Miracle-dz/UniFAR-FTUs huggingface dataset:
The clonal relationships between pre‐cancer and cancer revealed by ultra‐deep sequencing

The study of the relationships between pre‐cancer and cancer and identification of early driver mutations is becoming increasingly important as the value of molecular markers of early disease and personalised drug targets is recognized, especially now the extent of clonal heterogeneity in fully invasive disease is being realized. It has been assumed that pre‐cancerous lesions exhibit a fairly passive progression to invasive disease; the degree to which they, too, are heterogeneous is unknown. We performed ultra‐deep sequencing of thousands of selected mutations, together with copy number analysis, from multiple, matched pre‐invasive lesions, primary tumours and metastases from five patients with oral cancer, some with multiple primary tumours presenting either synchronously or metachronously, totalling 75 samples. This allowed the clonal relationships between the samples to be observed for each patient. We expose for the first time the unexpected variety and complexity of the relationships between this group of oral dysplasias and their associated carcinomas and, ultimately, the diversity of processes by which tumours are initiated, spread and metastasize. Instead of a series of genomic precursors of their adjacent invasive disease, we have shown dysplasia to be a distinct dynamic entity, refuting the belief that pre‐cancer and invasive tumours with a close spatial relationship always have linearly related genomes. We show that oral pre‐cancer exhibits considerable subclonal heterogeneity in its own right, that mutational changes in pre‐cancer do not predict the onset of invasion, and that the genomic pathway to invasion is neither unified nor predictable. Sequence data from this study have been deposited in the European Nucleotide Archive, Accession No. PRJEB6588. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Global health and the scientific research agenda.

In ,  million people died. Violence killed fewer than one million of them; famine contributed to about six million deaths; more than  million died of some form of disease. Many of these illnesses were the result primarily of old age and may have been unpreventable. That is unlikely to be true, however, of over a million deaths from malaria, nearly two million deaths from tuberculosis, nearly three million deaths from AIDS, and over four million deaths from respiratory disease. To suggest that many of these deaths could have been prevented might be to make one of two distinct claims. First, in the current state of our knowledge, available techniques exist for responding to the diseases mentioned above and for saving those who suffered from them. Second, these are scourges that we might hope to overcome in the course of future biomedical research. Part of the world’s burden of disease could have been alleviated if those who died had had access to drugs or treatments routinely available to others in different places. Another part could have been lightened if there had been more thoroughgoing efforts to discover methods of combating disease, methods that the actual course of biomedical research has so far not yet found. Global Health and the Scientific Research Agenda
Mitotic Spindle Positioning in the EMS Cell of Caenorhabditis elegans Requires LET-99 and LIN-5/NuMA

Asymmetric divisions produce daughter cells with different fates, and thus are critical for animal development. During asymmetric divisions, the mitotic spindle must be positioned on a polarized axis to ensure the differential segregation of cell fate determinants into the daughter cells. In many cell types, a cortically localized complex consisting of Gα, GPR-1/2, and LIN-5 (Gαi/Pins/Mud, Gαi/LGN/NuMA) mediates the recruitment of dynactin/dynein, which exerts pulling forces on astral microtubules to physically position the spindle. The conserved PAR polarity proteins are known to regulate both cytoplasmic asymmetry and spindle positioning in many cases. However, spindle positioning also occurs in response to cell signaling cues that appear to be PAR-independent. In the four-cell Caenorhabditis elegans embryo, Wnt and Mes-1/Src-1 signaling pathways act partially redundantly to align the spindle on the anterior/posterior axis of the endomesodermal (EMS) precursor cell. It is unclear how those extrinsic signals individually contribute to spindle positioning and whether either pathway acts via conserved spindle positioning regulators. Here, we genetically test the involvement of Gα, LIN-5, and their negative regulator LET-99, in transducing EMS spindle positioning polarity cues. We also examined whether the C. elegans ortholog of another spindle positioning regulator, DLG-1, is required. We show that LET-99 acts in the Mes-1/Src-1 pathway for spindle positioning. LIN-5 is also required for EMS spindle positioning, possibly through a Gα- and DLG-1-independent mechanism.
Isolated Winding-Coupled Bidirectional ZVS Converter With PWM Plus Phase-Shift (PPS) Control Strategy

A novel winding-coupled bidirectional dc/dc converter with zero-voltage-switching (ZVS) performance is proposed in this paper. In the low-voltage side, the parallel configuration is employed to share the large current and reduce the current ripple. In the high-voltage side, the series structure is adopted to sustain the high bus voltage and achieve large voltage ratio conversion. There are only two coupled inductors in the proposed interleaved bidirectional converter and their secondary windings are in series to serve as winding-coupled inductors. Furthermore, the two winding-coupled inductors can be integrated into a magnetic core to reduce the passive component numbers and improve the power density. Moreover, ZVS soft-switching operation is implemented for all the power switches to minimize the switching losses by introducing the active clamp scheme. In addition, the pulsewidth modulation plus phase-shift control strategy is employed to reduce the power MOSFET peak current and diminish the circulating losses. The duty cycle is applied to balance the voltages of both sides. The phase-shift angle is introduced to realize the power flow regulation. This decoupling control strategy is advantageous for bidirectional dc/dc conversion to realize high efficiency. Finally, a 1-kW prototype is built to verify the effectiveness of the proposed circuit.
The Role of Colour in Categorial Judgements

Two experiments are reported that extend the findings of Ostergaard and Davidoff (1985) on the role of colour in object processing. Two types of categorial judgements were investigated from pictorial stimuli: size judgement and living/non-living classifications. The effect of real size on size judgements (Paivio, 1975) was replicated. It was found that colour did not affect either of the categorial judgements, but the facilitation occurring in object naming tasks was confirmed. It is argued that semantic judgements can precede name retrieval, that physical colour input does not enter the semantic system, and that the representation of object colour information in the semantic system may be largely verbal.
The effect of gender on the outcome of forensic psychiatric assessment in Sweden: A case vignette study

BACKGROUND Previous research suggests that female violent offenders at risk of a prison sentence are more likely than their male counterparts to be assessed as having mental health problems of a nature or degree that would lead to a court requirement for hospital treatment. AIMS/HYPOTHESES To test the hypothesis that there is bias towards hospital disposal of female compared with male violent offenders with mental disorder. METHODS In Sweden, the National Board of Forensic Medicine oversees all assessments of mental disorder for the criminal courts. Twenty-six Board appointed forensic psychiatrists, psychologists and social workers each independently assessed six case vignettes for fit with criteria for 'severe mental disorder', a prerequisite for hospital disposal from court. Each gender neutral vignette described a person who had been convicted of serious assault and had a major mental disorder. A gender was then assigned to each offender randomly within a block design, thus varying between sets. Participants were blind to the main aim of the study and the gender variation. RESULTS There was no significant association between gender of the person assessed and judgement that s/he had a 'severe mental disorder'. An offender depicted as having mental retardation was more likely to be assessed as at high risk of criminal recidivism if portrayed as female, regardless of the sex, place of work or level of experience of the assessor. CONCLUSION We found no evidence of gender bias in determining appropriateness of a hospital disposal of an offender with mental disorder. The difference in assessment of recidivism according to sex of the patient was only in relation to mental retardation; further research would be needed to able to interpret this. As researchers in other countries have reported gender bias in disposals from court, our findings may provide support for a centralised forensic psychiatric assessment board and formal, on-going training. Copyright © 2015 John Wiley & Sons, Ltd.
Chemiluminescent assay of alkaline phosphatase in human gingival crevicular fluid: investigations with an experimental gingivitis model and studies on the source of the enzyme within crevicular fluid.

The purpose of this study was to investigate how levels of gingival crevicular fluid (GCF) alkaline phosphatase (ALP) change in relation to levels of plaque and gingival inflammation in 20 adults during a 21 day period of experimental gingivitis. The source of ALP within GCF was also investigated using a repeat sampling protocol; by determining enzyme levels derived from 30 putative periodontal pathogenic and non-pathogenic species; and by examining inhibition profiles from a variety of host and bacterial ALP isoenzymes. Total 30-s GCF ALP levels increased significantly (p < 0.002) during experimental gingivitis and preceded an increase in gingival index (GI) by approximately 7 days. Enzyme levels correlated with GCF volume (R = 0.7; p < 0.0001), but repeat sampling indicated that entry of ALP into the gingival crevice was independent of the rate of fluid flow. Only 5 of the bacterial species investigated produced clearly detectable levels of ALP in culture supernatants, these were P. gingivalis (381), P. intermedia (581), P. nigrescens (8944), Dentin P. gingivalis (TW 471: clinical isolate) and C. ochracea (25). Levamisole inhibition and studies on suspensions of washed plaque demonstrated that host-derived ALP contributed to > 80% of the enzyme in GCF. We conclude that elevated 30-s GCF ALP levels measured using the chemiluminescent assay reported, are detectable before increases in gingival indices and appear to be a better marker of gingival inflammation than ALP concentrations. The major source of ALP within GCF is host derived and in early inflammatory disease is likely to be of polymophonuclear leukocyte origin.
Pre- and Postoperative Gait Analysis in Patients with Spastic Diplegia: A Preliminary Report

Summary: The benefits of using computerized gait analysis to plan and evaluate operations were assessed by studying the data from 20 children with spastic diplegia and examining the changes in estimated external work of walking, stride length, walking velocity, and joint rotations pre- and postoperatively. Of the 20 patients, 13 improved, 6 were unchanged, and 1 was worse. None of the patients walked in a crouch postoperatively. By clinical evaluation, 19 of the 20 patients were better. Thus objective gait analysis imposed much more stringent criteria for improvement. Computerized gait analysis has enabled us to be more objective in the evaluation and documentation of outcome.
Intensity of Nordic Walking in young females with different peak O2 consumption

The purpose of this cross‐sectional study was to determine the physiological reaction to the different intensity Nordic Walking exercise in young females with different aerobic capacity values. Twenty‐eight 19–24‐year‐old female university students participated in the study. Their peak O2 consumption (VO2 peak kg−1) and individual ventilatory threshold (IVT) were measured using a continuous incremental protocol until volitional exhaustion on treadmill. The subjects were analysed as a whole group (n = 28) and were also divided into three groups based on the measured VO2 peak kg−1 (Difference between groups is 1 SD) as follows: 1. >46 ml min−1 kg−1 (n = 8), 2. 41–46 ml min−1 kg−1 (n = 12) and 3. <41 ml min−1 kg−1 (n = 8). The second test consisted of four times 1 km Nordic Walking with increasing speed on the 200 m indoor track, performed as a continuous study (Step 1 – slow walking, Step 2 – usual speed walking, Step 3 – faster speed walking and Step 4 – maximal speed walking). During the walking test expired gas was sampled breath‐by‐breath and heart rate (HR) was recorded continuously. Ratings of perceived exertion (RPE) were asked using the Borg RPE scale separately for every 1 km of the walking test. No significant differences emerged between groups in HR of IVT (172·4 ± 10·3–176·4 ± 4·9 beats min−1) or maximal HR (190·1 ± 7·3–191·6 ± 7·8 beats min−1) during the treadmill test. During maximal speed walking the speed (7·4 ± 0·4–7·5 ± 0·6 km h−1) and O2 consumption (30·4 ± 3·9–34·0 ± 4·5 ml min−1 kg−1) were relatively similar between groups (P > 0·05). However, during maximal speed walking, the O2 consumption in the second and third groups was similar with the IVT (94·9 ± 17·5% and 99·4 ± 15·5%, respectively) but in the first group it was only 75·5 ± 8·0% from IVT. Mean HR during the maximal speed walking was in the first group 151·6 ± 12·5 beats min−1, in the second (169·7 ± 10·3 beats min−1) and the third (173·1 ± 15·8 beats min−1) groups it was comparable with the calculated IVT level. The Borg RPE was very low in every group (11·9 ± 2·0–14·4 ± 2·3) and the relationship with VO2and HR was not significant during maximal speed Nordic Walking. In summary, the present study indicated that walking is an acceptable exercise for young females independent of their initial VO2 peak level. However, females with low initial VO2 peak can be recommended to exercise with the subjective ‘faster speed walking’. In contrast, females with high initial VO2 peak should exercise with maximal speed.
Peripheral oxygenation in term neonates

The aim of this study was to analyse changes in peripheral oxygenation in healthy term neonates within the first week of life with near-infrared spectroscopy and venous occlusion. Oxygen delivery did not change with increasing age. Oxygen consumption and fractional oxygen extraction increased, whereas tissue oxygenation index decreased with increasing age.
Primary Health Care: A Preferred Health Service Delivery Option for Women

It is well known that gender is a determinant of health, but less understood is whether differences in health status attributable to gender can be mitigated through the implementation of primary health care. Primary health care, notably distinct from primary care, refers to a wide-ranging approach to the delivery of a comprehensive variety of health services. This article traces the similarities between primary health care and women-centred care from their overlapping philosophical foundations to the similar health, social, and economic benefits of both approaches. It is argued that investments in primary health care positively impact women's health, and, as such, should be a preferred option for the delivery of women's community health services. Several models of health service delivery that operate in accordance with principles of primary health care and also address the key tenets of women's-centred care are examined and their merits are compared. The article also identifies the major impediments to the adoption of both primary health care and women's-centred care approaches.
Optical frequency combs in quantum dot fabry-perot lasers: Role of the spatial hole burning

The transmission of huge amount of data at Tbit/s rate in short distance optical interconnect has successfully employed quantum dot (QD) or quantum dash (QDash) multi-wavelength lasers (optical frequency combs) integrating one single section laser chip with the silicon photonics modulators [1]. The “comb” characteristics (i.e. self-phase locking of the lasing wavelengths separated by one cavity free spectral range) of single section QD and QDash lasers have been demonstrated in several experimental works [2-4], but the understanding of the fundamental physical effects behind the comb generation is still ongoing.
Ikaros Stability and Pericentromeric Localization Are Regulated by Protein Phosphatase 1*

Ikaros encodes a zinc finger protein that is involved in gene regulation and chromatin remodeling. The majority of Ikaros localizes at pericentromeric heterochromatin (PC-HC) where it regulates expression of target genes. Ikaros function is controlled by posttranslational modification. Phosphorylation of Ikaros by CK2 kinase determines its ability to bind DNA and exert cell cycle control as well as its subcellular localization. We report that Ikaros interacts with protein phosphatase 1 (PP1) via a conserved PP1 binding motif, RVXF, in the C-terminal end of the Ikaros protein. Point mutations of the RVXF motif abolish Ikaros-PP1 interaction and result in decreased DNA binding, an inability to localize to PC-HC, and rapid degradation of the Ikaros protein. The introduction of alanine mutations at CK2-phosphorylated residues increases the half-life of the PP1-nonbinding Ikaros mutant. This suggests that dephosphorylation of these sites by PP1 stabilizes the Ikaros protein and prevents its degradation. In the nucleus, Ikaros forms complexes with ubiquitin, providing evidence that Ikaros degradation involves the ubiquitin/proteasome pathway. In vivo, Ikaros can target PP1 to the nucleus, and a fraction of PP1 colocalizes with Ikaros at PC-HC. These data suggest a novel function for the Ikaros protein; that is, the targeting of PP1 to PC-HC and other chromatin structures. We propose a model whereby the function of Ikaros is controlled by the CK2 and PP1 pathways and that a balance between these two signal transduction pathways is essential for normal cellular function and for the prevention of malignant transformation.
Cancer-linked satellite 2 DNA hypomethylation does not regulate Sat2 non-coding RNA expression and is initiated by heat shock pathway activation

Epigenetic dysfunctions, including DNA methylation alterations, play major roles in cancer initiation and progression. Although it is well established that gene promoter demethylation activates transcription, it remains unclear whether hypomethylation of repetitive heterochromatin similarly affects expression of non-coding RNA from these loci. Understanding how repetitive non-coding RNAs are transcriptionally regulated is important given that their established upregulation by the heat shock (HS) pathway suggests important functions in cellular response to stress, possibly by promoting heterochromatin reconstruction. We found that, although pericentromeric satellite 2 (Sat2) DNA hypomethylation is detected in a majority of cancer cell lines of various origins, DNA methylation loss does not constitutively hyperactivate Sat2 expression, and also does not facilitate Sat2 transcriptional induction upon heat shock. In melanoma tumor samples, our analysis revealed that the HS response, frequently upregulated in tumors, is probably the main determinant of Sat2 RNA expression in vivo. Next, we tested whether HS pathway hyperactivation may drive Sat2 demethylation. Strikingly, we found that both hyperthermia and hyperactivated RasV12 oncogene, another potent inducer of the HS pathway, reduced Sat2 methylation levels by up to 27% in human fibroblasts recovering from stress. Demethylation occurred locally on Sat2 repeats, resulting in a demethylation signature that was also detected in cancer cell lines with moderate genome-wide hypomethylation. We therefore propose that upregulation of Sat2 transcription in response to HS pathway hyperactivation during tumorigenesis may promote localized demethylation of the locus. This, in turn, may contribute to tumorigenesis, as demethylation of Sat2 was previously reported to favor chromosomal rearrangements.
Adherence to Physical Therapy: A Qualitative Study

Objectives: To determine the strategies practicing PTs use to increase adherence to prescribed home exercise programs and to compare these theories to the current research. Background: Physical therapy is a popular treatment for physical disorders and musculoskeletal pain. For physical therapy to be effective, patients need to complete their prescribed treatment. Engstrom and Oberg (2005) found that only 24% of participants actually completed their exercise programs with full adherence. Methods and Measures: In-person, semi-structured interviews were performed. By interviewing PTs, this study evaluates how practicing PTs are dealing with nonadherence in their clinics and how they try to increase adherence. PTs used their clinical opinion, based on subjective reports from patients and clinical judgment, to determine adherence rates. Results: Five PTs were interviewed, and all reported the belief that patient education is the most important strategy for ensuring adherence; however, the literature supports patient self-efficacy and the therapist-patient alliance as important factors in predicting adherence. Although those interviewed engaged in many positive behaviors, PTs and the literature disagree on how to increase adherence. Of those interviewed, patients’ actual adherence is unknown, but it is estimated at higher than reported in the literature. Conclusion: The information given by PTs suggests that the field of physical therapy needs to reevaluate how to increase adherence and examine training programs to include training PTs to prevent or manage non-adherence.
General solutions of covariant superstring equations of motion.

The equations of motion arising from the Green-Schwarz Lagrangian for the superstring are solved for both commuting and anticommuting variables. The form of the solution depends on the number of independent Grassmann parameters; we are able to give the most general solution in some cases, but not all. The method of solution is to use an octonionic formalism for ten-dimensional vectors and spinors, and the solution is given in terms of a number of octonion parameters.
Enhancement of leukocyte membrane receptor expression after mechanical agitation.

Granulocyte and lymphocyte suspensions were exposed to slight mechanical agitation for 30 s on a tube mixer before being examined for membrane receptors by rosette techniques. Agitation caused an increase in the proportion of granulocytes bearing receptors for sheep erythrocytes (E-R), for the Fc portion of IgG (Fc gamma-R), and for C3b (C3b-R), and of lymphocytes bearing the Fc gamma-R. The proportion of E-R-bearing lymphocytes was not enhanced, with the exception of the 'early' or 'active' E-R-bearing cells. The increase in rosette formation was specific, i.e. rosette formation with ox or rabbit E was not induced by agitation. The increased proportion of membrane receptors was not associated with an increase in granulocyte phagocytosis of preopsonized zymosan particles, as measured by chemiluminescence. Membrane perturbation thus probably increases the availability of surface receptors.