Miracle-dz/UniFAR-FTUs huggingface dataset:
Crystal Structures of Bifunctional Penicillin-Binding Protein 4 from Listeria monocytogenes

ABSTRACT Penicillin-binding proteins (PBPs), which catalyze the biosynthesis of the peptidoglycan chain of the bacterial cell wall, are the major molecular target of bacterial antibiotics. Here, we present the crystal structures of the bifunctional peptidoglycan glycosyltransferase (GT)/transpeptidase (TP) PBP4 from Listeria monocytogenes in the apo-form and covalently linked to two β-lactam antibiotics, ampicillin and carbenicillin. The orientation of the TP domain with respect to the GT domain is distinct from that observed in the previously reported structures of bifunctional PBPs, suggesting interdomain flexibility. In this structure, the active site of the GT domain is occluded by the close apposition of the linker domain, which supports the hypothesis that interdomain flexibility is related to the regulation of GT activity. The acylated structures reveal the mode of action of β-lactam antibiotics toward the class A PBP4 from the human pathogen L. monocytogenes. Ampicillin and carbenicillin can access the active site and be acylated without requiring a structural rearrangement. In addition, the active site of the TP domain in the apo-form is occupied by the tartrate molecule via extensive hydrogen bond interactions with the catalytically important residues; thus, derivatives of the tartrate molecule may be useful in the search for new antibiotics to inhibit PBPs.
Bimonthly assessment of magnetization transfer magnetic resonance imaging parameters in multiple sclerosis: a 14-month, multicentre, follow-up study

This study was performed to assess the temporal evolution of damage within lesions and the normal-appearing white matter, measured using frequent magnetization transfer (MT) MRI, in relapsing—remitting multiple sclerosis (RRMS). The relationship of MT ratio (MTR) changes with measures of lesion burden, and the sample sizes needed to demonstrate a treatment effect on MTR metrics in placebo-controlled MS trials were also investigated. Bimonthly brain conventional and MT MRI scans were acquired from 42 patients with RRMS enrolled in the placebo arm of a 14-month, double-blind trial. Longitudinal MRI changes were evaluated using a random effect linear model accounting for repeated measures, and adjusted for centre effects. The Expanded Disability Status Scale (EDSS) score remained stable over the study period. A weak, but not statistically significant, decrease over time was detected for normal-appearing brain tissue (NABT) average MTR (—0.02% per visit; p = 0.14), and MTR peak height (—0.15 per visit; p = 0.17), while average lesion MTR showed a significant decrease over the study period (—0.07% per visit; p = 0.03). At each visit, all MTR variables were significantly correlated with T2 lesion volume (LV) (average coefficients of correlation ranging from —0.54 to —0.28, and p-values from <0.001 to 0.02). At each visit, NABT average MTR was also significantly correlated with T1-hypointense LV (average coefficient of correlation = —0.57, p < 0.001). The estimation of the sample sizes required to demonstrate a reduction of average lesion MTR (the only parameter with a significant decrease over the follow-up) ranged from 101 to 154 patients to detect a treatment effect of 50% in a 1-year trial with a power of 90%. The steady correlation observed between conventional and MT MRI measures over time supports the hypothesis of axonal degeneration of fibres passing through focal lesions as one of the factors contributing to the overall MS burden.
Acoustic Reflex in Hearing Loss Identification and Prediction

*Department of Speech, Brooklyn College, City University of New York, Brooklyn, New York † Department of Communication Arts and Sciences, Queens College, City University of New York, Flushing, New York, and Audiology and Speech Pathology Service, Veterans Administration Medical Center, East Orange, New Jersey Audiologists are often faced with the need to evaluate patients who are for one reason or another unable or unwilling to provide behavioral responses. As a result, there has been a longstanding desire to have an objective means by which hearing can be assessed based on physiological rather than behavioral responses. An ideal approach would be independent of the patient's nonauditory integrity and status at the time of the test. It would then be possible to evaluate hearing regardless of patient age, physical or mental ability to participate in the testing process, willingness to cooperate, and state of arousal, that is, whether he is awake, alert, asleep, comatose, or sedated. Virtually every physiological method ever used in audiology has been considered as a candidate for such an objective, physiological hearing test. Because the requirements for an ideal hearing test are so extensive, it is not surprising that each of these approaches has fallen short of the desired goal. The reasons for the failure of one method or the other to become accepted as the preferred objective technique include one or more of the following: questionable validity or reliability, insufficient flexibility to handle the variety of problems causing patients to be difficult to test, theoretical limitations, and minimal cost-effectiveness in terms of the time and expense compared with clinical yield. Most approaches have fallen out of use or have not been put into general use for these reasons. It seems clear that an approach capable of evaluating all aspects of auditory function in all difficult-to-test or untestable patients is not a feasible goal. We must thus look to approaches that are more limited in intent, but that have acceptable clinical utility and are also both commonly available and costeffective. The use of acoustic reflex-based approaches to hearing loss assessment provide a feasible way of addressing the longstanding problem. In this article we shall critically examine various approaches for hearing loss prediction or identification based on the acoustic-reflex threshold (ART). We will also attempt to identify those that have current or future promise as valid and reliable clinical tools.
Mechanism of Macrolide-Induced Inhibition of Pneumolysin Release Involves Impairment of Autolysin Release in Macrolide-Resistant Streptococcus pneumoniae

Streptococcus pneumoniae is a leading cause of community-acquired pneumonia. Over the past 2 decades, macrolide resistance among S. pneumoniae organisms has been increasing steadily and has escalated at an alarming rate worldwide. ABSTRACT Streptococcus pneumoniae is a leading cause of community-acquired pneumonia. Over the past 2 decades, macrolide resistance among S. pneumoniae organisms has been increasing steadily and has escalated at an alarming rate worldwide. However, the use of macrolides in the treatment of community-acquired pneumonia has been reported to be effective regardless of the antibiotic susceptibility of the causative pneumococci. Although previous studies suggested that sub-MICs of macrolides inhibit the production of the pneumococcal pore-forming toxin pneumolysin by macrolide-resistant S. pneumoniae (MRSP), the underlying mechanisms of the inhibitory effect have not been fully elucidated. Here, we show that the release of pneumococcal autolysin, which promotes cell lysis and the release of pneumolysin, was inhibited by treatment with azithromycin and erythromycin, whereas replenishing with recombinant autolysin restored the release of pneumolysin from MRSP. Additionally, macrolides significantly downregulated ply transcription followed by a slight decrease of the intracellular pneumolysin level. These findings suggest the mechanisms involved in the inhibition of pneumolysin in MRSP, which may provide an additional explanation for the benefits of macrolides on the outcome of treatment for pneumococcal diseases.
The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial

Background: Low-dose naltrexone (LDN) may promote psychological well-being as well as generalized health especially in autoimmune disorders. The objective of this study is to assess the effect of LDN on the Quality of Life (QoL) of patients with relapsing—remitting and secondary progressive multiple sclerosis (MS) using the scales and composite scores of the MSQoL-54 questionnaire. Methods: A 17-week randomized, double-blind, placebo-controlled, parallel-group, crossover-design clinical trial was conducted in two universities. A total of 96 adult patients aged between 15 and 65 years with relapsing—remitting (RR) or secondary progressive (SP) clinically definite MS with disease duration longer than 6 months enrolled into the study. The primary outcome of the study was comparison of the scores of physical and mental health by conducting independent t-test of the results obtained in the middle and at the end of study between the two groups. Results: Variables including presence of pain, energy, emotional well-being, social, cognitive, and sexual functions, role limitation due to physical and emotional problems, health distress, and overall QoL did not show any meaningful statistically difference between the two groups. Factor analysis revealed that health perception scores were statistically different between the groups before starting, in the middle, and at the end of the study. Conclusion: The study clearly illustrates that LDN is a relatively safe therapeutic option in RRMS and SPMS but its efficacy is under question and probably a long duration trial is needed in the future.
Stress and the Major Cardiovascular Disorders

The increasing stress of life in the 20th century is well known to all of us, yet its relationship to cardiovascular disease is at best obscure. Dr Eliot begins with a survey of the causes of stress in the modern age and the physiologic changes it can induce. He proposes a 20th-century "invisible entrapment" syndrome, in which humans are unable to physically act out their fight (increased sympathetic tone) or flight (increased adrenocorticotropic hormone) responses to daily events. This situation often leads to chronic psychological tension and stress. The book thoroughly reviews the inconclusive literature of the pathophysiologic mechanisms of acute myocardial infarction and sudden coronary death. It supports stressinduced, functional etiologies for both events with intriguing electron micrographs. The book also supports the Page theory of essential hypertension, in which sporadic, stress-induced elevations of blood pressure eventually cause permanent renovascular changes, resulting in a fixed hypertension that may require
Mutations in the Bacterial Ribosomal Protein L3 and Their Association with Antibiotic Resistance

ABSTRACT Different groups of antibiotics bind to the peptidyl transferase center (PTC) in the large subunit of the bacterial ribosome. Resistance to these groups of antibiotics has often been linked with mutations or methylations of the 23S rRNA. In recent years, there has been a rise in the number of studies where mutations have been found in the ribosomal protein L3 in bacterial strains resistant to PTC-targeting antibiotics but there is often no evidence that these mutations actually confer antibiotic resistance. In this study, a plasmid exchange system was used to replace plasmid-carried wild-type genes with mutated L3 genes in a chromosomal L3 deletion strain. In this way, the essential L3 gene is available for the bacteria while allowing replacement of the wild type with mutated L3 genes. This enables investigation of the effect of single mutations in Escherichia coli without a wild-type L3 background. Ten plasmid-carried mutated L3 genes were constructed, and their effect on growth and antibiotic susceptibility was investigated. Additionally, computational modeling of the impact of L3 mutations in E. coli was used to assess changes in 50S structure and antibiotic binding. All mutations are placed in the loops of L3 near the PTC. Growth data show that 9 of the 10 mutations were well accepted in E. coli, although some of them came with a fitness cost. Only one of the mutants exhibited reduced susceptibility to linezolid, while five exhibited reduced susceptibility to tiamulin.
Resistance Selection Studies Comparing the Activity of Razupenem (PTZ601) to Vancomycin and Linezolid against Eight Methicillin-Resistant and Two Methicillin-Susceptible Staphylococcus aureus Strains

ABSTRACT Multistep and single-step resistance selection studies were performed with razupenem, linezolid, and vancomycin against 10 methicillin (meticillin)-resistant and -susceptible Staphylococcus aureus strains. After 20 daily subcultures, razupenem yielded only clones with MICs of >4 μg/ml in one strain (8 μg/ml) whose parent's MIC was already 4 μg/ml. After 18 to 49 passages in 6/10 strains, razupenem MICs rose from 0.016 to 2 μg/ml (parents) to 0.125 to 8 μg/ml (with clones stable after 10 drug-free subcultures). Single-step mutant selection frequencies were similarly low for razupenem and comparators.
Online Stator and Rotor Resistance Estimation Scheme Using Artificial Neural Networks for Vector Controlled Speed Sensorless Induction Motor Drive

This paper presents a new method of online estimation for the stator and rotor resistances of the induction motor for speed sensorless indirect vector controlled drives, using artificial neural networks. The error between the rotor flux linkages based on a neural network model and a voltage model is back propagated to adjust the weights of the neural network model for the rotor resistance estimation. For the stator resistance estimation, the error between the measured stator current and the estimated stator current using neural network is back propagated to adjust the weights of the neural network. The rotor speed is synthesized from the induction motor state equations. The performance of the stator and rotor resistance estimators and torque and flux responses of the drive, together with these estimators, are investigated with the help of simulations for variations in the stator and rotor resistances from their nominal values. Both resistances are estimated experimentally, using the proposed neural network in a vector controlled induction motor drive. Data on tracking performances of these estimators are presented. With this speed sensorless approach, the rotor resistance estimation was made insensitive to the stator resistance variations both in simulation and experiment. The accuracy of the estimated speed achieved experimentally, without the speed sensor clearly demonstrates the reliable and high-performance operation of the drive
Preferential increase of B-cell activating factor in the cerebrospinal fluid of neuromyelitis optica in a white population

Background: Anti-aquaporin-4 antibodies are believed to have a central pathogenetic role in neuromyelitis optica (NMO). B-cell activating factor (BAFF) is one of the crucial factors that determines the fate and survival of B cells and may play a role in induction of antibody-mediated autoimmunity. Objectives: To evaluate the blood and cerebrospinal fluid (CSF) levels of BAFF in NMO and multiple sclerosis (MS) patients. Methods: Peripheral blood samples were collected from 21 definite NMO patients, 22 healthy controls and 45 MS patients and CSF from 8 NMO and 11 MS patients. BAFF levels were measured using an ELISA technique. Results: We found significantly higher levels of BAFF in the CSF of NMO patients compared with that in MS (215.6 ± 41 pg/ml in NMO and 77.4 ± 11 pg/ml in MS, p < 0.001). There were no differences in serum BAFF levels between NMO, MS and healthy donors. MS patients treated with interferon-beta (IFNβ) or glatiramer acetate (GA) had significantly higher serum BAFF levels, as compared with untreated patients (1227 ± 203 pg/ml in untreated MS, 2253 ± 83.4 pg/ml in GA-treated, p < 0.01, and 2106 ± 277.9 pg/ml in interferon-treated, p < 0.05) Conclusion: The presence of increased BAFF, a soluble factor associated with B-cell activation in the proximity of the disease target organ (CSF) in NMO, and its increase in association with immunomodulating treatments, may help our understanding of the immunopathogenetic mechanisms involved in this disease and contribute to more successful and targeted therapeutic intervention.
High-dose frequency beta-interferons increase the risk of liver test abnormalities in multiple sclerosis: a longitudinal study

Background: Post-marketing studies and case reports have linked beta-interferon (IFNβ) treatment with liver enzyme abnormalities and liver injuries in patients with multiple sclerosis (MS). Few predictors of risk exist. Objective: We investigated the effect of IFNβ and other patient characteristics on levels of the liver enzyme, alanine aminotransferase (ALT). Method: Repeated ALT test results were reviewed retrospectively for 1064 MS patients prescribed an IFNβ as their first immunomodulatory drug. Liver enzyme abnormality was defined as an ALT elevation twice the upper limit of normal (≥2 ULN). The Generalized Estimating Equation (GEE) was used to analyze the effect of age (≤35, >35–40, >40–45, >45 years), gender, disease duration, IFNβ product, and duration of treatment (≤5, >5–15, >15–40, >40 months) on de novo liver enzyme abnormality. Results: Over a mean treatment period of 38.7 months (SD = 34.9), 12.4% (95/766) of MS patients developed de novo liver enzyme abnormality. Multivariable GEE results showed a dose frequency response effect of IFNβs on liver enzyme abnormality: OR = 3.8(95% CI: 1.6–9.2) for IFNβ-1a 44 µg SC, and OR = 3.4 (95% CI: 1.5–7.9) for IFNβ-1b 250 µg SC compared with the lower frequency IFNβ-1a 30 µg IM. Younger age (≤40 years), male gender, and ≤15 months of IFNβ exposure were also independent predictors. Conclusion: A dose frequency response effect was observed, with high-frequency IFNβs having the greatest risk. The first 15 months of treatment, men, and younger patients were also associated with elevated risk. Regular ALT monitoring in MS patients appears prudent; long-term consequences of ALT elevations should be further investigated.
Why do females care more than males?

Females tend to provide more parental care than males. Previous efforts to account for this have been confused because it is difficult to express the costs of care for males and females in the same currency. Here I propose a null model that does so, using the Fisherian constraint that total male and female reproduction must be equal. The model shows that, contrary to a number of recent analyses, lower probability of parentage for males does tend to make males less likely than females to provide care. It also shows how sexual selection stemming from premating asymmetries in investment promotes similar post–mating asymmetries.
Prevalence of anaemia in pregnancy at Greytown, South Africa

Context : Anaemia in pregnancy is a leading cause of maternal and perinatal morbidity and mortality mainly in developing countries. It is a preventable medical condition through public health interventions which are potentially feasible and cost-effective. In order to strengthen planning and management, the prevalence of anaemia in pregnancy at a district hospital was ascertained. Objectives : To describe antenatal booking visits, haemoglobin levels and to estimate the prevalence of Anaemia in pregnancy based on the criteria set by South Africa (National) and World Health organization and to identify the risk factors. Study-Design, Setting and Subjects : A retrospective cross-sectional descriptive study was conducted using antenatal clinic register of a rural district (Greytown) Hospital of KwaZulu-Natal Province during January to December 2003. A total of 711 pregnant women from 1486 booking visits were recruited. Main Outcome Measures : Percentage of attendees had low haemoglobin, effects on haemoglobin concentration of age and gestational age (trimester). Results : Based on the South African (Haemoglobin Conclusion : The prevalence of Anaemia in pregnancy is high and evidence of late booking for antenatal care in Greytown comparable with other findings in Africa. There is an urgent need for Health Education and promotion of this population for early bookings for antenatal care and management of anemia. Tropical Journal of Obstetrics and Gynaecology Vol. 23(1) 2006: 3-7
Relative Fecal Abundance of Extended-Spectrum-β-Lactamase-Producing Escherichia coli Strains and Their Occurrence in Urinary Tract Infections in Women

ABSTRACT Extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli (ESBL E. coli) strains are of major concern because few antibiotics remain active against these bacteria. We investigated the association between the fecal relative abundance (RA) of ESBL-producing E. coli (ESBL-RA) and the occurrence of ESBL E. coli urinary tract infections (UTIs). The first stool samples passed after suspicion of UTI from 310 women with subsequently confirmed E. coli UTIs were sampled and tested for ESBL-RA by culture on selective agar. Predictive values of ESBL-RA for ESBL E. coli UTI were analyzed for women who were not exposed to antibiotics when the stool was passed. ESBL E. coli isolates were characterized for ESBL type, phylogroup, relatedness, and virulence factors. The prevalence of ESBL E. coli fecal carriage was 20.3%, with ESBL E. coli UTIs being present in 12.3% of the women. The mean ESBL-RA (95% confidence interval [CI]) was 13-fold higher in women exposed to antibiotics at the time of sampling than in those not exposed (14.3% [range, 5.6% to 36.9%] versus 1.1% [range, 0.32% to 3.6%], respectively; P < 0.001) and 18-fold higher in women with ESBL E. coli UTI than in those with another E. coli UTI (10.0% [range, 0.54% to 100%] versus 0.56% [range, 0.15% to 2.1%[, respectively; P < 0.05). An ESBL-RA of <0.1% was 100% predictive of a non-ESBL E. coli UTI. ESBL type, phylogroup, relatedness, and virulence factors were not found to be associated with ESBL-RA. In conclusion, ESBL-RA was linked to the occurrence of ESBL E. coli UTI in women who were not exposed to antibiotics and who had the same clone of E. coli in urine samples and fecal samples. Especially, a low ESBL-RA appeared to be associated with a low risk of ESBL E. coli infection.
A functional p.82G>S polymorphism in the RAGE gene is associated with multiple sclerosis in the Chinese population

Background: The receptor for advanced glycation end products (RAGE) and its proinflammatory ligand, S100-calgranulins, are critically implicated in the pathological progression of multiple sclerosis (MS). A functional polymorphism within the V-type immunoglobulin domain of RAGE gene, p.82G>S (c.557G>A), has been shown to affect ligand binding affinity and thus may affect susceptibility to MS. Methods: The RAGE p.82G>S polymorphism was genotyped in 144 MS patients and 156 healthy controls using polymerase chain reaction – restriction fragment length polymorphism. A replication study was performed on a second cohort comprising 138 patients and 150 controls. The relationship between the RAGE p.82G>S polymorphism and circulating levels of soluble RAGE (sRAGE), a secreted decoy receptor against RAGE signaling, was also investigated. Results: In both initial and replication cohorts, an increased MS risk was detected in RAGE p.82G>S variant allele carriers (odds ratio [OR] = 1.786, p = 0.0134 and OR = 1.732, p = 0.0210, respectively). This association signal persisted in subgroups of women and patients with relapsing–remitting MS. Moreover, compared with the wild-type 82GG carriers, carriers of the variant allele presented a faster progression of disability and a reduced serum sRAGE level. Conclusions: The present study provides preliminary evidence that the gain-of-function p.82G>S polymorphism in the RAGE gene is associated with an increased risk of MS in the Chinese population.