Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel Antibacterial Targets and Compounds Revealed by a High-Throughput Cell Wall Reporter Assay

ABSTRACT A high-throughput phenotypic screen based on a Citrobacter freundii AmpC reporter expressed in Escherichia coli was executed to discover novel inhibitors of bacterial cell wall synthesis, an attractive, well-validated target for antibiotic intervention. Here we describe the discovery and characterization of sulfonyl piperazine and pyrazole compounds, each with novel mechanisms of action. E. coli mutants resistant to these compounds display no cross-resistance to antibiotics of other classes. Resistance to the sulfonyl piperazine maps to LpxH, which catalyzes the fourth step in the synthesis of lipid A, the outer membrane anchor of lipopolysaccharide (LPS). To our knowledge, this compound is the first reported inhibitor of LpxH. Resistance to the pyrazole compound mapped to mutations in either LolC or LolE, components of the essential LolCDE transporter complex, which is required for trafficking of lipoproteins to the outer membrane. Biochemical experiments with E. coli spheroplasts showed that the pyrazole compound is capable of inhibiting the release of lipoproteins from the inner membrane. Both of these compounds have significant promise as chemical probes to further interrogate the potential of these novel cell wall components for antimicrobial therapy. IMPORTANCE The prevalence of antibacterial resistance, particularly among Gram-negative organisms, signals a need for novel antibacterial agents. A phenotypic screen using AmpC as a sensor for compounds that inhibit processes involved in Gram-negative envelope biogenesis led to the identification of two novel inhibitors with unique mechanisms of action targeting Escherichia coli outer membrane biogenesis. One compound inhibits the transport system for lipoprotein transport to the outer membrane, while the other compound inhibits synthesis of lipopolysaccharide. These results indicate that it is still possible to uncover new compounds with intrinsic antibacterial activity that inhibit novel targets related to the cell envelope, suggesting that the Gram-negative cell envelope still has untapped potential for therapeutic intervention.
Cytogenetics of Prostatic Adenocarcinoma and Precursor Lesions : Analysis of 25 Radical Prostatectomies and I 7 Adjacent

Twenty-five radical prostatectomy specimens were screened for the presence of numerical chromosome changes within the adenocarcinoma ;ti well as in I7 adjacent prostatic intraepithelial neoplasias (PIN) by means of interphase in situ hybridization (ISH) to routinely processed tissue sections. To this end a defined alfoid repetitive DNA probe set was used, specific for the centromeres of chromosomes I, 7, 8, 10, 15, and Y. The cytogenetic information was correlated with histopathological and clinical features s; well as with DNA ploidy. Numerical aberrations of at least one chromosome were shown in I3 of 25 cases (52%). Alterations of chromosome 8 and loss of the Y chromosome were the most frequent findings (both 20%), followed by loss of chromosomes I 5 ( I 6%) and I0 ( 12%). Gain of chromosome 7 was seen in 8% of cases. No aberrations of chromosomes 7,8, 10, and I5 were found in the adjacent PIN lesions, whereas loss of the Y chromosome in both PIN and tumor occurred in two cases. Also, (low level) aneuploidy was observed in 76% of these PIN lesions. Ploidy of the carcinomas as assessed by ISH correlated well with ploidy measured by DNA flow cytometry (FCM; P < 0.02). Due to the more specific correspondence between ISH and tumor pathology, pathologic grade correlated with ISH aneuploidy (P < 0.05), whereas FCM ploidy did not. Furthermore, genetic heterogeneity within a tumor was seen, as judged by the focal appearance of chromosomal aberrations. Chromosomal alterations occurred in all grades and stages, although loss of chromosome 10, gain of chromosome 7, and aberrations of chromosome 8 tended t o predominate in more advanced cancers. Genes Chromosom Cancer /2:24 1-250 (I 995).
Maximum Energy Deposition During Resistive Stage and Overvoltage at Current Driven Nanosecond Wire Explosion

A wire explosion in a gaseous and condensed media extends possibilities of studying of phase transition of the wire material. The copper and tungsten wires of the diameter of d=25 mum were exploded in vacuum, air, and water by current pulse with the rate increase of ~ 50 A/ns. Energy deposited into the wires at different stages of explosion in the media and maximum voltage reached during wire explosion was estimated from the experiments. Laser probing measurements were performed with the second harmonic of a YAG:Nd+3 laser (lambda=0.53 mum; Deltat=10 ns). Shadow images of the expanding wire materials and shock waves leading the explosion were obtained at different times during the discharge
Molecular identification of chromosome Y sequences in Brazilian patients with Turner syndrome

The investigation of Y-specific sequences in patients with Turner Syndrome (TS) with karyotype 45,X or mosaic, has a fundamental role in the clinical management of these patients. The relationship between the presence of Y chromosome fragments and a higher risk of gonadoblastoma in TS has already been established. The aim of the study was to investigate the presence of Y-chromosome fragments in a population of 42 female Brazilian patients with TS from Mato Grosso state. Cytogenetic analysis has shown the karyotypes 45,X in 27 of them (64.3%) and mosaic in 15 (35.7%). The presence of the Y-primers SRY, DYZ3, ZFY, DYZ1, DYS1 and PABY was investigated in all patients. These markers were amplified by polymerase chain reaction (PCR) technique, using DNA genomic from peripheral blood lymphocytes. None of these patients had shown any Y-chromosome fragments when they were analysed only by the classic cytogenetic technique. The PCR analysis with the Y-specific sequences ZFY and DYZ3 were identified in two different patients (4.8%), both with karyotype 45,X. It was concluded that PCR is efficient in the investigation of hidden Y-fragments in TS patients. Therefore, this method should be included in the routine assistance of these patients.
Genetic variation in the COL6A1 region is associated with congenital heart defects in trisomy 21 (Down's syndrome)

Genetic variation in the COL6A1‐COL6A2 gene cluster on chromosome 21 was studied in 113 controls and 58 European families (including control and family subgroups of British/Irish origin) having a child with trisomy 21. There were statistically significant differences among subgroups of trisomic children with and without congenital heart defects (CHD) in distributions of definitive, 3‐RFLP haplotype classes received from their nondisjoining and disjoining parents. Haplotypes received by trisomic children with CHD from their disjoining parents were not a random sample of controls' haplotypes. Analysis of parental single‐RFLP genotypes and linkage disequilibrium patterns confirmed this parent subgroup differed from a random sample of controls. There were no significant differences in parent subgroup genotype distribution at any of nine control loci distributed along chromosome 21q. This sample showed an association between genetic variation in the COL6A1 gene region and congenital heart defects in trisomy 21.
Different mutational function of low‐ and high‐linear energy transfer heavy‐ion irradiation demonstrated by whole‐genome resequencing of Arabidopsis mutants

Heavy-ion irradiation is a powerful mutagen that possesses high linear energy transfer (LET). Several studies have indicated that the value of LET affects DNA lesion formation in several ways, including the efficiency and the density of double-stranded break induction along the particle path. We assumed that the mutation type can be altered by selecting an appropriate LET value. Here, we quantitatively demonstrate differences in the mutation type induced by irradiation with two representative ions, Ar ions (LET: 290 keV μm-1 ) and C ions (LET: 30.0 keV μm-1 ), by whole-genome resequencing of the Arabidopsis mutants produced by these irradiations. Ar ions caused chromosomal rearrangements or large deletions (≥100 bp) more frequently than C ions, with 10.2 and 2.3 per mutant genome under Ar- and C-ion irradiation, respectively. Conversely, C ions induced more single-base substitutions and small indels (<100 bp) than Ar ions, with 28.1 and 56.9 per mutant genome under Ar- and C-ion irradiation, respectively. Moreover, the rearrangements induced by Ar-ion irradiation were more complex than those induced by C-ion irradiation, and tended to accompany single base substitutions or small indels located close by. In conjunction with the detection of causative genes through high-throughput sequencing, selective irradiation by beams with different effects will be a powerful tool for forward genetics as well as studies on chromosomal rearrangements.
Fat consumption and schizophrenia

This report describes the statistical association between the average ratings of course and outcome of schizophrenia in 8 national centres participating in the World Health Organization international 2‐year follow‐up study (1) and the amount of fat in the average national diets as published by the Food and Agriculture Organization of the United Nations (2). Highly significant correlations were found between favourable ratings of course and outcome of schizophrenia and a low percentage of total fat (r= 0.80–0.90; P<0.05) and of fat from land animals and birds (composed mainly of saturated fat) (r= 0.91–0.95; P<0.01). High percentage of fat from vegetables, fish and seafood (having a relatively high content of unsaturated fatty acids) tended to be associated with a favourable course and outcome (r= 0.23–0.50; P>0.10). A multivariate analysis revealed that 97% (P= 0.0002) of the variation in the overall outcome of schizophrenia between the national centres could be explained by the combined variation in the percentages of fat from land animals and birds and from vegetables, fish and seafood, respectively, in the national diets. These results suggest that the course and outcome of schizophrenia may be influenced through diet. They should encourage investigators to perform controlled clinical trials of low‐fat diets with a sufficient amount of essential fatty acids.
Radicicol‐mediated inhibition of Bcr‐Ab1 in K562 cells induced p38‐MAPK dependent erythroid differentiation and PU.1 down‐regulation

Constitutive tyrosine kinase activity of the breakpoint cluster region (Bcr)‐Abl fusion protein is characteristic of chronic myelogenous leukemia (CML). As resistance against Imatinib a Bcr‐abl inhibitor used in CML, was described, Heat shock protein (Hsp90) became an alternative target as inhibition of Bcr‐Abl‐Hsp90 complex leads to proliferation arrest. Here, we used natural product Radicicol (Rad), a macrocyclic antifungal, as an Hsp90 inhibitor to investigate the effect of Bcr‐Ab1 inactivation on erythroid gene expression and subsequently on the transcription factors involved in their regulation. We showed that all erythroid genes studied were over‐expressed after Rad treatment while Bcr‐Abl expression was inhibited. Specific transcription factor NF‐E2 was induced in Rad‐treated cells as well as GATA‐1 cofactors Friend of GATA (FOG)1 and SP1, whereas PU.1 was downregulated. Moreover, p38 mitogen activated protein kinase (MAPK) inhibition prevented Rad‐mediated differentiation of K562 in correlation with decreased γ‐globin expression and suppression of Rad‐mediated inhibition of PU.1. In conclusion, our results show that Radicicol leads to Bcr‐Abl inactivation via Hsp90 inhibition inducing reactivation of the erythroid program in K562 cells.
Plague and the poor in Renaissance Florence

dealing in the busy and practical world with such a wide range of opinions; and second, the closing of the gulf of misunderstanding between the reforming organizations and orthodox medicine. Neither of these is insuperable; but the third, the increasing spectre of malpractice, may be. At all events, it is clear that histories of childbirth such as this one are not only motivated by, but essential ammunition for the reformers in both ofthe last two groups-although I would not be surprised if the most radical feminists find this book too balanced, too kind to the medical profession, in short, too scholarly for their liking. None of the above criticisms detracts from the fact that this study is a major and most valuable additition to our understanding of the complex factors which have affected decision-making in obstetric care over the past two hundred years. Her purpose is to explain the plague legislation that Florence, like other Italian cities, promulgated in the second half of the fifteenth century. That legislation, she argues, should not simply be seen as part of a gradual evolution in plague control beginning in 1348. Nor can it be related to developments in "professional" medical thinking. Rather, it was a direct and justifiable response to the changed character of fifteenth-century epidemics, particularly the "minor plagues". These seemed to be concentrated in the poorer areas of the city. They encouraged the notion that plague was spread by contagion, not miasma. They also confirmed the association of disease with poverty and disorder. Hence isolation hospitals, quarantine and health boards: plague control was social control. Stated so baldly, the theory is hardly novel. What is new is the subtle epidemiology adduced in its support. Dr Carmichael analyses the causes of death listed during epidemics by the Florentine Grain Office and the Physicians' Guild in their Books of the Dead. She extracts more detail from these than did Herlihy and Klapisch-Zuber when studying the 1427 catasto (1978), and she marries the results to an array of modern medical research. Full weight is thus given to the range ofinfectious diseases that accompanied plague, with some of which it might easily have been confused. The suspicion remains, however, that much of this work is of more use to the general historian of disease than to the student of plague control. Even with the help of comparative Mantuan evidence, it is not clear how often …
Parents' Health Beliefs Influence Breastfeeding Patterns among Iranian Women.

OBJECTIVES To determine factors related to breastfeeding and its perceived health benefits among Iranian mothers. METHODS A cross-sectional study was performed using 240 postpartum women who were selected randomly from eight public health care centers in Hamadan, Iran, in 2012. Mothers who breastfed (BF) and mothers who never breastfed (NBF) were given a structured questionnaire to collect their demographic data and information regarding their health beliefs and attitude towards child-rearing. Descriptive and logistic regression were used for data analysis. RESULTS The mean length of breastfeeding was 11.6 (standard deviation=12.5) weeks. There was no difference in demographic variables, such as age, type of medical insurance, number of living children, employment, education, and household income (p>0.050), between mothers that breastfed and those that did not. Mothers' perception of the severity of child illness was higher in those who breastfed than those who never breastfed (p=0.050). In contrast, BF mothers had higher perceived confidence of medical care to prevent diseases (p<0.050) and a higher perception of reverse parent-child roles than NBF mothers (p<0.050). CONCLUSION Mothers' health beliefs and attitude to parenting has a significant role in choosing to breastfeed. Physicians and healthcare providers may provide supportive information that influence a mother's breastfeeding behavior.
Degradation of III–V inversion-type enhancement-mode MOSFETs

We performed gate ramp voltage stress on III-V InGaAs based MOSFETs. Stress induces trapped charge and it also leads to interface trap generation, which has detrimental effects on the subthreshold slope and on the transconductance. At high electric fields, before the hard breakdown, a very low-frequency high-current random telegraph noise appears at the gate, which seems to be not correlated with the soft breakdowns commonly observed in other devices.
Effect of an artificial Ascaridia galli infection on egg production, immune response, and liver lipid reserve of free‐range laying hens

Abstract This study was conducted to determine the effect of Ascaridia galli infection on free‐range laying hens. Lohmann Brown laying hens (n = 200) at 17 wk of age were allocated to 4 treatment groups (n = 50 per group), each with 5 replicate pens of 10 hens. Hens in 3 treatment groups were orally inoculated with different doses of embryonated A. galli eggs: low (250 eggs), medium (1,000 eggs), and high (2,500 eggs) levels, whereas hens of the control group were not infected. Infection levels were monitored using excreta egg counts and mature A. galli worm counts in the intestine. Anti A. galli antibody titers (IgY) in the serum were measured prior to infection, and at 6, 11, 15, and 20 wk post infection (PI) and in egg yolk at 11 and 20 wk PI. Parameters evaluated included feed intake, egg production, egg weight, egg mass, FCR, liver weight, liver fat, and intra epithelial immune cell infiltration. The results showed no difference in feed intake, body weight, or FCR among any treatment groups (P > 0.05). Egg production was lower in the low infection group compared to other groups at 20 wk of age (P < 0.01). Serum IgY was higher in the infected groups’ hens at 20 wk PI compared to control group hens (P < 0.01). Yolk IgY increased significantly over time and was higher in infected hens compared to hens of the control group at 11 and 20 wk PI (P < 0.001). No differences were observed in liver lipid content or intraepithelial lymphocytes infiltration among treatment groups. Ascaridia galli eggs in the coprodeum content and adult A. galli worm count were higher in infected hens compared to hens of the control group (P < 0.01). In conclusion, the effects of artificial infection with A. galli on the parameters investigated were minor, and egg yolk antibody may be a more reliable indicator of A. galli infection than serum antibody or excreta egg count.
A coiled-coil- and C2-domain-containing protein is required for FAZ assembly and cell morphology in Trypanosoma brucei

Trypanosoma brucei, a flagellated protozoan parasite causing human sleeping sickness, relies on a subpellicular microtubule array for maintenance of cell morphology. The flagellum is attached to the cell body through a poorly understood flagellum attachment zone (FAZ), and regulates cell morphogenesis using an unknown mechanism. Here we identified a new FAZ component, CC2D, which contains coiled-coil motifs followed by a C-terminal C2 domain. T. brucei CC2D is present on the FAZ filament, FAZ-juxtaposed ER membrane and the basal bodies. Depletion of CC2D inhibits the assembly of a new FAZ filament, forming a FAZ stub with a relatively fixed size at the base of a detached, but otherwise normal, flagellum. Inhibition of new FAZ formation perturbs subpellicular microtubule organization and generates short daughter cells. The cell length shows a strong linear correlation with FAZ length, in both control cells and in cells with inhibited FAZ assembly. Together, our data support a direct function of FAZ assembly in determining new daughter cell length by regulating subpellicular microtubule synthesis.
Dual Diagnosis Resource Needs in Spain: A National Survey of Professionals

Objective: Since provision of integrated services for patients with dual pathology or dual disorders (coexistence of an addictive disorder and another mental health disorder) is an important challenge in mental health, this study assessed health care professionals’ perceptions and knowledge of the current state of specific resources for patients with dual pathology in Spain. Methods: We conducted a national survey of health care professionals seeing patients with dual pathology in treatment facilities throughout Spain. Participants completed a specific online questionnaire about the needs of and available resources for patients with dual pathology. Results: A total of 659 professionals, mostly psychologists (n = 286, 43.4%) or psychiatrists (n = 217, 32.9%), participated in the study. Nearly all participants who responded to these items reported that specific resources for dual pathology were needed (n = 592/635, 93.2%); 76.7% (n = 487) identified intermediate resources, 68.8% (n = 437) acute detoxification units, and 64.6% (n = 410) medium-stay rehabilitation units as particularly necessary. In the opinion of 54.0% of respondents (n = 343), integrated mental health and addiction treatment services were available. Of the participants who answered these items, only a small proportion (n = 162/605, 26.8%) reported that there were appropriate outpatient programs for dual pathology, 30.4% (n = 184/605) specific hospitalization units, 16.9% (n = 99/587) subacute inpatient units, 34.2% (n = 201/587) outpatient intermediate resources, 15.5% (n = 91/587) day hospitals, and 21.5% (n = 126/587) day centers. Conversely, 62.5% (n = 378/587) of participants reported a greater presence of specific detoxification/withdrawal units, 47.3% (n = 286/587) psychiatric acute admission units, and 41.9% (n = 246/587) therapeutic communities. In the professionals’ opinion, the presence of specialty programs was low; 11.6% of respondents (n = 68/587) reported that vocational programs and 16.7% (n = 98/587) reported that occupational rehabilitation programs were available. Employee turnover was common: 51.9% of respondents (n = 314/605) stated that employee turnover was occasional to frequent. Conclusions: According to the professionals surveyed, specific health care resources for the management of dual pathology are currently insufficient, underlining the need for additional efforts and strategies for treating individuals with comorbid disorders.
Observation of Partial Wave Resonances in Low-Energy O2–H2 Inelastic Collisions

Quantum Collision Course Our experience of a world apparently governed by classical physics is a consequence of the fact that quantum mechanical effects average out in size regimes much larger than nanometers. Even at the molecular level, the quantized nature of rotational energy distributions is often obscured by averaging effects. Chefdeville et al. (p. 1094; see the Perspective by Casavecchia and Alexander) have observed a striking manifestation of quantized rotation in the scattering trajectories of colliding H2 and O2 molecular beams. The experimentally resolved partial wave resonances show essentially complete agreement with theoretical calculations and deviate starkly from classical collision paradigms. Purely quantum mechanical effects are manifested in an experiment probing crossed molecular beams. [Also see Perspective by Casavecchia and Alexander] Partial wave resonances predicted to occur in bimolecular collision processes have proven challenging to observe experimentally. Here, we report crossed-beam experiments and quantum-scattering calculations on inelastic collisions between ground-state O2 and H2 molecules that provide state-to-state cross sections for rotational excitation of O2 (rotational state N = 1, j = 0) to O2 (N = 1, j = 1) in the vicinity of the thermodynamic threshold at 3.96 centimeter−1. The close agreement between experimental and theoretical results confirms the classically forbidden character of this collision-induced transition, which occurs exclusively in a purely quantum mechanical regime via shape and Feshbach resonances arising from partial waves with total angular momentum (J) = 2 to 4.