Miracle-dz/UniFAR-FTUs huggingface dataset:
(R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells

Significance Protein methyltransferases constitute an emerging but undercharacterized class of therapeutic targets with diverse roles in normal human biology and disease. Small-molecule “chemical probes” can be powerful tools for the functional characterization of such enzymes, and here we report the discovery of (R)-PFI-2—a first-in-class, potent, highly selective, and cell-active inhibitor of the methyltransferase activity of SETD7 [SET domain containing (lysine methyltransferase) 7]—and two related compounds for control and chemoproteomics studies. We used these compounds to characterize the role of SETD7 in signaling, in the Hippo pathway, that controls cell growth and organ size. Our work establishes a chemical biology tool kit for the study of the diverse roles of SETD7 in cells and further validates protein methyltransferases as a druggable target class. SET domain containing (lysine methyltransferase) 7 (SETD7) is implicated in multiple signaling and disease related pathways with a broad diversity of reported substrates. Here, we report the discovery of (R)-PFI-2—a first-in-class, potent (Kiapp = 0.33 nM), selective, and cell-active inhibitor of the methyltransferase activity of human SETD7—and its 500-fold less active enantiomer, (S)-PFI-2. (R)-PFI-2 exhibits an unusual cofactor-dependent and substrate-competitive inhibitory mechanism by occupying the substrate peptide binding groove of SETD7, including the catalytic lysine-binding channel, and by making direct contact with the donor methyl group of the cofactor, S-adenosylmethionine. Chemoproteomics experiments using a biotinylated derivative of (R)-PFI-2 demonstrated dose-dependent competition for binding to endogenous SETD7 in MCF7 cells pretreated with (R)-PFI-2. In murine embryonic fibroblasts, (R)-PFI-2 treatment phenocopied the effects of Setd7 deficiency on Hippo pathway signaling, via modulation of the transcriptional coactivator Yes-associated protein (YAP) and regulation of YAP target genes. In confluent MCF7 cells, (R)-PFI-2 rapidly altered YAP localization, suggesting continuous and dynamic regulation of YAP by the methyltransferase activity of SETD7. These data establish (R)-PFI-2 and related compounds as a valuable tool-kit for the study of the diverse roles of SETD7 in cells and further validate protein methyltransferases as a druggable target class.
Ourselves Alone: Household Work Strategies in a Deprived Community

This paper is concerned with examining the nature of household work strategies in a low income estate in Belfast. It is based on a survey of one in four households within the estate and interviews with one hundred and twenty two school pupils from the area. The paper is divided into three parts. The first section assesses the extent to which male unemployment leads to a renegotiation of the domestic division of labour within the household. The second part of the paper relates to the presence or absence of consumer durables within the household and assesses whether this is connected to the employment status of household members. It examines whether the presence of consumer durables influences the time spent on household labour. The final part of the paper focuses on male involvement in non-routine household tasks.
Acquired Personality Disturbances Associated With Bilateral Damage to the Ventromedial Prefrontal Region

Personality changes in 7 participants with bilateral ventromedial prefrontal lesions (PF-BVM), 14 participants with prefrontal lesions but not bilateral ventromedial involvement (PF-NBVM), and 36 with nonprefrontal lesions (NPF) were investigated with the Iowa Rating Scales of Personality Change. Informants rated 30 specific characteristics for degree of disturbance and change from premorbid personality. PF-BVM participants showed a higher rate of acquired disturbances than NPF participants in blunted emotional experience, apathy, low emotional expressiveness, inappropriate affect, poor frustration tolerance, irritability, lability, indecisiveness, poor judgment, social inappropriateness, lack of planning, lack of initiation and persistence, and lack of insight. Differences between the PF-BVM and PF-NBVM groups were significant for several of these characteristics. All 7 PF-BVM participants developed a syndrome, including general dampening of emotional experience; poorly modulated emotional reactions; defective decision making, especially in the social realm; impaired goal-directed behavior; and striking lack of insight. Similarities between this syndrome of "acquired sociopathy" and developmental psychopathy in characteristic personality disturbances and psychophysiological abnormalities suggest that diminished emotionality, impaired decision making, and psychosocial dysfunction may be related to ventromedial prefrontal dysfunction in both groups.
Vesicular stomatitis virus mutant with altered polyadenylic acid polymerase activity in vitro

In vitro RNA synthesis by purified virions of a stock of tsG16(I) was aberrant compared with that of wild-type (wt) vesicular stomatitis virus. RNA made in vitro by tsG16(I) contained a larger proportion of A residues in polyadenylic acid [poly(A)] tracts than did RNA synthesized by wt virus, tsG13(I), tsG21(II) or tsG41(IV). Experiments to determine whether the aberrant polyadenylation was correlated with the known thermolability of the tsG16(I) L protein were inconclusive. Total product RNA made by tsG16(I) was methylated to almost the same extent as wt RNA, contained the same major methylated 5' cap structure as wt RNA, and was translated as well in a reticulocyte cell-free system, yielding the same molecular weight proteins in similar ratios. Most polyadenylated [poly(A)+] RNA made by tsG16(I) was considerably larger than wt poly(A)+ RNA and richer in AMP:UMP residues; however, the protein-coding capacities of mutant and wt poly(A)+ RNAs were similar. This suggested that most mRNAs made in vitro by tsG16(I) might possess very long poly(A)+ tracts, and digestion of RNA by T1 RNase supported this. It appeared, therefore, that a virally coded component of vesicular stomatitis virus could affect polyadenylation. This could be the poly(A) polymerase itself, a protein involved in control of polyadenylation, or a protein which affects an event spatially and temporally connected with polyadenylation (such as initiation of the subsequent mRNA).
Abnormal cholesterol metabolism in Smith‐Lemli‐Opitz syndrome

&NA; Smith‐Lemli‐Opitz syndrome (SLOS) is a common autosomal recessive disorder. Children with SLOS present with specific facial dysmorphism and have multiple congenital anomalies including cleft palate, congenital heart disease, genitourinary anomalies, and limb abnormalities. They also manifest severe failure to thrive and mental retardation. A metabolic defect at the final step in the cholesterol biosynthetic pathway has been described in SLOS patients. This defect results in markedly reduced cholesterol levels and abnormal accumulation of cholesterol precursors, particularly 7‐dehydrocholesterol. This newly described metabolic defect in humans is one of only a few metabolic errors known to cause multiple birth defects. The biochemical profile of reduced plasma cholesterol levels in association with markedly elevated levels of the cholesterol precursor 7‐dehydrocholesterol is now used to confirm the diagnosis of SLOS, which was formerly made on purely clinical grounds. This biochemical abnormality has been confirmed in dozens of patients with SLOS in both the United States and Europe. The severe cholesterol deficiency seen in these patients has multiple effects on health and early childhood development, because cholesterol is an essential component of many cell functions, which explains many of the clinical findings seen in SLOS.
Association between functional tooth units and chewing ability in older adults: a systematic review.

OBJECTIVES To systematically review the current evidence on the relationship between dentition status and chewing ability in older adults, as the latter was subjectively perceived by questionnaires. BACKGROUND Tooth loss is associated with functional impairment regarding chewing ability, depending on the number and the location of the remaining teeth. METHODS A search of the English literature was undertaken using the appropriate electronic databases and keywords in order to answer the question of this review. Independent extraction of the related articles was carried out by two authors using predefined eligibility criteria. RESULTS Full-text analysis was performed for 51 articles of possible relevance. Finally, data were extracted from 18 studies, published in 20 articles that met the inclusion criteria. CONCLUSIONS Although there was a conflict between the studies relevant to the number of functional tooth units needed to maintain adequate oral function, it was revealed that chewing ability was closely related to the number and distribution of teeth remaining. Treatment plan should focus on the preservation of the strategic parts of the dental arch that are critical for adequate oral function. Long-term prospective studies, comprising well-defined criteria, clinical variables, methods and utilising comprehensive questionnaires, should be preferred to obtain a clearer picture on the association between masticatory ability and functional tooth units.
Cumulative Illness and Neuropsychological Decline in Hospitalized Geriatric Patients

A substantial portion of elderly patients admitted for inpatient rehabilitation treatment evidence cognitive dysfunction. Frequently, such patients also present with considerable medical comorbidity, that is, multiple concurrent illnesses. Identifying the potential role of cumulative illness in the etiology of cognitive decline in this group of frail elderly is limited by a lack of empirical information as little is known about this relationship. The goal of the present research was thus to investigate the relationship between cumulative illness and cognitive dysfunction while controlling for age and neurological and psychiatric symptomatology as these are previously known to affect cognitive function. Results indicate that cumulative illness predicts neuropsychological decline beyond the effects attributable to advanced age, mood, neurological pathology and psychiatric impairments. Even mild illness, if cumulative across several physical systems, can be predictive of cognitive deficits in this frail population. Of 11 organ systems studied, impairment of the vascular system was associated with the most diffuse profile of declined neuropsychological performance. Performances on measures of reasoning and judgment showed the strongest associations with cumulative illness. Implications of findings for neuropsychological diagnosis and prognosis are reviewed.
multiCMFD: fast and efficient system for multiple copy-move forgeries detection in image

Due to excess uses of digital contents for communication and using image handling software and tools manipulation of these contents, detection of copy-move manipulation has become a prominent and interesting research area. The proposed copy-move forgery detection system is based on SIFT key-points extraction and density-based clustering algorithm. Extracted SIFT descriptors are matched using the generalized 2NN procedure. Thereafter, a density-based clustering algorithm is utilized to reduce or remove the false matches for improving detection accuracy. The proposed system is tested using MICC-F220, MICC-F2000 and MICC-F8multi, standard datasets. Due to the generalized 2NN matching procedure, the proposed system is able to detect multiple forgeries present in the image. Experimental results show the detection accuracy of the proposed system is more in comparison to existing systems and it is computationally efficient.
DISPARITIES IN LATIN AMERICA AND THE CARIBBEAN : THE ROLE OF SOCIAL AND ECONOMIC DETERMINANTS

The Latin American and Caribbean (LAC) region demonstrates the greatest disparities in income and in other socioeconomic determinants of health. Although research in many developed countries has provided strong evidence on the extent and strength of the relationships between these determinants and health, relatively little has been established on this relationship in the context of the countries in LAC. Nevertheless, available evidence shows that the distributions of health status and access to health services among different socioeconomic groups follow patterns that place the most vulnerable groups in situations of continuing and often growing disadvantage. Evidence also shows that such social and economic advantages are more strongly related to health outcomes than are need-based allocations of health services. This is a particular problem in LAC, where disparities in socioeconomic factors have continued to increase since 1980. Although general health has improved in LAC countries, gains in health status have not been made equally among various socioeconomic groups. Overall health improvement does not imply diminishing disHEALTH DISPARITIES IN LATIN AMERICA AND THE CARIBBEAN: THE ROLE OF SOCIAL AND ECONOMIC DETERMINANTS
Phantomless Auto-Calibration and Online Calibration Assessment for a Tracked Freehand 2-D Ultrasound Probe

This paper presents a method for automatically calibrating and assessing the calibration quality of an externally tracked 2-D ultrasound (US) probe by scanning arbitrary, natural tissues, as opposed a specialized calibration phantom as is the typical practice. A generative topic model quantifies the posterior probability of calibration parameters conditioned on local 2-D image features arising from a generic underlying substrate. Auto-calibration is achieved by identifying the maximum a-posteriori image-to-probe transform, and calibration quality is assessed online in terms of the posterior probability of the current image-to-probe transform. Both are closely linked to the 3-D point reconstruction error (PRE) in aligning feature observations arising from the same underlying physical structure in different US images. The method is of practical importance in that it operates simply by scanning arbitrary textured echogenic structures, e.g., in-vivo tissues in the context of the US-guided procedures, without requiring specialized calibration procedures or equipment. Observed data take the form of local scale-invariant features that can be extracted and fit to the model in near real-time. Experiments demonstrate the method on a public data set of in vivo human brain scans of 14 unique subjects acquired in the context of neurosurgery. Online calibration assessment can be performed at approximately 3 Hz for the US images of $640\times 480$ pixels. Auto-calibration achieves an internal mean PRE of 1.2 mm and a discrepancy of [2 mm, 6 mm] in comparison to the calibration via a standard phantom-based method.
Travailleurs maghrébins et portugais en France. Le poids de l'origine

This paper analyses the relative position of French, Portuguese and North African workers in the French labour market. We notably show that given the sex, the qualification, the potential experience, the localisation and the sector of activity, Portuguese have a lower propensity of being unemployed, a lower duration of unemployment and higher wages than natives, whereas North African are disadvantaged according to all these criteria. We analyse how specificities of the communities regarding the French fluency, the real experience, the propensity to return and the density of the community network are likely to explain these differences.
Antibiotics and energy delivery to the phagocytosis-associated respiratory burst in chronic hemodialysis patients: a comparison of cefodizime and cotrimoxazole.

Twenty-three stabilized chronic uremic patients with no active or recent infection were treated for 10 days with either cefodizime (5 x 2 g intravenously, n = 10) or cotrimoxazole (960 mg orally b.i.d., n = 8) in order to evaluate the effects on the depressed polymorphonuclear metabolic response to phagocytic challenge; a separate group of 5 patients received placebo. Ex vivo evaluation in whole blood of energy delivery to the phagocytosis-associated respiratory burst activity in response to latex and zymosan challenge was determined by measuring hexose-monophosphate shunt NAD(P)H-oxidase-related glycolytic activity. Cefodizime induced a statistically significant increase in the baseline-depressed glycolytic response for both latex and zymosan challenge, in contrast to cotrimoxazole and placebo. Depressed phagocytosis-related metabolic function in hemodialyzed patients was stimulated by cefodizime in recommended therapeutic doses but not by cotrimoxazole, the effect persisting for at least 2 weeks after the end of treatment.
Context‐aware movement analytics: implications, taxonomy, and design framework

Movement of an entity is greatly affected by its internal and external contexts. Such consequential influence has created new paradigms for context‐aware movement data mining and analysis. The significance of incorporating contextual information and movement data is becoming quite evident because of the growing interest in context‐aware movement analysis. Despite such importance, there is limited consensus among researchers on the definition of context and context‐aware system design in movement studies. Therefore, this paper comprehensively reviews current concepts of context and provides a definition and a taxonomy for context in movement analysis. The paper proceeds by providing a definition of context‐aware systems in the movement area after a complete review and comparison of the present definitions present in the literature. Inspired by related works, the paper further suggests a holistic three‐layer design framework tailored to context‐aware systems in movement studies to examine in greater depth the techniques applied during the design stages. The paper outlines the challenges and emergent issues in future research directions in context‐aware movement analysis. The present study is an attempt to bridge the gap between solely using context and developing context‐aware systems, thus paving the way for further research in movement applications. WIREs Data Mining Knowl Discov 2018, 8:e1233. doi: 10.1002/widm.1233
Effects of metformin on clinical and biochemical parameters in polycystic ovary syndrome.

OBJECTIVE To assess the effects of 6 months of metformin therapy on clinical and biochemical parameters in polycystic ovary syndrome (PCOS) and to evaluate those parameters in responders and nonresponders to identify the subjects who respond to an insulin sensitizer in PCOS. STUDY DESIGN Sixty-six diagnosed PCOS patients were recruited. Baseline characteristics (menstrual history, hirsutism scoring, acne grading, body mass index [BMI], serum luteinizing hormone and follicule-stimulating hormone [LH/FSH] ratio, testosterone,fasting insulin and glucose/insulin index) were assessed initially and 6 months after metformin therapy. Three groups were constructed on the basis of menstrual symptoms: oligomenorrhea (group I), amenorrhea (group II) and hypomenorrhea (group III). Responders were those who had improvements in menstrual pattern or conceived. Response was compared in 3 groups, and biochemical parameters were compared in responders and nonresponders. RESULTS There were 44 (66.6%) oligomenorrheic, 17 (25.7%) amenorrheic and 5 (7.5%) hypomenorrheic cases and 31 (46.5%) infertile women. In total, 85.7% responded to treatment; the rest (14.3%) were nonresponders. Among responders, 62.29% achieved regular periods, 22.95% experienced improvements in their menstrual abnormalities, and 13% conceived. Overall, a significant reduction occurred in BMI (P =.04), mean testosterone (P = .03) and mean fasting insulin levels (P = .01), but no significant improvement was observed in hirsutism, acne, LH/FSH ratio or glucose/insulin index. A total of 9.75%, 18.75% and 30% did not respond in the oligomenorrheic, amenorrheic and hypomenorrheic groups, respectively (P = .04). Testosterone and insulin were reduced significantly in responders (P = .05 and .01, respectively) but not in nonresponders (P = .26 and .73). An initial high LH/FSH ratio and lower testosterone levels were associated with a better response. CONCLUSION Six months of metformin therapy improved menstrual cyclicity and fertility in women with PCOS. It resulted in a decline in testosterone and insulin levels. Oligomenorrheic patients with an increased LH/FSH ratio and lower testosterone levels responded better.
Glucose-6-Phosphate Dehydrogenase Deficiency and Homozygous Sickle Cell Disease in Congo

G6PD genotypes were determined in Brazzaville (Congo) on 188 HbSS patients (109 females, 79 males) and 210 controls (115 females and 95 males) with HbAA. DNA samples were analyzed by the polymerase chain reaction (PCR). The frequencies of G6PD B, A+ and A– alleles were 56.9, 20.8 and, 22.2% in the patients versus 56.3, 21.2 and, 22.5% in the controls, respectively. The prevalence of G6PD genotypes in HbSS did not differ (p > 0.05) from that found in the controls. Prevalence of G6PD deficiency did not change when patients were stratified by age, suggesting that there is no advantage of the association of G6PD deficiency with HbSS. Red blood cell count, mean corpuscular volume and mean corpuscular hemoglobin were not modified by the G6PD genotypes, while Hb level was lower in HbSS with G6PD A–. Our study suggests that in Congo, G6PD deficiency does not offer any biological advantage to sicklers.
Outcomes of Phase II Clinical Trials with Single-Agent Therapies in Advanced/Metastatic Non–Small Cell Lung Cancer Published between 2000 and 2009

Purpose: We analyzed the outcomes of single-agent phase II clinical trials in non–small cell lung cancer (NSCLC) to determine trial parameters that predicted clinical activity. Exoerimental Design: Data on response rate (RR), progression-free survival (PFS), and overall survival (OS) from all English language, single-agent phase II trials in advanced/metastatic NSCLC indexed by PubMed (January 2000 through December 2009) were abstracted. Results: A total of 143 single-agent phase II trials (7,701 patients) were identified. The median RR was 10%, PFS 2.8 months, and OS 7.6 months. RR and PFS correlated with OS (r = 0.46, P < 0.001, r = 0.52, P < 0.001, respectively) and RR correlated with PFS (r = 0.61, P < 0.001). Treatment arms enriched for patients with molecular targets had a higher median RR (48.8% vs. 9.7%, P = 0.005), longer median PFS (6 vs. 2.8 months, P = 0.005), and OS (11.3 vs. 7.5 months, P = 0.05) as compared with those of unselected patients. In multivariate analysis, only studies enriched for patients with molecular targets or including drugs that eventually gained FDA/EMA approval were associated with a higher RR, and longer PFS/OS. Conclusions: In phase II trials in NSCLC, RR and PFS correlated with OS. Studies enriched for patients with putative molecular drug targets were associated with higher therapeutic benefit as compared with those of unselected populations. Clin Cancer Res; 18(22); 6356–63. ©2012 AACR.