatic potential in close proximity to the extension of the covalent bond. Herein, we use a variety of 30 nitrogen-bearing heterocycles, halogenated systematically by chlorine, bromine, or iodine, yielding 468 different ligands that are used to exemplify scaffold effects on halogen bonding strength. As a template interaction partner, we have chosen N-methylacetamide representing the ubiquitously present protein backbone. Adduct formation energies were obtained at a MP2/TZVPP level of theory. We used the local maximum of the electrostatic potential on the molecular surface in close proximity to the σ-hole, V S,max, as a descriptor for the magnitude of the positive electrostatic potential characterizing the tuning of the σ-hole. Free optimization of the complexes gave reasonable correlations with V S,max but was found to be of limited use because considerable numbers of chlorinated and brominated ligands lost their halogen bond or showed significant secondary interactions. Thus, starting from a close to optimal geometry of the halogen bond, we used distance scans to obtain the best adduct formation energy for each complex. This approach provided superior results for all complexes exhibiting correlations with R2 > 0.96 for each individual halogen. We evaluated the dependence of V S,max from the molecular surface onto which the positive electrostatic potential is projected, altering the isodensity values from 0.001 au to 0.050 au. Interestingly, the best overall fit using a third-order polynomial function (R2 = 0.99, RMSE = 0.562 kJ/mol) with rather smooth transitions between all halogens was obtained for V S,max calculated from an isodensity surface at 0.014 au.
Parental Dietary Protein Source and the Role of CMKLR1 in Determining the Severity of Dahl Salt-Sensitive Hypertension

Studies from our laboratory have revealed an important role for the maternal diet and the dietary protein source in the development of hypertension and renal injury in Dahl salt-sensitive (SS) rats. The current study sought to compare salt-induced hypertension, renal damage, and immune cell infiltration in the offspring of breeders fed either a casein- or gluten-based diet, with the hypothesis that offspring from gluten-fed breeders would fail to develop these SS phenotypes. When fed identical diets post-weaning, the F1 generation gluten offspring demonstrated lower mean arterial pressure (149.1±3.1 versus 162.5±5.8 mm Hg), albuminuria (166.2±34.6 versus 250.9±27.8 mg/day), and outer medullary protein casting (7.4±0.8% versus 13.1±1.3%) in response to high salt compared with the casein offspring (n=9–11). The gluten offspring also had fewer CD45+ leukocytes, CD11b/c+ monocytes/macrophages, CD3+ T cells, and CD45R+ B cells infiltrating the kidney. Analysis of the F2 generation gluten offspring also exhibited lower mean arterial pressure and renal damage compared with rats born from casein breeders (n=7–9), with no difference in renal immune cell infiltration. CMKLR1—receptor for the novel prohypertensive adipokine chemerin—was found via polymerase chain reaction array to be significantly upregulated (2.99-fold) in renal T cells isolated from F2 offspring of casein-fed versus gluten-fed parents. Furthermore, CMKLR1 inhibition via &agr;-NETA (2-[&agr;-naphthoyl] ethyltrimethylammonium iodide) treatment significantly attenuated renal immune cell infiltration, hypertension, and renal damage in SS rats fed high salt. Together, these data demonstrate the influence of the parental diet in determining the salt-induced hypertension, renal damage, and inflammatory phenotype of the offspring.
The Kinesin Light Chain–Related Protein PAT1 Promotes Superoxide Anion Production in Human Phagocytes

Superoxide anion production by the phagocyte NADPH oxidase plays a crucial role in host defenses and inflammatory reaction. The phagocyte NADPH oxidase is composed of cytosolic components (p40phox, p47phox, p67phox, and Rac1/2) and the membrane flavocytochrome b558, which is composed of two proteins: p22phox and gp91phox/NOX2. p22phox plays a crucial role in the stabilization of gp91phox in phagocytes and is also a docking site for p47phox during activation. In the current study, we have used a yeast two-hybrid approach to identify unknown partners of p22phox. Using the cytosolic C-terminal region of p22phox as bait to screen a human spleen cDNA library, we identified the protein interacting with amyloid precursor protein tail 1 (PAT1) as a potential partner of p22phox. The interaction between p22phox and PAT1 was further confirmed by in vitro GST pulldown and overlay assays and in intact neutrophils and COSphox cells by coimmunoprecipitation. We demonstrated that PAT1 is expressed in human neutrophils and monocytes and colocalizes with p22phox, as shown by confocal microscopy. Overexpression of PAT1 in human monocytes and in COSphox cells increased superoxide anion production and depletion of PAT1 by specific small interfering RNA inhibited this process. These data clearly identify PAT1 as a novel regulator of NADPH oxidase activation and superoxide anion production, a key phagocyte function.
Expression and Purification of Chemokine MIP-3α (CCL20) through a Calmodulin-Fusion Protein System

Human macrophage inflammatory protein 3α (MIP-3α), also known as CCL20, is a 70 amino acid chemokine that selectively binds and activates chemokine receptor 6 (CCR6). This chemokine is responsible for inducing the migration of immature dendritic cells, effector, or memory T-cells, and B-cells. Moreover, the MIP-3α protein has been shown to display direct antimicrobial, antiviral and antiprotozoal activities. Because of the potential therapeutic uses of this protein, the efficient production of MIP-3α is of great interest. However, bacterial recombinant production of the MIP-3α protein has been limited by the toxicity of this extremely basic protein (pI 9.7) toward prokaryotic cells, and by solubility problems during expression and purification. In an attempt to overcome these issues, we have investigated the bacterial recombinant expression of MIP-3α by using several common expression and fusion tags, including 6× histidine (His), small ubiquitin modifier protein (SUMO), thioredoxin (TRX), ketosteroid isomerase (KSI), and maltose binding protein (MBP). We have also evaluated a recently introduced calmodulin (CaM)-tag that has been used for the effective expression of many basic antimicrobial peptides (AMPs). Here, we show that the CaM fusion tag system effectively expressed soluble MIP-3α in the cytoplasm of Escherichia coli with good yields. Rapid purification was facilitated by the His-tag that was integrated in the CaM-fusion protein system. Multidimensional nuclear magnetic resonance (NMR) studies demonstrated that the recombinant protein was properly folded, with the correct formation of disulfide bonds. In addition, the recombinant MIP-3α had antibacterial activity, and was shown to inhibit the formation of Pseudomonas aeruginosa biofilms.
Convergent Estimation Mechanism Design for Nonlinear Fuzzy Systems With Faults

The convergent estimation for a class of nonlinear Takagi–Sugeno fuzzy systems is concerned, where time-varying process faults and input disturbances are both involved. A convergent estimation mechanism (CEM) based on a set of fuzzy iterative estimation observers is constructed for the nonlinear fuzzy system; meanwhile, the convergence of the mean sequence of estimation errors (for both states and faults) to zero (vector) is proved. However, in the existing literature, the estimation errors can only be proved to be uniformly ultimately bounded when the fault is time varying. In the design procedure, the disturbances on systems in consideration can be isolated effectively in the obtained fuzzy iterative error dynamics through introducing a suitable isolation technique. Numerical examples give the simulation results to show the effectiveness and merits of the proposed CEM.
Acute exacerbations of progressive-fibrosing interstitial lung diseases

Acute exacerbation of interstitial lung disease (ILD) is associated with a poor prognosis and high mortality. Numerous studies have documented acute exacerbation in idiopathic pulmonary fibrosis (IPF), but less is known about these events in other ILDs that may present a progressive-fibrosing phenotype. We propose defining acute exacerbation as an acute, clinically significant respiratory deterioration, typically less than 1 month in duration, together with computerised tomography imaging showing new bilateral glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILDs. Drawing on observations in IPF, it is suspected that epithelial injury or proliferation and autoimmunity are risk factors for acute exacerbation in ILDs that may present a progressive-fibrosing phenotype, but further studies are required. Current acute exacerbation management strategies are based on recommendations in IPF, but no randomised controlled trials of acute exacerbation management have been performed. Although there are no formal strategies to prevent the development of acute exacerbation, possible approaches include antifibrotic drugs (such as nintedanib and pirfenidone), and minimising exposure to infection, airborne irritants and pollutants. This review discusses the current knowledge of acute exacerbation of ILDs that may present a progressive-fibrosing phenotype and acknowledges limitations of the data available. Acute exacerbation can occur in ILDs associated with a progressive-fibrosing phenotype, other than IPF; and are associated with significant morbidity. There are pressing needs to identify patients at risk of AE and for therapies that reduce this risk. http://ow.ly/tEA330mNE0r
Better Doctor-Patient Relationships Are Associated with Men Choosing More Active Depression Treatment

Background: Men tend to have low rates of treatment uptake for depression. The quality of the relationship with their family physician may be a factor influencing attitudes toward treatment. The present study was developed to explore this issue in a nationally representative sample of Canadian men. Methods: An online survey of 1000 Canadian men was conducted to inquire about men's relationship with their family physician and hypothetical treatment choices for depression. Main analyses were conducted among 819 men who indicated having a regular primary care physician. Results: Two thirds of men with a family physician (n = 534; 65%) indicated they would pursue treatment if they were suffering from depression. Multinomial logistic regression, controlling for age, employment, education level, and current depressive symptoms indicated that positive perceptions of the patient-doctor relationship were associated with men being more likely to opt for pharmacotherapy (n = 183; odds ratio [OR], 1.06; P < .001), and individual psychotherapy (n = 277; OR, 1.04; P < .001), compared with a wait-and-see/no treatment approach (n = 285). Conclusion: The quality of the doctor-patient relationship is an important element in helping men choose active treatment for depression.
Expression of the axon‐guidance protein receptor Neuropilin 1 is increased in the spinal cord and decreased in muscle of a mouse model of amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a degenerative motor neuron disorder. It is supposed that ALS is at least in part an axonopathy. Neuropilin 1 is an important receptor of the axon repellent Semaphorin 3A and a co‐receptor of vascular endothelial growth factor. It is probably involved in neuronal and axonal de‐/regeneration and might be of high relevance for ALS pathogenesis and/or disease progression. To elucidate whether the expression of either Neuropilin1 or Semaphorin3A is altered in ALS we investigated these proteins in human brain, spinal cord and muscle tissue of ALS‐patients and controls as well as transgenic SOD1G93A and control mice. Neuropilin1 and Semaphorin3A gene and protein expression were assessed by quantitative real‐time PCR (qRT‐PCR), western blot and immunohistochemistry. Groups were compared using either Student t‐test or Mann–Whitney U test. We observed a consistent increase of Neuropilin1 expression in the spinal cord and decrease of Neuropilin1 and Semaphorin3A in muscle tissue of transgenic SOD1G93A mice at the mRNA and protein level. Previous studies have shown that damage of neurons physiologically causes Neuropilin1 and Semaphorin3A increase in the central nervous system and decrease in the peripheral nervous system. Our results indicate that this also occurs in ALS. Pharmacological modulation of expression and function of axon repellents could be a promising future therapeutic option in ALS.
ARHGAP18: A Flow‐Responsive Gene That Regulates Endothelial Cell Alignment and Protects Against Atherosclerosis

Background Vascular endothelial cell (EC) alignment in the direction of flow is an adaptive response that protects against aortic diseases, such as atherosclerosis. The Rho GTPases are known to regulate this alignment. Herein, we analyze the effect of ARHGAP18 on the regulation of EC alignment and examine the effect of ARHGAP18 deficiency on the development of atherosclerosis in mice. Methods and Results We used in vitro analysis of ECs under flow conditions together with apolipoprotein E−/− Arhgap18 −/− double‐mutant mice to study the function of ARHGAP18 in a high‐fat diet–induced model of atherosclerosis. Depletion of ARHGAP18 inhibited the alignment of ECs in the direction of flow and promoted inflammatory phenotype, as evidenced by disrupted junctions and increased expression of nuclear factor‐κB and intercellular adhesion molecule‐1 and decreased endothelial nitric oxide synthase. Mice with double deletion in ARHGAP18 and apolipoprotein E and fed a high‐fat diet show early onset of atherosclerosis, with lesions developing in atheroprotective regions. Conclusions ARHGAP18 is a protective gene that maintains EC alignments in the direction of flow. Deletion of ARHGAP18 led to loss of EC ability to align and promoted atherosclerosis development.
Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma.

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials. gov as #NCT02315326.
Correlates and stability of alternate stimuli in a computer-based measure of inspection time

Abstract Inspection time tasks assess the ability to make a simple visual discrimination, typically in milliseconds. Typically, IT stimuli consists of a pi-shaped figure, in which subjects select the side with the significantly longer leg. To prevent storage in iconic memory, a backward mask is then introduced. However, some participants have reported that the mask may cause the shorter leg to appear to lengthen, creating a possible strategy that facilitates performance. As a result, alternative stimuli/masks have been developed; however, these alternative stimuli may be processed differently. This study assessed the cognitive correlates and stability of an alternative stimuli/mask. Results indicated that processing of the stimuli was influenced by an interaction between the complexity of the stimuli and the number of times it was presented. Specifically, the alternative stimulus/mask produced slower processing, particularly at the time of a second administration; however, it contributed an important and unique relationship with speeded, general intelligence.
The phytochemical and anti‐inflammatory studies of Dillenia suffruticosa leaves

The Dillenia suffruticosa leaves (Dilleniaceae), a folk medicine recommended in Southeast Asia for treating inflammation, were phytochemically studied for the first time and assessed for suppression of λ‐carrageenan‐induced paw oedema in rats. The crude methanolic extract orally administered at 5,000 mg/kg, displayed no toxicity and at 250 to 1,000 mg/kg significantly suppressed the paw oedema. Two‐isolated triterpenoids, betulinic acid (1) and koetjapic acid (2) orally administered at 50 mg/kg, significantly reduced the paw oedema, (p < 0.001) and (p < 0.005) at the fourth h onwards to 47.36% ± 2.23 and 53.43% ± 7.09, respectively, from 95.90% ± 6.88 oedema induced by λ‐carrageenan alone. 1 and the isolated flavonoids of vitexin (3), tiliroside (4), and kaempferol (5), displayed moderately more of cyclooxygenase (COX)‐2 than COX‐1 enzyme inhibition, whereas 2 was slightly more inhibition of COX‐1. The in silico molecular docking studies provided support to the in vitro COX studies that the isolated compounds formed H‐bonding with the amino acid residues at the COX‐2 catalytic sites. The triterpenoids were bound to the peroxidase, possibly inhibiting the peroxidase reaction, whereas the flavonoids interacted more at the cyclooxygenase, resembling celecoxib, therefore providing evidences that these compounds were responsible for the anti‐inflammatory properties of D. suffruticosa.
Artificial intelligence, bias and clinical safety

In medicine, artificial intelligence (AI) research is becoming increasingly focused on applying machine learning (ML) techniques to complex problems, and so allowing computers to make predictions from large amounts of patient data, by learning their own associations.1 Estimates of the impact of AI on the wider economy globally vary wildly, with a recent report suggesting a 14% effect on global gross domestic product by 2030, half of which coming from productivity improvements.2 These predictions create political appetite for the rapid development of the AI industry,3 and healthcare is a priority area where this technology has yet to be exploited.2 3 The digital health revolution described by Duggal et al 4 is already in full swing with the potential to ‘disrupt’ healthcare. Health AI research has demonstrated some impressive results,5–10 but its clinical value has not yet been realised, hindered partly by a lack of a clear understanding of how to quantify benefit or ensure patient safety, and increasing concerns about the ethical and medico-legal impact.11 This analysis is written with the dual aim of helping clinical safety professionals to critically appraise current medical AI research from a quality and safety perspective, and supporting research and development in AI by highlighting some of the clinical safety questions that must be considered if medical application of these exciting technologies is to be successful. Clinical decision support systems (DSS) are in widespread use in medicine and have had most impact providing guidance on the safe prescription of medicines,12 guideline adherence, simple risk screening13 or prognostic scoring.14 These systems use predefined rules, which have predictable behaviour and are usually shown to reduce clinical error,12 although sometimes inadvertently introduce safety issues themselves.15 16 Rules-based systems have also been developed to address diagnostic uncertainty17–19 …
Accuracy and the role of experience in dynamic computer guided dental implant surgery: An in-vitro study

Background To compare the accuracy of implant placement using the conventional freehand method and a dynamic navigation system; to assess the role of the surgeon’s experience in implant placement using these two methods. Material and Methods A randomized in-vitrostudy was conducted. Six resin mandible models and 36 implants were used. Two researchers with differing clinical experience (novice and experienced) placed implants using either the Navident dynamic navigation system (navigation group) or the conventional freehand method (freehand group). Accuracy was measured by overlaying the real position in the postoperative CBCT on the virtual presurgical placement of the implant in a CBCT image. Descriptive and bivariate analyses of the data were performed. Results The navigation group showed significantly higher accuracy for all the variables studied except 3D entry and depth deviation. This system significantly enhanced the accuracy of the novice professional in several outcome variables in comparison with the freehand implant placement method. However, when the implants were placed by the experienced clinician the dynamic navigation system only improved angulation deviation. Significant differences were found between the 2 professionals when the freehand method was employed. Similar deviations were observed for the implants placed with the navigation system. Conclusions Dynamic computer assisted surgery systems allow more accurate implant placement in comparison with the conventional freehand method, regardless of the surgeon’s experience. However, this system seems to offer more advantages to novice professionals, since it allows them to reduce their deviations significantly and achieve similar results to those of experienced clinicians. Key words:Computer guided surgery, dynamic computer guided surgery, implant navigation system, dental implants.
Relationship status and drinking-related outcomes in a community sample of lesbian and bisexual women

Although marriage tends to be protective against hazardous drinking among women in the general population, few studies have compared drinking rates, levels, or problems based on relationship status among sexual minority women (SMW; lesbian, bisexual). We examined associations between relationship status (committed relationship/cohabiting; committed/not cohabiting; single) and past-year drinking outcomes using data from a diverse sample of 696 SMW interviewed in wave 3 of the 17-year longitudinal Chicago Health and Life Experiences of Women study. The mean age of SMW in the sample was 40.01 (SD = 14.15; range 18–82). A little more than one-third (37%) of the sample was White, 36% was African American, and 23% Latina; 4% reported another or multirace/ethnicity. Compared to SMW in committed cohabiting relationships, single SMW were significantly more likely to be heavy drinkers. SMW in committed noncohabiting relationships were more likely to report alcohol-related problem consequences, and both single SMW and those in committed noncohabiting relationships were more likely to report one or more symptoms of potential alcohol dependence. Findings underscore the importance of exploring relationship factors that may influence drinking and drinking-related problems among SMW.