Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis.

OBJECTIVE To determine the frequency of and clinicopathologic phenotypes associated with FUS/TLS mutations in a large cohort of amyotrophic lateral sclerosis (ALS) cases from the north of England. DESIGN Genetic screening project with neuropathologic examination of postmortem tissue in selected cases. The clinical details of selected cases are also presented. SETTING Neurology departments of 2 university teaching hospitals in the north of England. PARTICIPANTS The 15 exons of FUS/TLS were sequenced in an initial cohort of 42 familial ALS (FALS) and 117 sporadic ALS (SALS) cases. Exons 14 and 15 were subsequently screened in a larger cohort of 431 SALS cases. Regions mutated in ALS cases were also screened in 293 controls. MAIN OUTCOME MEASURE Evaluation of gene-sequencing chromatographs and detailed histopathologic analysis of the central nervous system. RESULTS Four heterozygous mutations, 1 of which is novel, were identified in 6 patients with ALS (4 with FALS and 2 with SALS). Two of the substitutions were not found to be present in controls, and neuropathology in these cases revealed neuronal and/or glial cytoplasmic inclusions positive for the FUS/TLS protein. One of these cases is also the first reported SALS case with an FUS/TLS mutation. The other 2 substitutions identified were also identified in control cases. Neuropathology in these cases revealed typical SALS pathology, suggesting that they are likely to represent benign polymorphisms. CONCLUSIONS FUS/TLS mutations represented approximately 5% of FALS cases screened. A FUS/TLS mutation was also identified in a single SALS case. Subsequent screening of this region in a larger cohort of SALS cases, however, did not reveal any additional mutations.
Activity‐dependent changes in eye influence during monocular blockade: Increases in the effects of visual stimulation on 2‐DG uptake in the adult rat geniculostriate system

We examined the effects of loss of monocular retinal activity 2‐deoxyglucose (2‐DG) uptake in the adult rat geniculostriate system. Of particular interest was whether the influence of the normally functioning eye changed during long‐term contralateral retinal silence. Group 1 rats were subjected to short‐term (24 hours) and group 2 rats to long‐term (21–90 days) monocular tetrodotoxin (TTX) blockade, and metabolic activity was assessed during exposure to square‐wave gratings. Group 1 rats exhibited patterns of cortical glucose utilization commensurate with complete monocular loss of retinal activity: minimal 2‐DG uptake in contralateral monocular area 17 and dorsal lateral geniculate nucleus (LGN), and a bilateral depression in the binocular regions; 2‐DG uptake was highest in the monocular regions fed by the stimulated normal eye (in both area 17 and the LGN) and these regions appeared unaffected by the monocular blockade. After repeated injections of TTX (group 2), metabolic activity in binocular area 17 and binocular LGN increased bilaterally relative to the metabolically active monocular regions contralateral to the normal eye. Group 3 rats were monocularly TTX‐injected for 30 or 60 days, and, 24 hours before 2‐DG, all retinal activity was eliminated by means of binocular TTX injections or binocular enucleation. Glucose utilization in the binocular regions of both area 17 and the LGN in these rats was depressed to levels seen in monocular area 17 after complete and recent loss of activity from the contralateral eye, indicating that the metabolic increase which occurred in the binocular regions during long‐term monocular retinal blockade was dependent upon the neuronal processing of retinal information from the non‐TTX eye. We conclude that, in the adult rat, an activity‐dependent, physiologically based shift in ocular influence occurred in the binocular geniculostriate system during long‐term monocular retinal inactivation.
Opening the Adaptive Toolbox

This is a discussion of the following three papers appearing in this special issue on adaptive designs: ‘A regulatory view on adaptive/flexible clinical trial design’ by H. M. James Hung, Robert T. O'Neill, Sue‐Jane Wang and John Lawrence; ‘Confirmatory clinical trials with an adaptive design’ by Armin Koch; and ‘FDA's critical path initiative: A perspective on contributions of biostatistics’ by Robert T. O'Neill. (© 2006 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Mutations of SQSTM1 are associated with severity and clinical outcome in paget disease of bone

Paget disease of bone (PDB) is a common disorder characterized by increased bone turnover at one of more sites throughout the skeleton. Genetic factors play an important role in the pathogenesis of PDB, and the most important predisposing gene is SQSTM1, which is mutated in about 10% of patients. Here we investigated the relationship between SQSTM1 mutation status, disease severity, and clinical outcome in 737 patients who took part in a randomized study of two different management strategies for the disease. Mutations of SQSTM1 were detected in 80 of 737 (10.9%) patients. Mutation carriers had an earlier age at diagnosis (59.4 ±11.5 versus 65.0 ± 10.4 years, p < .0001) and a greater number of affected bones (3.2 ± 1.2 versus 2.1 ± 1.2, p < .001) and more commonly required orthopedic surgery (26.2% versus 16.1%, p = .024) and bisphosphonate therapy (86.3% versus 75.2%, p = .01) than those without mutations. Quality of life, as assessed by the short‐form‐36 (SF36) physical summary score, was significantly reduced in carriers (34.0 ± 11.3 versus 37.1 ± 11.4, p = .036). During the study, fractures were more common in carriers (12.5% versus 5.3%, p = .011), although most of these occurred in unaffected bone. This study demonstrates that SQSTM1 mutations are strongly associated with disease severity and complications of PDB. Genetic testing for SQSTM1 mutations may be of value in identifying individuals at risk of developing severe disease, but further studies will be required to determine if a program of genetic testing and early intervention in these individuals would be cost‐effective or be of benefit in preventing these complications. © 2010 American Society for Bone and Mineral Research.
Effect of hormone replacement therapy on bone density in a patient with severe osteoporosis caused by anorexia nervosa

Osteoporosis is a recognised complication of anorexia nervosa, in part because of oestrogen deficiency.1 Data on the effect of oestrogen supplementation in osteoporotic patients with anorexia nervosa are limited. The effect of oestrogen supplementation on bone density in a patient with severe osteoporosis because of anorexia nervosa is reported. The patient presented at the age of 26 years with a history of intermittent back pain and kyphosis. Her menarche was at the age of 13 years when she weighed 53 kg. At that time she developed a restrictive eating habit but continued to menstruate until the age of 19 years when she became amenorrhoeic and weighed 32 kg. Although she received psychological support her weight only improved temporarily. She remained underweight at 41 kg for the two years preceding presentation. The patient admitted to drinking minimal amounts of milk, although did have yoghurts regularly. The only exercise she did was walking as part of daily activities. There was no history of binge eating or vomiting and she denied laxative, diuretic, alcohol or drug abuse. On examination her height was 1.57 m, weight 41 kg …
Genetic reductionist approach for dissecting individual roles of GGDEF proteins within the c-di-GMP signaling network in Salmonella

Bacteria have developed an exclusive signal transduction system involving multiple diguanylate cyclase and phosphodiesterase domain-containing proteins (GGDEF and EAL/HD-GYP, respectively) that modulate the levels of the same diffusible molecule, 3′-5′-cyclic diguanylic acid (c-di-GMP), to transmit signals and obtain specific cellular responses. Current knowledge about c-di-GMP signaling has been inferred mainly from the analysis of recombinant bacteria that either lack or overproduce individual members of the pathway, without addressing potential compensatory effects or interferences between them. Here, we dissected c-di-GMP signaling by constructing a Salmonella strain lacking all GGDEF-domain proteins and then producing derivatives, each restoring 1 protein. Our analysis showed that most GGDEF proteins are constitutively expressed and that their expression levels are not interdependent. Complete deletion of genes encoding GGDEF-domain proteins abrogated virulence, motility, long-term survival, and cellulose and fimbriae synthesis. Separate restoration revealed that 4 proteins from Salmonella and 1 from Yersinia pestis exclusively restored cellulose synthesis in a c-di-GMP–dependent manner, indicating that c-di-GMP produced by different GGDEF proteins can activate the same target. However, the restored strain containing the STM4551-encoding gene recovered all other phenotypes by means of gene expression modulation independently of c-di-GMP. Specifically, fimbriae synthesis and virulence were recovered through regulation of csgD and the plasmid-encoded spvAB mRNA levels, respectively. This study provides evidence that the regulation of the GGDEF-domain proteins network occurs at 2 levels: a level that strictly requires c-di-GMP to control enzymatic activities directly, restricted to cellulose synthesis in our experimental conditions, and another that involves gene regulation for which c-di-GMP synthesis can be dispensable.
Epidemiological survey of the orthopaedic status of severe haemophilia A and B patients in France

One hundred and 16 patients contributed to an analysis of the impact of the consequences of severe haemophilia A or B (factor levels < 2%) on orthopaedic status, resources consumed in relation to this status and resultant cost, and quality of life as perceived by the patient, using the MOS 36‐Item‐Short‐Form Health Survey (SF‐36). This French cross‐sectional study involved outpatients regularly attending a haemophilia treatment centre. Data were collected retrospectively over a period of 1 year by the physician of the haemophilia treatment centre. Patients had a mean age of 23, and consisted of 50% students, 25% salaried workers, 17.2% with no professional activity and 7.8% physically impaired; 82.8% of them had type A haemophilia. Mean pain score was 2.5 per patient for the six main joints; 7.7 for the clinical score and 18.8 for the radiological score, with a mean number of bleeds of 16.3 per year per patient. During the year prior to inclusion, and because of their orthopaedic status, 22.4% of patients were hospitalized, 76.7% attended for an outpatient visit and 76.7% required at least one special investigation; 97.4% received replacement therapy, 41.4% required treatment for joint pain and 42.2% orthopaedic equipment. The less affected dimensions were the physical function (76.8 ± 22.2) and the social relations (76.1 ± 23.1). Least good quality of life scores concerned the pain (60.2 ± 25.2), perception of general health (59.3 ± 23.1) and vitality (57.8 ± 19.5) dimensions. The age was a discriminant criterion since quality of life was better in patients of the 18–23 age group for five dimensions. Mean annual treatment costs of a patient with severe haemophilia were determined as 425 762 French francs ($73 029). Loss of production was estimated at a mean of 4609 French francs ($791) per active patient over the course of the year. Results showed indirect evidence of the usefulness of early home treatment.
Effect of Moderate Hypoxia/Reoxygenation on Mitochondrial Adaptation to Acute Severe Hypoxia

In an experimental model, it was shown that repetitive periods of hypoxia/reoxygenation (H/R) [5 cycles of 5 min hypoxia (12% O_2 in N_2) followed by 15 min normoxia, daily for three weeks] attenuated basal and stimulated in vitro lipid peroxidation, as well as H_2O_2 production in liver and brain mitochondria of rats exposed to acute severe hypoxia. Adaptation to moderate H/R enhanced in mitochondria the production and activity of reactive oxygen species scavengers, such as glutathione, manganese superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase. It was demonstrated that the maintenance of GSH-redox cycle by activation of glutathione reductase and NADP^+-dependent isocitrate dehydrogenase is an integral part of the biochemical adaptive mechanism of oxidative tolerance to new damaging factor. Brain mitochondria showed more sensitivity to oxidative stress than liver mitochondria, and long-lasting sessions of H/R affect differentially their pro-/antioxidant homeostasis.
Laparoscopic resection for rectal cancers: lessons learned from 579 cases

Objective:The aim of this study is to evaluate the short-term outcomes and long-term survival of laparoscopic rectal cancer resection at a single institution with 579 cases over a 15-year period. Summary Background Data:The use of laparoscopic resection for colon cancer has been shown to be safe with comparable oncological outcomes. However, the role of laparoscopic resection for rectal cancer is still controversial with few studies looking into long-term outcomes. Methods:From May 1992 to April 2007, 579 patients underwent laparoscopic resection for rectosigmoid and rectal cancer. The clinical data of these patients were retrospectively reviewed from a prospectively collected database. Data evaluated includes short- and long-term results, with survival outcomes calculated using the Kaplan-Meier method. Results:Over this 15-year period, 316 patients had laparoscopic anterior resection for rectosigmoid and upper rectal cancer, 152 patients had laparoscopic sphincter-saving total mesorectal excision, 92 patients had laparoscopic abdominoperineal resection, 17 patients had laparoscopic Hartmann procedure for rectal cancer, and 2 patients had proctocolectomy. The median age of these patients was 68 years (range, 35–95). The overall early and late operative morbidity was 18.8% and 9.7%, respectively. Conversion to open surgery was required in 5.4%of patients. Anastomotic leak rate was 3.5%. The median follow-up time was 56 months (range, 8–288). Port-site recurrence occurred in 2 patients. Locoregional recurrence occurred in 7.4% of patients after curative resection. The overall 5- and 10-year survivals for rectal cancer were 70% and 45.5%, respectively. The cancer-specific 5- and 10- year survival was 76% and 56%, respectively. Conclusions:The results of this study with large number of patients over a long follow-up period suggested that laparoscopic resection for rectal cancer is safe with good long-term oncological outcomes.
Effects of aCaloricRestrictionWeight LossDiet andExercise on In fl ammatory Biomarkers in Overweight / Obese Postmenopausal Women : A Randomized Controlled Trial

Obese and sedentary persons have increased risk for cancer; inflammation is a hypothesized mechanism. We examined the effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in 439 women. Overweight and obese postmenopausal women were randomized to 1-year: caloric restriction diet (goal of 10% weight loss, N1⁄4 118), aerobic exercise (225 min/wk of moderate-to-vigorous activity, N1⁄4 117), combined diet þ exercise (N 1⁄4 117), or control (N 1⁄4 87). Baseline and 1-year high-sensitivity C-reactive protein (hs-CRP), serumamyloidA (SAA), interleukin-6 (IL-6), leukocyte, andneutrophil levelsweremeasured by investigators blind to group. Inflammatory biomarker changes were compared using generalized estimating equations. Models were adjusted for baseline bodymass index (BMI), race/ethnicity, and age. Four hundred and thirty-eight (N1⁄4 1 in diet þ exercise group was excluded) were analyzed. Relative to controls, hs-CRP decreased by geometric mean (95% confidence interval, P value): 0.92mg/L (0.53–1.31, P< 0.001) in the diet and 0.87mg/L (0.51–1.23, P< 0.0001) in the dietþ exercise groups. IL-6 decreased by 0.34 pg/mL (0.13–0.55, P1⁄4 0.001) in the diet and 0.32 pg/mL (0.15–0.49, P < 0.001) in the diet þ exercise groups. Neutrophil counts decreased by 0.31 10/L (0.09–0.54, P 1⁄4 0.006) in the diet and 0.30 10/L (0.09–0.50, P1⁄4 0.005) in the dietþ exercise groups. Diet anddietþ exercise participantswith 5% or more weight loss reduced inflammatory biomarkers (hs-CRP, SAA, and IL-6) compared with controls. The diet and dietþ exercise groups reduced hs-CRP in all subgroups of baseline BMI, waist circumference, CRP level, and fasting glucose. Our findings indicate that a caloric restriction weight loss diet with or without exercise reduces biomarkers of inflammation in postmenopausal women, with potential clinical significance for cancer risk reduction. Cancer Res; 72(9); 2314–26. 2012 AACR.
Alliteration and Sound Change in Early English

This study uses evidence from early English verse to reconstruct the course of some central phonological changes in the history of the language. It builds on the premise that alliteration reflects faithfully the acoustic identity and similarity of stressed syllable onsets. Individual chapters cover the history of the velars, the structure and history of vowel-initial syllable onsets, the behavior of onset clusters, and the chronology and motivation of cluster reduction (gn-, kn-, hr-, hl-, hn-, hw-, wr-, wl-). Examination of the patterns of group alliteration in Old and Middle English reveals a hierarchy of clusterinternal cohesiveness which leads to new conclusions regarding the causes for the special treatment of sp-, st-, skin alliteration. The analysis draws on current phonetically-based Optimality-Theoretic models. The book presents valuable new information about the medieval poetic canon and elucidates the relationship between orality and literacy in the evolution of English verse.
Controllability analysis of multi-valued logical control networks

The controllability of multi-valued logical control networks is discussed in this paper. Using the vector form of multi-valued logical variable, the multi-valued logical control network is expressed as a bilinear discrete time system about the state and control variables. Based on the algebraic form, two definitions of controllability avoiding undesirable states set C are introduced: One is for the general controllability avoiding C, and the other one is for s fixed times controllability avoiding C. Also two necessary and sufficient conditions are given for each case.
Herbivory and plant growth rate determine the success of El Niño Southern Oscillation‐driven tree establishment in semiarid South America

While climatic extremes are predicted to increase with global warming, we know little about the effect of climatic variability on biome distribution. Here, we show that rainy El Niño Southern Oscillation (ENSO) events can enhance tree recruitment in the arid and semiarid ecosystems of north‐central Chile and northwest Peru. Tree‐ring studies in natural populations revealed that rainy El Niño episodes have triggered forest regeneration in Peru. Field experiments indicate that tree seedling recruitment in Chile is much less successful than in Peru due mostly to larger mortality caused by herbivores. The dramatic impact of herbivores in Chile was derived from the combined result of slower plant growth and the presence of exotic herbivores (European rabbits and hares). The interplay of herbivory and climatic effects we demonstrated implies that rainy ENSO events may represent ‘windows of opportunity’ for forest recovery if herbivore pressure is minimized at the right moment.
Trust and Risk Perception in Western Europe: A Cross‐National Study

The relationship between trust and risk perception was investigated, within and across four European countries (Sweden, Spain, United Kingdom, and France). Survey data were collected in 1996; total number of respondents was approximately 1,000 (United Kingdom and Spain), 1,350 (France), and 2,050 (Sweden). Trust was a significant predictor of perceived risk within countries, but the strength of the relationship varied from weak (Spain and France) to moderate (United Kingdom and Sweden). General trust was also a significant source of variation in perceived risk among countries, but much of the variation in perceived risk remained unexplained. Correlations between trust and risk perception also varied depending on the type of risk (i.e., nuclear risks were more influenced by trust) and trust measure (i.e., general trust explained perceived risk better than specific trust). It is concluded that trust may be an element in models explaining risk perception, but it is not as powerful as often argued in the risk perception literature.
Efficiency of Dinucleosides as the Backbone to Pre-Organize Multi-Porphyrins and Enhance Their Stability as Sandwich Type Complexes with DABCO

Flexible linkers such as uridine or 2′-deoxyuridine pre-organize bis-porphyrins in a face-to-face conformation, thus forming stable sandwich complexes with a bidentate base such as 1,4-diazabicyclo[2.2. 2]octane (DABCO). Increased stability can be even greater when a dinucleotide linker is used. Such pre-organization increases the association constant by one to two orders of magnitude when compared to the association constant of DABCO with a reference porphyrin. Comparison with rigid tweezers shows a better efficiency of nucleosidic dimers. Thus, the choice of rigid spacers is not the only way to pre-organize bis-porphyrins, and well-chosen nucleosidic linkers offer an interesting option for the synthesis of such devices.
Deep features-based expression-invariant tied factor analysis for emotion recognition

Video-based facial expression recognition is an open research challenge not solved by the current state-of-the-art. On the other hand, static image based emotion recognition is highly important when videos are not available and human emotions need to be determined from a single shot only. This paper proposes sequential-based and image-based tied factor analysis frameworks with a deep network that simultaneously addresses these two problems. For video-based data, we first extract deep convolutional temporal appearance features from image sequences and then these features are fed into a generative model that constructs a low-dimensional observed space for all individuals, depending on the facial expression sequences. After learning the sequential expression components of the transition matrices among the expression manifolds, we use a Gaussian probabilistic approach to design an efficient classifier for temporal facial expression recognition. Furthermore, we analyse the utility of proposed video-based methods for image-based emotion recognition learning static tied factor analysis parameters. Meanwhile, this model can be used to predict the expressive face image sequences from given neutral faces. Recognition results achieved on three public benchmark databases: CK+, JAFFE, and FER2013, clearly indicate our approach achieves effective performance over the current techniques of handling sequential and static facial expression variations.