Miracle-dz/UniFAR-FTUs huggingface dataset:
HC2091 Kills Mycobacterium tuberculosis by Targeting the MmpL3 Mycolic Acid Transporter

ABSTRACT Tuberculosis, caused by the intracellular pathogen Mycobacterium tuberculosis, is a deadly disease that requires a long course of treatment. The emergence of drug-resistant strains has driven efforts to discover new small molecules that can kill the bacterium. Here, we report characterizations of the compound HC2091, which kills M. tuberculosis in a time- and dose-dependent manner in vitro and inhibits M. tuberculosis growth in macrophages. Whole-genome sequencing of spontaneous HC2091-resistant mutants identified single-nucleotide variants in the mmpL3 mycolic acid transporter gene. HC2091-resistant mutants do not exhibit cross-resistance with the well-characterized Mycobacterium membrane protein large 3 (MmpL3) inhibitor SQ109, suggesting a distinct mechanism of interaction with MmpL3. Additionally, HC2091 does not modulate bacterial membrane potential or kill nonreplicating M. tuberculosis, thus acting differently from other known MmpL3 inhibitors. RNA sequencing (RNA-seq) transcriptional profiling and lipid profiling of M. tuberculosis treated with HC2091 or SQ109 show that the two compounds target a similar pathway. HC2091 has a chemical structure dissimilar to those of previously described MmpL3 inhibitors, supporting the notion that HC2091 is a new class of MmpL3 inhibitor.
Light-Matter Response Functions in Quantum-Electrodynamical Density-Functional Theory: Modifications of Spectra and of the Maxwell Equations

We introduce linear-response theory for non-relativistic quantum-electrodynamics in the long wavelength limit, which allows us to treat correlated excited-state phenomena of matter-photon systems from first principles. By using quantum-electrodynamical density-functional theory we can reformulate the resulting fully coupled photon-matter response equations as a pseudo-eigenvalue problem. This provides a direct extension of the conventional matter-only response theory. Our approach can be solved numerically very efficiently and existing ab-initio density-functional response implementations can be easily extended to take the full photon-matter response into account. We highlight how the coupling between light and matter changes the usual response functions and introduces new types of response functions that measure the matter-photon subsystem responses. We show how correlating light and matter changes the Maxwell equations and highlight how the spectra of real systems are changed upon strongly coupling to the photon field. A key feature of treating the combined matter-photon response is that natural lifetimes of excitations become directly accessible from first principles and no artificial broadening of spectra is required anymore. By introducing a straightforward extension of the random-phase approximation for the coupled matter-photon problem, we are able to present the first ab-initio spectra for a real molecular system that is coupled to the quantized electromagnetic field.
Is Implicit Theory of Mind a Real and Robust Phenomenon? Results From a Systematic Replication Study

Recently, theory-of-mind research has been revolutionized by findings from novel implicit tasks suggesting that at least some aspects of false-belief reasoning develop earlier in ontogeny than previously assumed and operate automatically throughout adulthood. Although these findings are the empirical basis for far-reaching theories, systematic replications are still missing. This article reports a preregistered large-scale attempt to replicate four influential anticipatory-looking implicit theory-of-mind tasks using original stimuli and procedures. Results showed that only one of the four paradigms was reliably replicated. A second set of studies revealed, further, that this one paradigm was no longer replicated once confounds were removed, which calls its validity into question. There were also no correlations between paradigms, and thus, no evidence for their convergent validity. In conclusion, findings from anticipatory-looking false-belief paradigms seem less reliable and valid than previously assumed, thus limiting the conclusions that can be drawn from them.
Implications of white matter damage in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which involves the progressive degeneration of motor neurons. ALS has long been considered a disease of the grey matter; however, pathological alterations of the white matter (WM), including axonal loss, axonal demyelination and oligodendrocyte death, have been reported in patients with ALS. The present review examined motor neuron death as the primary cause of ALS and evaluated the associated WM damage that is guided by neuronal-glial interactions. Previous studies have suggested that WM damage may occur prior to the death of motor neurons, and thus may be considered an early indicator for the diagnosis and prognosis of ALS. However, the exact molecular mechanisms underlying early-onset WM damage in ALS have yet to be elucidated. The present review explored the detailed anatomy of WM and identified several pathological mechanisms that may be implicated in WM damage in ALS. In addition, it associated the pathophysiological alterations of WM, which may contribute to motor neuron death in ALS, with similar mechanisms of WM damage that are involved in multiple sclerosis (MS). Furthermore, the early detection of WM damage in ALS, using neuroimaging techniques, may lead to earlier therapeutic intervention, using immunomodulatory treatment strategies similar to those used in relapsing-remitting MS, aimed at delaying WM damage in ALS. Early therapeutic approaches may have the potential to delay motor neuron damage and thus prolong the survival of patients with ALS. The therapeutic interventions that are currently available for ALS are only marginally effective. However, early intervention with immunomodulatory drugs may slow the progression of WM damage in the early stages of ALS, thus delaying motor neuron death and increasing the life expectancy of patients with ALS.
Superconducting nanowire single-photon detectors: physics and applications

Single-photon detectors based on superconducting nanowires (SSPDs or SNSPDs) have rapidly emerged as a highly promising photon-counting technology for infrared wavelengths. These devices offer high efficiency, low dark counts and excellent timing resolution. In this review, we consider the basic SNSPD operating principle and models of device behaviour. We give an overview of the evolution of SNSPD device design and the improvements in performance which have been achieved. We also evaluate device limitations and noise mechanisms. We survey practical refrigeration technologies and optical coupling schemes for SNSPDs. Finally we summarize promising application areas, ranging from quantum cryptography to remote sensing. Our goal is to capture a detailed snapshot of an emerging superconducting detector technology on the threshold of maturity.
Vestibular-Evoked Myogenic Potentials in Bilateral Vestibulopathy

Bilateral vestibulopathy (BVP) is a chronic condition in which patients have a reduction or absence of vestibular function in both ears. BVP is characterized by bilateral reduction of horizontal canal responses; however, there is increasing evidence that otolith function can also be affected. Cervical and ocular vestibular-evoked myogenic potentials (cVEMPs/oVEMPs) are relatively new tests of otolith function that can be used to test the saccule and utricle of both ears independently. Studies to date show that cVEMPs and oVEMPs are often small or absent in BVP but are in the normal range in a significant proportion of patients. The variability in otolith function is partly due to the heterogeneous nature of BVP but is also due to false negative and positive responses that occur because of the large range of normal VEMP amplitudes. Due to their variability, VEMPs are not part of the diagnosis of BVP; however, they are helpful complementary tests that can provide information about the extent of disease within the labyrinth. This article is a review of the use of VEMPs in BVP, summarizing the available data on VEMP abnormalities in patients and discussing the limitations of VEMPs in diagnosing bilateral loss of otolith function.
BgaA acts as an adhesin to mediate attachment of some pneumococcal strains to human epithelial cells

Streptococcus pneumoniae colonization of the respiratory tract is an essential precursor for pneumococcal disease. To colonize efficiently, bacteria must adhere to the epithelial-cell surface. S. pneumoniae possesses surface-associated exoglycosidases that are capable of sequentially deglycosylating human glycans. Two exoglycosidases, neuraminidase (NanA) and β-galactosidase (BgaA), have previously been shown to contribute to S. pneumoniae adherence to human epithelial cells, as deletion of either of these genes results in reduced adherence. It has been suggested that these enzymes may modulate adherence by cleaving sugars to reveal a receptor on host cells. Pretreatment of epithelial cells with exogenous neuraminidase restores the adherence of a nanA mutant, whereas pretreatment with β-galactosidase does not restore the adherence of a bgaA mutant. These data suggest that BgaA may not function to reveal a receptor, and implicate an alternative role for BgaA in adherence. Here we demonstrate that β-galactosidase activity is not required for BgaA-mediated adherence. Addition of recombinant BgaA (rBgaA) to adherence assays and pretreatment of epithelial cells with rBgaA both significantly reduced the level of adherence of the parental strain, but not the BgaA mutant. One possible explanation of these data is that BgaA is acting as an adhesin and that rBgaA is binding to the receptor, preventing bacterial binding. A bead-binding assay demonstrated that BgaA can bind directly to human epithelial cells, supporting the hypothesis that BgaA is an adhesin. Preliminary characterization of the epithelial-cell receptor suggests that it is a glycan in the context of a glycosphingolipid. To further establish the relevance of this adherence mechanism, we demonstrated that BgaA-mediated adherence contributed to adherence of a recent clinical isolate to primary human epithelial cells. Together, these data suggest a novel role for BgaA as an adhesin and suggest that this mechanism could contribute to adherence of at least some pneumococcal strains in vivo.
Education and Dementia in the Context of the Cognitive Reserve Hypothesis: A Systematic Review with Meta-Analyses and Qualitative Analyses

Background Cognitive reserve (CR) or brain reserve capacity explains why individuals with higher IQ, education, or occupational attainment have lower risks of developing dementia, Alzheimer’s disease (AD) or vascular dementia (VaD). The CR hypothesis postulates that CR reduces the prevalence and incidence of AD or VaD. It also hypothesizes that among those who have greater initial cognitive reserve (in contrast to those with less reserve) greater brain pathology occurs before the clinical symptoms of disease becomes manifest. Thus clinical disease onset triggers a faster decline in cognition and function, and increased mortality among those with initial greater cognitive reserve. Disease progression follows distinctly separate pathological and clinical paths. With education as a proxy we use meta-analyses and qualitative analyses to review the evidence for the CR hypothesis. Methodology/Principal Findings We searched PubMed, PsycoINFO, EMBASE, HealthStar, and Scopus databases from January 1980 to June 2011 for observational studies with clear criteria for dementia, AD or VaD and education. One hundred and thirty-three articles with a variety of study designs met the inclusion criteria. Prevalence and incidence studies with odds ratios (ORs), relative risks or original data were included in the meta-analyses. Other studies were reviewed qualitatively. The studies covered 437,477 subjects. Prevalence and incidence studies with pooled ORs of 2.61 (95%CI 2.21–3.07) and 1.88 (95%CI 1.51–2.34) respectively, showed low education increased the risk of dementia. Heterogeneity and sensitivity tests confirmed the evidence. Generally, study characteristics had no effect on conclusions. Qualitative analyses also showed the protective effects of higher education on developing dementia and with clinical disease onset hastening a decline in cognition and function, and greater brain pathology. Conclusion/Significance This systematic review and meta-analyses covering a wide range of observational studies and diverse settings provides robust support for the CR hypothesis. The CR hypothesis suggests several avenues for dementia prevention.
ICSV 14 Cairns • Australia 9-12 July , 2007 1 IDENTIFICATION OF MACHINE TOOL CHATTER FOR MILLING OPERATIONS WITH RUNOUT

Detection of undesired machine tool vibrations during milling operations is an important task for manufacturing engineers. Monitoring of frequency spectra is an efficient tool of chatter detection since these spectra usually have a clear, systematic structure. However, for some special cases, stability of the cutting process cannot be assessed based purely on the frequency spectra due to the disturbing effect of the runout of the tool. In this paper, it is shown that the stability of these cases can be assessed by the analysis of the vibration signal instead of the frequency spectra. Theoretical results are confirmed by experimental cutting tests.
Association of glutathione S-transferase T1, M1, and P1 polymorphisms in the breast cancer risk: a meta-analysis

Background Several case–control studies investigating the relationship between genetic polymorphisms of glutathione S-transferase (GST) M1, GSTT1, and GSTP1 (rs1695) and the risk of breast cancer have reported contradictory results. We therefore performed a meta-analysis to clarify this issue. Materials and methods An updated meta-analysis using PubMed and Web of Knowledge databases for the eligible case–control studies was performed. Random- or fixed-effects model was used. Results A total of 10,067 cancer cases and 12,276 controls in 41 independent case–control studies from 19 articles were included in this meta-analysis. Significant increase in risk of breast cancer for Asians was found in GSTM1-null genotype (P=0.012, odds ratio [OR] =1.17, 95% confidence interval [CI] =1.04–1.32) and GSTT1-null genotype (P=0.039, OR =1.19, 95% CI =1.01–1.41). In addition, our results showed that the GSTP1 (rs1695) polymorphisms can significantly increase the risk among Caucasians (P=0.042, OR =1.16, 95% CI =1.01–1.34). Sensitivity analysis and publication bias further confirmed the dependability of the results in this meta-analysis. Conclusion Our results demonstrate that both GSTM1- and GSTT1-null polymorphisms are associated with an increased risk of breast cancer in Asians and that GSTP1 Val105Ile (rs1695) polymorphism is associated with an increased breast cancer risk in Caucasians.
Mitochondria, glycogen, and lipid droplets in skeletal muscle during testosterone treatment and strength training: a randomized, double‐blinded, placebo‐controlled trial

Low testosterone levels in aging men are associated with insulin resistance. Mitochondrial dysfunction, changes in glycogen metabolism, and lipid accumulation are linked to insulin resistance in skeletal muscle. In this randomized, double‐blinded, placebo‐controlled study, we investigated the effects of six‐month testosterone replacement therapy (TRT) and strength training (ST) on mitochondrial, glycogen, and lipid droplet (LD) content in skeletal muscle of aging men with subnormal bioavailable testosterone (BioT) levels. Mitochondrial, glycogen, and LD volume fractions in muscle biopsies were estimated by transmission electron microscopy. Insulin sensitivity (insulin‐stimulated Rd) and body composition were assessed by euglycemic‐hyperinsulinemic clamp and dual X‐ray absorptiometry, respectively. TRT significantly increased total testosterone levels, BioT, and lean body mass (LBM) (p < 0.05), whereas percent body fat decreased (p < 0.05), and insulin sensitivity was unchanged. Baseline mitochondrial volume fraction correlated inversely with percent body fat (ρ = −0.43; p = 0.003). Δ‐mitochondrial fraction correlated positively with Δ‐total testosterone (ρ = 0.70; p = 0.02), and Δ‐glycogen fraction correlated inversely with Δ‐LBM (ρ = −0.83; p = 0.002) during six‐month TRT, but no significant changes were observed in mitochondrial, glycogen, and LD volume fractions during TRT and ST. In conclusion, in this exploratory small‐scale study, the beneficial effects of six‐month TRT on total testosterone, LBM, and percent body fat were not followed by significant changes in fractions of mitochondria, glycogen, or lipid in skeletal muscle of aging men with lowered testosterone levels. Six‐month ST or combined three‐month ST+TRT did not change intramyocellular mitochondria, glycogen, and LD fractions compared to placebo. However, further studies with a larger sample size are needed.
Advanced oxidation protein products induce pre‐osteoblast apoptosis through a nicotinamide adenine dinucleotide phosphate oxidase‐dependent, mitogen‐activated protein kinases‐mediated intrinsic apoptosis pathway

Osteoblast apoptosis contributes to age‐related bone loss. Advanced oxidation protein products (AOPPs) are recognized as the markers of oxidative stress and potent inducers of apoptosis. We have demonstrated that AOPP accumulation was correlated with age‐related bone loss. However, the effect of AOPPs on the osteoblast apoptosis still remains unknown. Exposure of osteoblastic MC3T3‐E1 cells to AOPPs caused the excessive generation of reactive oxygen species (ROS) by activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Increased ROS induced phosphorylation of mitogen‐activated protein kinases (MAPKs), which subsequently triggered intrinsic apoptosis pathway by inducing mitochondrial dysfunction, endoplasmic reticulum stress, and Ca2+ overload and eventually leads to apoptosis. Chronic AOPP loading in aged Sprague‐Dawley rats induced osteoblast apoptosis and activated NADPH oxidase signaling cascade, in combination with accelerated bone loss and deteriorated bone microstructure. Our study suggests that AOPPs induce osteoblast apoptosis by the NADPH oxidase‐dependent, MAPK‐mediated intrinsic apoptosis pathway.
Dietary inclusion of dried Artemisia annua leaves for management of coccidiosis and growth enhancement in chickens

Coccidiosis constitutes a major problem in poultry rearing. Recourse to the use of prophylactic chemotherapy, for example, is only a short-term solution. Ostensibly, the drugs used are effective but they are also expensive. In the present study, the influence of adding dried Artemisia annua L. leaves as a botanical coccidistat in coccidia-infested broilers was investigated. Concurrently, the feed consumption pattern and weight gain in broilers as well as egg production rate and size in layers, respectively, were also evaluated. In untreated broilers, trophozoites increased an average of four-fold over 84 days. Inhibition of parasite growth in birds fed with rations containing A. annua leaves was observed just like with a commercial anticoccidial therapy. In addition, there was a higher feed intake which resulted in higher weight gain in the broilers. Weekly egg production rate, size and intensity of egg yolk colour were equally improved in all the layers fed with a mixture of commercial mash and A. annua leaves. This is an implicit indication that the addition of A. annua leaves to poultry feed serves as a potentially rich source of medication and nourishment for the birds.
MiR‐21 ameliorates age‐associated skin wound healing defects in mice

The cellular and molecular mechanisms responsible for the age‐associated delay of cutaneous wound healing are still not well understood. Previous studies have shown that miR‐21 plays key roles during skin wound healing. We presumed that dysregulation of miR‐21 may be involved in age‐associated defects in wound healing and that miR‐21 may be one potential therapeutic target by which to ameliorate wound defects in elderly subjects.
Extracranial Course of the Facial Nerve Revisited

Introduction: The extrapetrous course of the facial nerve has been a matter of study and debate since XIX century. Two different classifications have been classically proposed and widely accepted by most of the authors. Nevertheless, there are reported cases which do not fit in any of those. The aim of this study is to propose a new and useful classification. Material and methods: We have used 23 embalmed Caucasian adult cadavers (11 male and 12 female) belonging to the Bodies Donation and Dissecting Rooms Centre of the University Complutense of Madrid. The extra‐petrous facial nerve was dissected in the possible specimens resulting in 38 facial nerves. The studied parameters were length, diameter of divisions, terminal branches, and nerve connections. Results: In every specimen two main divisions were found, temporofacial and cervicofacial. They divided into five terminal branches from cranial to caudal: temporal, zygomatic, buccal, marginal or mandibular, and cervical. Based on the comparison with previous proposed classifications, we have unified the patterns in 12 types being the most frequent types the type 3 (eight cases, 21.05%), with connections between temporal, zygomatic and buccal branches and the type 8 (eight cases, 21.05%), a complex network between temporal, zygomatic, buccal, and mandibular branches. The number of terminal branches was so variable. Conclusion: We propose a new 12‐patterned classification which summarizes the previous ones. However, we consider that a good study of the number of terminal branches, connections between branches or with other cranial nerves are more useful for surgeons to avoid injuries to the facial nerve during surgery than complex classifications. Anat Rec, 302:599–608, 2019. © 2018 Wiley Periodicals, Inc.
Proton pump inhibitor use and cancer mortality

Proton pump inhibitors (PPIs) are commonly used as a supplement to cancer therapy. Yet, their effect on cancer mortality is largely unknown. Using data from Danish nationwide registries and Cox models regressing of both propensity scores and drug use, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer‐specific and noncancer death among PPI users (≥2 prescriptions within six months after diagnosis; n = 36,066) compared with nonusers (<2 prescriptions, n = 311,853) or users of histamine H2‐receptor antagonists (H2RA; n = 5,152). Adjusted HRs for cancer‐specific mortality among postdiagnostic PPI users as compared with nonusers or H2RA users were 1.29 (95% CI, 1.27–1.32) and 1.15 (95% CI, 1.10–1.20), respectively. HRs for cancer mortality associated with PPI use were highest for ovarian (1.35; 95% CI, 1.20–1.52) and lowest for esophageal cancer (0.91; 95% CI, 0.81–1.04). The associations were stronger among new PPI users after cancer diagnosis, indicating potential confounding. To test the effect of PPIs on tumor growth in a model system free for confounding factors, we investigated the effect of pantoprazole on tumor growth in mice. Pantoprazole (5 mg/kg/day) enhanced tumor growth (p = 0.033) and reduced the antitumor activity of gemcitabine (p = 0.008) in fibrosarcoma‐bearing Balb/c mice, but not in immunodeficient Balb/c nude mice. In breast carcinoma‐bearing FVB/N mice, pantoprazole had no effect on tumor growth alone but it reduced the life‐prolonging effect of doxorubicin significantly (p = 0.007). Taken together, these data raise concerns about the increasing use of PPIs and calls for further studies addressing their safety among cancer patients.