Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition Activity of Avibactam against Nocardia farcinica (cid:2) -Lactamase FAR IFM10152

Nocardia farcinica , one of the most frequent pathogenic species respon-sible for nocardiosis, is characterized by frequent brain involvement and resistance to (cid:2) -lactams mediated by a class A (cid:2) -lactamase. Kinetic parameters for hydrolysis of various (cid:2) -lactams by FAR IFM10152 from strain IFM 10152 were determined by spectrophotometry revealing a high catalytic activity ( k cat / K m ) for amoxicillin, aztreonam, and nitroceﬁn. For cephems, k cat / K m was lower but remained greater than 10 4 M (cid:2) 1 s (cid:2) 1 . A low catalytic activity was observed for meropenem, imipenem, and ceftazidime hydrolysis. FAR IFM10152 inhibition by avibactam and clavulanate was compared using nitroceﬁn as a reporter substrate. FAR IFM10152 was efﬁcaciously inhibited by avibactam with a carbamoylation rate constant ( k 2 / K i ) of (1.7 (cid:3) 0.3) (cid:4) 10 4 M (cid:2) 1 s (cid:2) 1 . The 50% effective concentrations (EC 50 s) of avibactam and clavulanate were 0.060 (cid:3) 0.007 (cid:3) M and 0.28 (cid:3) 0.06 (cid:3) M, respectively. Amoxicillin, cefotaxime, imipenem, and meropenem MICs were measured for ten clinical strains in the presence of avibactam and clavulanate. At 4 (cid:3) g/ml, avibactam and clavulanate restored amoxicillin susceptibility in all but one of the tested strains but had no effect on the MICs of cefotaxime, imipenem, and meropenem. At 0.4 (cid:3) g/ml, amoxicillin susceptibility (MIC (cid:4) 8 (cid:3) g/ml) was restored for 9 out of 10 strains by avibactam but only for 4 out of 10 strains by clavulanate. Together, these results indicate that avibactam was at least as potent as clavulanate, suggesting that the amoxicillin-avibactam combination could be considered as an option for the rescue treatment of N. farcinica infections if clavulanate cannot be used.
Multiple single objective Pareto sampling

We detail a new nonPareto evolutionary multiobjective algorithm, multiple single objective Pareto sampling (MSOPS), that performs a parallel search of multiple conventional target vector based optimisations, e.g. weighted min-max. The method can be used to generate the Pareto set and analyse problems with large numbers of objectives. The method allows bounds and discontinuities of the Pareto set to be identified and the shape of the surface to be analysed, despite not being able to visualise the surface easily. A new combination metric is also introduced that allows the shape of the objective surface that gives rise to discontinuities in the Pareto surface to be analysed easily.
Magnetic ordering effects in the Raman spectra of La 1-x Mn 1-x O 3

Temperature-dependent Raman spectra of polycrystalline ${\mathrm{La}}_{1\ensuremath{-}x}{\mathrm{Mn}}_{1\ensuremath{-}x}{\mathrm{O}}_{3}$ samples, referred to as ${\mathrm{LaMnO}}_{3+\ensuremath{\delta}}$ for convenience, were correlated to their structural and magnetic properties for different $\ensuremath{\delta}. $ For $\ensuremath{\delta}l~0.05,$ a softening of the $\ensuremath{\sim}610 {\mathrm{cm}}^{\ensuremath{-}1}$ Raman mode is observed below the magnetic ordering temperature. This softening is reduced as $\ensuremath{\delta}$ increases from 0.00 to 0.05. This behavior is not associated with lattice anomalies, and is interpreted in terms of a spin-phonon coupling caused by a phonon modulation of the superexchange integral. A quantitative analysis of this effect is presented.
Altered WNT signaling in hiPSC NPCs derived from four schizophrenia patients

Schizophrenia (SZ) is a devastating psychiatric disorder hypothesized to be a neurodevelopmental condition (1, 2); arising as a consequence of dysregulation of brain development (3, 4). WNT signaling is important for neural patterning, proliferation and migration, and synapse formation (reviewed by (5)); moreover, converging post-mortem (6, 7), rodent (8, 9) and pharmacological (10) evidence suggests that WNT signaling may contribute to SZ (reviewed by (11, 12)). We utilized human induced pluripotent stem cell (hiPSC) derived forebrain patterned neural progenitor cells (NPCs) (13, 14) to investigate canonical WNT activity in a pilot cohort of four SZ patients. Because all research described herein was performed on deidentified human samples obtained for broadly consented scientific research by either American Type Culture Collection (ATCC) or the Coriell Cell Repository, is was found to be exempt by the Internal Review Committee of the Icahn School of Medicine at Mount Sinai. This work was also reviewed by the Embryonic Stem Cell Research Oversight Committee at the Icahn School of Medicine at Mount Sinai. We compared global transcription of forebrain hiPSC NPCs from six control and four SZ patients by RNAseq (Table cultured as described 14). As previously reported, hiPSC forebrain NPCs differentiate to a mixed neuronal population of
Reduced A-to-I editing of endogenous Alu RNAs in severe COVID-19 disease

Severe COVID-19 disease is associated with elevated inflammatory responses. One form of Aicardi-Goutières Syndrome caused by inactivating mutations in ADAR results in reduced A-to-I editing of endogenous double-stranded RNAs (dsRNAs), induction of IFNs, interferon-stimulated genes (ISGs), other inflammatory mediators, morbidity and mortality. Alu elements, ~10% of the human genome, are the most common A-to-I editing sites. Using leukocyte whole-genome RNA sequencing data, we find reduced A-to-I editing of Alu dsRNAs in patients with severe COVID-19 disease. Dendritic cells infected with COVID-19 also exhibit reduced A-to-I editing of Alu dsRNAs. Unedited Alu dsRNAs, but not edited Alu dsRNAs, are potent inducers of IRF and NF-kB transcriptional responses, IL6, IL8 and ISGs. Thus, decreased A-to-I editing that may lead to accumulation of unedited Alu dsRNAs and increased inflammatory responses, is associated with severe COVID-19 disease. In summary, our results demonstrate reduced Alu dsRNA A-to-I editing in COV-S and FLU-S. A better understanding of how reduced A-to-I editing contributes to deleterious immune responses observed in COV-S may point to new therapeutic targets to inhibit the ‘cytokine storm’ associated with COV-S, as well as other severe viral or bacterial infections.
Cre-loxP –Mediated Recombination between the SIL and SCL Genes Leads to a Block in T-Cell Development at the CD4 (cid:1) CD8 (cid:1) to CD4 + CD8 + Transition 1

In the most common form of stem cell leukemia ( SCL ) gene rearrangement, an interstitial deletion of 82 kb brings SCL under the control of regulatory elements that normally govern expression of the ubiquitously expressed SCL interrupting locus ( SIL ) gene, which is located directly upstream of SCL . To investigate the effect of this fusion in a mouse model, a bacterial artificial chromosome (BAC) clone containing both human SIL and SCL genes was isolated, and loxP sites were inserted into intron 1 of both the SIL and SCL genes, corresponding to the sites at which recombination occurs in human T-cell acute lymphocytic leukemia patients. This BAC clone was used to generate transgenic SILloxloxSCL mice. These transgenic mice were subsequently bred to Lck-Cre mice that express the Cre recombinase specifically in the thymus. The BAC transgene was recombined between the two loxP sites in over 50% of the thymocytes from SILloxloxSCL/Cre double-transgenic mice, bringing the SCL gene under the direct control of SIL regulatory elements. Aberrant SCL gene expression in the thymus was verified by reverse transcription–polymerase chain reaction. Using FACS analysis, we found that mice carrying both SILloxloxSCL and Cre transgenes have increased CD4 (cid:1) /CD8 (cid:1) thymocytes compared with transgene-negative mice. In the spleen, these transgenic mice show a marked reduction in the number of mature CD4 + or CD8 + cells. These results demonstrate that condi-tional activation of SCL under control of SIL regulatory elements can impair normal T-cell development.
Binding of (cid:98) -Amyloid to the p75 Neurotrophin Receptor Induces Apoptosis A Possible Mechanism for Alzheimer’s Disease

Alzheimer’s disease is a neurodegenerative disorder characterized by the extracellular deposition in the brain of aggregated (cid:98) -amyloid peptide, presumed to play a pathogenic role, and by preferential loss of neurons that express the 75-kD neurotrophin receptor (p75 NTR ). Using rat cortical neurons and NIH-3T3 cell line engineered to stably express p75 NTR , we find that the (cid:98) -amyloid peptide specifically binds the p75 NTR . Furthermore, 3T3 cells expressing p75 NTR , but not wild-type control cells lacking the receptor, undergo apoptosis in the presence of aggregated (cid:98) -amyloid. Normal neural crest–derived melanocytes that express physiologic levels of p75 NTR undergo apoptosis in the presence of aggregated (cid:98) -amyloid, but not in the presence of control peptide synthesized in reverse. These data imply that neuronal death in Alzheimer’s disease is mediated, at least in part, by the interaction of (cid:98) -amyloid with p75 NTR , and suggest new targets for therapeutic intervention. ( J. Clin. Invest. 1997. 100:2333–2340.)
A Novel Genetic Model of Constitutively Active Integrin CD11b/ CD18

Pharmacological activation of integrin CD11b/CD18 ( α M β 2 , Mac-1, CR3) shows anti-inflammatory benefits in a variety of animal models of human disease, and it is a novel therapeutic strategy. Reasoning that genetic models can provide an orthogonal and direct system for the mechanistic study of CD11b agonism, we present here a novel knock-in (KI) model of constitutive active CD11b in mice. We genetically targeted the Itgam gene (which codes for CD11b) to introduce a point mutation that results in the I332G substitution in the protein. The I332G mutation in CD11b promotes an active, higher affinity conformation of the ligand-binding I/A-domain (CD11b α A-domain). In vitro, this mutation increased adhesion of KI neutrophils to fibrinogen, and decreased neutrophil chemotaxis to a formyl-Met-Leu-Phe (fMLF) gradient. In vivo, CD11b I332G animals showed a reduction in recruitment of neutrophils and macrophages in a model of sterile peritonitis. This genetic activation of CD11b also protected against development of atherosclerosis in the setting of hyperlipidemia via reduction of macrophage recruitment into atherosclerotic lesions. Thus, our animal model of constitutive genetic activation of CD11b can be a useful tool for the study of integrin activation and its potential contribution to modulating leukocyte recruitment and alleviating different inflammatory diseases.
Early Life Exposures Association between the pregnancy exposome and fetal growth

Background: Several environmental contaminants were shown to possibly inﬂuence fetal growth, generally from single exposure family studies, which are prone to publication bias and confounding by co-exposures. The exposome paradigm offers perspectives to avoid selective reporting of ﬁndings and to control for confounding by co-exposures. We aimed to characterize associations of fetal growth with the pregnancy chemical and external exposomes. Methods: Within the Human Early-Life Exposome project, 131 prenatal exposures were assessed using biomarkers and environmental models in 1287 mother–child pairs from six European cohorts. We investigated their associations with fetal growth using a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering each exposure independently. We corrected for exposure measurement error and tested for exposure– exposure and sex–exposure interactions. Results: The DSA model identiﬁed lead blood level, which was associated with a 97 g birth weight decrease for each doubling in lead concentration. No exposure passed the multiple testing-corrected signiﬁcance threshold of ExWAS; without multiple testing correction, this model was in favour of negative associations of lead, ﬁne particulate matter concentration and absorbance with birth weight, and of a positive sex-speciﬁc association of parabens with birth weight in boys. No two-way interaction between exposure variables was identiﬁed. Conclusions: This ﬁrst large-scale exposome study of fetal growth simultaneously considered > 100 environmental exposures. Compared with single exposure studies, our approach allowed making all tests (usually reported in successive publications) explicit. Lead exposure is still a health concern in Europe and parabens health effects warrant further investigation. data. 38 We applied both the Benjamini and Yekutieli false discovery rate correction 39 and the Li et al . family wise error rate correction 40 approaches for multiple hypothesis testing.
The Reaction of Cytochrome o in Escherichia coli with Oxygen LOW-TEMPERATURE KINETIC AND SPECTRAL STUDIES

1. The reactions of cytochrome o in intact cells of aerobically grown Escherichia coli with 0z and CO have been studied at low temperature. 2. Flash photolysis of CO-liganded cells in the presence of02 and at temperatures between -79 and - 102°C results in the oxidation of kinetically heterogeneous b-type cytochromes (including cytochrome o), but not of cytochrome d. 3. The reaction of reduced cytochrome o with 02 involves 02 binding to give intermediate(s) with spectral characteristics similar to that of the reduced oxidase-CO complex. Observation in the a-region suggests that unexplained ligand dissociation accompanies the initial 02 binding. 4. At temperatures below -98°C, an 'end point' in the reaction is reached; further reaction and oxidation of cytochrome o occurs on raising the temperature. 5. There is a linear relationship between the rate of formation of the oxygen compound and the O2 concentration up to 0.5 mm. The second-order constant for its formation (k+1) is 0.91 M-1 s-s at - 101°C. The reaction is not readily reversible, the value of k_1 being 1.4 x 10- s-' and the kd 1.5 x IO-'M. 6. The energy of activation for this reaction at low temperatures is 29.9kJ (7.1 kcal)/mol. 7. The reaction with 02 is distinguished from that with CO by the markedly lower velocity and high photolytic reversiblity of the latter. 8. Comparisons are drawn between the intermediate(s) in the 02 reaction of cytochrome o in E. coli and those identified in other bacteria and in the reaction of cytochrome aa3
The dark side of morality: Neural mechanisms underpinning moral convictions and judgments about violence

People are motivated by shared social values that, when held with moral conviction, can serve as compelling mandates capable of facilitating support for ideological violence. The current study examined this dark side of morality by identifying specific cognitive and neural mechanisms associated with beliefs about the appropriateness of sociopolitical violence, and determining the extent to which the engagement of these mechanisms was predicted by moral convictions. Participants reported their moral convictions about a variety of sociopolitical issues prior to undergoing functional MRI scanning. During scanning, they were asked to evaluate the appropriateness of violent protests that were ostensibly congruent or incongruent with their views about sociopolitical issues. Complementary univariate and multivariate analytical strategies comparing neural responses to congruent and incongruent violence identified neural mechanisms implicated in processing salience and in the encoding of subjective value. As predicted, neuro-hemodynamic response was modulated parametrically by individuals’ beliefs about the appropriateness of congruent relative to incongruent sociopolitical violence in ventromedial prefrontal cortex, and by moral conviction in ventral striatum. Overall moral conviction was predicted by neural response to congruent relative to incongruent violence in amygdala. Together, these findings indicate that moral conviction about sociopolitical issues serves to increase their subjective value, overriding natural aversion to interpersonal harm. mechanisms underpinning moral convictions about sociopolitical issues and beliefs about the appropriateness of ideological violence. Believing violence to be appropriate was associated with parametric increases in vmPFC, while stronger moral conviction was associated with parametric increases in VS and, overall, correlated negatively with activation in amygdala. Together, these findings indicate that moral convictions about sociopolitical issues may raise their subjective value, overriding our natural aversion to interpersonal harm. Value-based decision-making in social contexts provides a powerful platform for understanding sociopolitical and moral decision-making. Disentangling the neurocognitive mechanisms fundamental to value and choice can reveal—at a granular level —physiological boundaries that ultimately constrain our moral psychologies. The theoretical advances afforded by such an undertaking enable more accurate predictions about moral conviction and its impact on social decision-making. areas demonstrating significantly greater hemodynamic response to photographs depicting acts of sociopolitical violence that are purportedly congruent compared to incongruent with participants’ sociopolitical views. The opposite contrast did not reveal regions in which hemodynamic response was increased for incongruent compared to incongruent sociopolitical violence.
[Ca2+], during Excitation-Contraction Coupling in Cardiac Myocytes

The intracellular calcium ([Ca2+]i) transient in adult rat heart cells was examined using the fluorescent calcium indicator fluo-3 and a laser scanning confocal microscope. We find that the electrically evoked [Ca2+]j transient does not rise at a uniform rate at all points within the cell during the [Ca2+]i transient. These spatial non-uniformities in [Ca2+], are observed immediately upon depolarization and largely disappear by the time the peak of the [Ca2+]i transient occurs. Importantly, some of the spatial non-uniformity in [Ca2+]j varies randomly in location from beat to beat. Analysis of the spatial character of the non-uniformities suggests that they arise from the stochastic nature of the activation of SR calcium-release channels. The non-uniformities in [Ca2+]i are markedly enhanced by low concentrations of Cd2 , suggesting that activation of L-type calcium channels is the primary source of activator calcium for the calcium transient. In addition, the pattern of calcium release in these conditions was very similar to the spontaneous calcium sparks that are observed under resting conditions and which are due to spontaneous calcium release from the SR. The spatial non-uniformity in the evoked [Ca2+]i transient under normal conditions can be explained by the temporal and spatial summation of a large number of calcium sparks whose activation is a stochastic process. The results are discussed with respect to a stochastic local control model for excitation-contraction (E-C) coupling, and it is proposed that the fundamental unit of E-C coupling consists of one dihydropyridine receptor activating a small group of ryanodine receptors (possibly four) in a square packing model.
Who is Interested in Carpooling and Why: The Importance of Individual Characteristics, Role Preferences and Carpool Markets

Carpooling is an informal form of commuter ride-sharing that can mitigate traffic congestion and parking demand. While ride-sharing and carpool formation require both a driver and at least one passenger, there has been a lack of studies that explore potential users of carpooling and their role preferences (driver versus passenger); perceived incentives, attitudes and current mode choices may affect their willingness to carpool and their role preferences. This study examined the factors affecting individuals’ carpooling decisions and carpool role preferences using data from Ohio State University’s 2012 Campus Travel Pattern Survey. Based on individuals’ stated interests and choices, three market segments were identified: current carpool users, potential carpool users, and not-interested commuters. The analyses revealed that incentives and deterrents to carpooling significantly differ by role preference. People favoring the passenger role emphasized safety, flexibility and parking cost-savings, whereas those favoring the driver role tended to find value in the convenience and opportunities for socializing through a carpool trip. People receptive to both roles emphasized flexibility and all types of cost reductions. Although most people did not elect technological aids as a meaningful intervention, potential carpool users, particularly those favoring the passenger role, were more likely to seek these aids. Using probit and bivariate probit regressions, carpool interest and choice were found to be associated with commute distance, university affiliation, marital status, current travel mode, and personal attitude. Concern for the environment, and the propensity to make stops while commuting were positively associated with both carpooling interest and decision to carpool.
Lysophosphatidylcholine acyltransferase 3 deficiency activates the Wnt/ β -catenin pathway and thereby impairs adipogenesis in preadipocytes

Levels of polyunsaturated phosphatidylcholine (PC) influence plasma membrane structure and function. PC is synthesized de novo in the Kennedy pathway and then undergoes extensive deacylation/reacylation remodeling via Lands’ cycle (non-Kennedy pathway). The reacylation is catalyzed by lysophosphatidylcholine acyltransferase (LPCAT). Four LPCAT isoforms are known to date, among which LPCAT3 is the major isoform in adipose tissue, but its exact role in adipogenesis is unclear. Here, we investigated whether LPCAT3 activity affects the adipogenic differentiation potential of 3T3L1 cells to uncover the underlying mechanisms in adipocyte differentiation. Lentivirus-mediated LPCAT3 shRNA expression stably knocked down LPCAT3 in 3T3L1 preadipocytes and LPCAT3 deficiency dramatically reduced the levels of cellular polyunsaturated PCs. Importantly, we found that this deficiency activated the β -catenin dependent Wnt signaling pathway, which suppressed the expression of adipogenesis-related genes, thereby inhibiting 3T3L1 preadipocyte differentiation and lipid accumulation. Moreover, three different Wnt/ β -catenin pathway inhibitors reversed the effect of LPCAP3 deficiency, suggesting that Wnt/ β -catenin pathway activation is one of the causes for the observed phenotypes. To the best of our knowledge, we show here for the first time