Miracle-dz/UniFAR-FTUs huggingface dataset:
Alcohol Consumption in Relation to Plasma Sex Hormones, Prolactin, and Sex Hormone–Binding Globulin in Premenopausal Women

Background: Alcohol consumption is a consistent risk factor for breast cancer, and evidence suggests premenopausal plasma hormones are associated with breast cancer. Methods: Plasma concentrations of estradiol, estrone, estrone sulfate, testosterone, androstenedione, progesterone, prolactin, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and sex hormone–binding globulin (SHBG) were measured in samples collected in 1996–99. Average alcohol intake was calculated from semiquantitative food frequency questionnaires collected in 1995 and 1999. We used generalized linear models to calculate geometric mean hormone concentrations across alcohol categories and the percentage difference for the highest versus lowest category. Results: Comparing women who consumed >20 g/d with nondrinkers, levels were 25.7% higher for luteal estrone (geometric mean, 106 vs. 84.5 pg/mL; Ptrend = 0.001), 27.2% higher for luteal estradiol (182 vs. 143 pg/mL; Ptrend = 0.006), and 16.8% higher for SHBG (85.6 vs. 73.3 nmol/L; Ptrend = 0.03); concentrations of free testosterone were 17.9% lower (0.16 vs. 0.20 ng/dL; Ptrend = 0.002). Women consuming >10 g/d compared with nondrinkers had 26.5% higher concentrations of follicular estrone sulfate (950 vs. 751 pg/mL; Ptrend = 0.04). We did not observe significant associations between alcohol and the other sex hormones evaluated. Significant positive associations were observed with beer intake, but not other alcohol types, for DHEA (Pinteraction = 0.003) and androstenedione (Pinteraction = 0.006). Conclusion: Alcohol consumption was significantly positively associated with plasma luteal estrogen concentrations, but not with androgen levels, nor estrone or estradiol measured in the follicular phase. Impact: Differences in premenopausal estrogen levels may contribute to the association between alcohol and breast cancer. Cancer Epidemiol Biomarkers Prev; 23(12); 2943–53. ©2014 AACR.
Experiments on Density-Constrained Graph Clustering

Clustering a graph means identifying internally dense subgraphs that are only sparsely interconnected. Formalizations of this notion lead to measures that quantify the quality of a clustering and to algorithms that actually find clusterings. Since, most generally, corresponding optimization problems are hard, heuristic clustering algorithms are used in practice, or other approaches that are not based on an objective function. In this work, we conduct a comprehensive experimental evaluation of the qualitative behavior of greedy bottom-up heuristics driven by cut-based objectives and constrained by intracluster density, using both real-world data and artificial instances. Our study documents that a greedy strategy based on local movement is superior to one based on merging. We further reveal that the former approach generally outperforms alternative setups and reference algorithms from the literature in terms of its own objective, while a modularity-based algorithm competes surprisingly well. Finally, we exhibit which combinations of cut-based inter- and intracluster measures are suitable for identifying a hidden reference clustering in synthetic random graphs and discuss the skewness of the resulting cluster size distributions. Our results serve as a guideline to the usage of bicriterial, cut-based measures for graph clusterings.
Accelerated fracture healing in mice lacking the 5-lipoxygenase gene

Background and purpose Cyclooxygenase-2 (COX-2) promotes inflammation by synthesizing pro-inflammatory prostaglandins from arachidonic acid. Inflammation is an early response to bone fracture, and ablation of COX-2 activity impairs fracture healing. Arachidonic acid is also converted into leukotrienes by 5-lipoxygenase (5-LO). We hypothesized that 5-LO is a negative regulator of fracture healing and that in the absence of COX-2, excess leukotrienes synthesized by 5-LO will impair fracture healing. Methods Fracture healing was assessed in mice with a targeted 5-LO mutation (5-LOKO mice) and control mice by radiographic and histological observations, and measured by histomorphometry and torsional mechanical testing. To assess effects on arachidonic acid metabolism, prostaglandin E2, F2α, and leukotriene B4 levels were measured in the fracture calluses of control, 5-LOKO COX-1KO, and COX-2KO mice by enzyme linked immunoassays. Results Femur fractures in 5-LOKO mice rapidly developed a cartilaginous callus that was replaced with bone to heal fractures faster than in control mice. Femurs from 5-LOKO mice had substantially better mechanical properties after 1 month of healing than did control mice. Callus leukotriene levels were 4-fold higher in mice homozygous for a targeted mutation in the COX-2 gene (COX-2KO), which indicated that arachidonic acid was shunted into the 5-LO pathway in the absence of COX-2. Interpretation These experiments show that 5-LO negatively regulates fracture healing and that shunting of arachidonic acid into the 5-LO pathway may account, at least in part, for the impaired fracture healing response observed in COX-2KO mice.
Severe Osteogenesis Imperfecta in Cyclophilin B–Deficient Mice

Osteogenesis Imperfecta (OI) is a human syndrome characterized by exquisitely fragile bones due to osteoporosis. The majority of autosomal dominant OI cases result from point or splice site mutations in the type I collagen genes, which are thought to lead to aberrant osteoid within developing bones. OI also occurs in humans with homozygous mutations in Prolyl-3-Hydroxylase-1 (LEPRE1). Although P3H1 is known to hydroxylate a single residue (pro-986) in type I collagen chains, it is unclear how this modification acts to facilitate collagen fibril formation. P3H1 exists in a complex with CRTAP and the peptidyl-prolyl isomerase cyclophilin B (CypB), encoded by the Ppib gene. Mutations in CRTAP cause OI in mice and humans, through an unknown mechanism, while the role of CypB in this complex has been a complete mystery. To study the role of mammalian CypB, we generated mice lacking this protein. Early in life, Ppib-/- mice developed kyphosis and severe osteoporosis. Collagen fibrils in Ppib-/- mice had abnormal morphology, further consistent with an OI phenotype. In vitro studies revealed that in CypB–deficient fibroblasts, procollagen did not localize properly to the golgi. We found that levels of P3H1 were substantially reduced in Ppib-/- cells, while CRTAP was unaffected by loss of CypB. Conversely, knockdown of either P3H1 or CRTAP did not affect cellular levels of CypB, but prevented its interaction with collagen in vitro. Furthermore, knockdown of CRTAP also caused depletion of cellular P3H1. Consistent with these changes, post translational prolyl-3-hydroxylation of type I collagen by P3H1 was essentially absent in CypB–deficient cells and tissues from CypB–knockout mice. These data provide significant new mechanistic insight into the pathophysiology of OI and reveal how the members of the P3H1/CRTAP/CypB complex interact to direct proper formation of collagen and bone.
A Major Determinant for Membrane Protein Interaction Localizes to the Carboxy-Terminal Domain of the Mouse Coronavirus Nucleocapsid Protein

ABSTRACT The two major constituents of coronavirus virions are the membrane (M) and nucleocapsid (N) proteins. The M protein is anchored in the viral envelope by three transmembrane segments flanked by a short amino-terminal ectodomain and a large carboxy-terminal endodomain. The M endodomain interacts with the viral nucleocapsid, which consists of the positive-strand RNA genome helically encapsidated by N protein monomers. In previous work with the coronavirus mouse hepatitis virus (MHV), a highly defective M protein mutant, MΔ2, was constructed. This mutant contained a 2-amino-acid carboxy-terminal truncation of the M protein. Analysis of second-site revertants of MΔ2 revealed mutations in the carboxy-terminal region of the N protein that compensated for the defect in the M protein. To seek further genetic evidence corroborating this interaction, we generated a comprehensive set of clustered charged-to-alanine mutants in the carboxy-terminal domain 3 of N protein. One of these mutants, CCA4, had a highly defective phenotype similar to that of MΔ2. Transfer of the CCA4 mutation into a partially diploid MHV genome showed that CCA4 was a loss-of-function mutation rather than a dominant-negative mutation. Analysis of multiple second-site revertants of CCA4 revealed mutations in both the M protein and the N protein that could compensate for the original lesion in N. These data more precisely define the region of the N protein that interacts with the M protein. Further, we found that fusion of domain 3 of the N protein to the carboxy terminus of a heterologous protein caused it to be incorporated into MHV virions.
Activation of climbing fibers

Cells in the inferior olive are the sole source of climbing fibers to the cerebellum. In this article, we review some of the discharge properties of olivary cells that are important for understanding its functional role in cerebellar processing. It is generally believed that climbing fiber input supplies the cerebellum with information related to movement errors in order to improve motor performance. As a whole, olivary properties are not consistent with this function. The properties are consistent with the hypothesis that the olive is important for associating arbitrary sensory stimuli with somatosensory events. Although such associations would not be useful for improving the accuracy of motor commands, they may be useful for organizing appropriate behaviors to cope with the predicted event.
Hippocampal Functioning and Verbal Associative Memory in Adolescents with Congenital Hypothyroidism

Thyroid hormone (TH) is essential for normal development of the hippocampus, which is critical for memory and particularly for learning and recalling associations between visual and verbal stimuli. Adolescents with congenital hypothyroidism (CH), who lack TH in late gestation and early life, demonstrate weak verbal recall abilities, reduced hippocampal volumes, and abnormal hippocampal functioning for visually associated material. However, it is not known if their hippocampus functions abnormally when remembering verbal associations. Our objective was to assess hippocampal functioning in CH using functional magnetic resonance imaging (fMRI). Fourteen adolescents with CH and 14 typically developing controls (TDC) were studied. Participants studied pairs of words and then, during fMRI acquisition, made two types of recognition decisions: in one they judged whether the pairs were the same as when seen originally and in the other, whether individual words were seen before regardless of pairing. Hippocampal activation was greater for pairs than items in both groups, but this difference was only significant in TDC. When we directly compared the groups, the right anterior hippocampus was the primary region in which the TDC and CH groups differed for this pair memory effect. Results signify that adolescents with CH show abnormal hippocampal functioning during verbal memory processing.
Screening for Narrow Angles in the Japanese Population Using Scanning Peripheral Anterior Chamber Depth Analyzer

the start button. The SPAC also reports 3 categorical grades for risk of angle closure: S (for “suspect angle closure” , if there were ≥4 measured points exceeding the 95% confidence interval [CI]), P (for “potential angle closure”, if there were ≥4 points exceeding the 72% CI), and no suffix (for “normal”) [18]. It has been previously reported that the results of peripheral anterior chamber measurement by SPAC were well correlated with those by the van Herick technique as well as Shaffer’s grading system and the ultrasound biomicroscope [19]. Pentacam-Scheimpflug (rotating scheimpflug imaging) uses the Scheimpflug principle in order to obtain images of the anterior segment [10]. It has a rotating Scheimpflug camera that takes up to 50 slit images of the anterior segment in less than 2 seconds [20]. Soft‐ ware is then used to construct a three‐dimensional image. It calculates data for corneal topography (anterior and posterior corneal surface) and thickness, anterior chamber depth (ACD), lens opacification and lens thickness. It also provides data on corneal wavefront of the anterior and posterior corneal surface using Zernike polynomials. Com‐ pared with SPAC, Pentacam is highly expensive.
Confidence Corridors for Multivariate Generalized Quantile Regression

We focus on the construction of confidence corridors for multivariate nonparametric generalized quantile regression functions. This construction is based on asymptotic results for the maximal deviation between a suitable nonparametric estimator and the true function of interest, which follow after a series of approximation steps including a Bahadur representation, a new strong approximation theorem, and exponential tail inequalities for Gaussian random fields. As a byproduct we also obtain multivariate confidence corridors for the regression function in the classical mean regression. To deal with the problem of slowly decreasing error in coverage probability of the asymptotic confidence corridors, which results in meager coverage for small sample sizes, a simple bootstrap procedure is designed based on the leading term of the Bahadur representation. The finite-sample properties of both procedures are investigated by means of a simulation study and it is demonstrated that the bootstrap procedure considerably outperforms the asymptotic bands in terms of coverage accuracy. Finally, the bootstrap confidence corridors are used to study the efficacy of the National Supported Work Demonstration, which is a randomized employment enhancement program launched in the 1970s. This article has supplementary materials online.
Understanding the Impact of Drought on Foliar and Xylem Invading Bacterial Pathogen Stress in Chickpea

In field conditions, plants are concurrently exposed to multiple stresses, where one stressor impacts the plant's response to another stressor, and the resultant net effect of these stresses differs from individual stress response. The present study investigated the effect of drought stress on interaction of chickpea with Pseudomonas syringae pv. phaseolicola (Psp; foliar pathogen) and Ralstonia solanacearum (Rs; xylem inhabiting wilt causing pathogen), respectively, and the net-effect of combined stress on chlorophyll content and cell death. Two type of stress treatments were used to study the influence of each stress factor during combined stress, viz., imposition of drought stress followed by pathogen challenge (DP), and pathogen inoculated plants imposed with drought in course of pathogen infection (PD). Drought stress was imposed at different levels with pathogen inoculum to understand the influence of different stress intensities on stress interaction and their net impact. Drought stressed chickpea plants challenged with Psp infection (DPsp) showed reduced in planta bacterial number compared to Psp infection alone. Similarly, Rs infection of chickpea plants showed reduced in planta bacterial number under severe drought stress. Combined drought and Psp (DPsp) infected plants showed decreased cell death compared to plants infected only with Psp but the extent of cell death was similar to drought stressed plants. Similarly, chlorophyll content in plants under combined stress was similar to the individual drought stressed plants; however, the chlorophyll content was more compared to pathogen only infected plants. Under combined drought and Rs infection (DRs), cell death was similar to individual drought stress but significantly less compared to only Rs infected plants. Altogether, the study proposes that both stress interaction and net effect of combined stress could be majorly influenced by first occurring stress, for example, drought stress in DP treatment. In addition, our results indicate that the outcome of the two stress interaction in plant depends on timing of stress occurrence and nature of infecting pathogen.
Automated Segmentability Index for Layer Segmentation of Macular SD-OCT Images

Purpose To automatically identify which spectral-domain optical coherence tomography (SD-OCT) scans will provide reliable automated layer segmentations for more accurate layer thickness analyses in population studies. Methods Six hundred ninety macular SD-OCT image volumes (6.0 × 6.0 × 2.3 mm3) were obtained from one eyes of 690 subjects (74.6 ± 9.7 [mean ± SD] years, 37.8% of males) randomly selected from the population-based Rotterdam Study. The dataset consisted of 420 OCT volumes with successful automated retinal nerve fiber layer (RNFL) segmentations obtained from our previously reported graph-based segmentation method and 270 volumes with failed segmentations. To evaluate the reliability of the layer segmentations, we have developed a new metric, segmentability index SI, which is obtained from a random forest regressor based on 12 features using OCT voxel intensities, edge-based costs, and on-surface costs. The SI was compared with well-known quality indices, quality index (QI), and maximum tissue contrast index (mTCI), using receiver operating characteristic (ROC) analysis. Results The 95% confidence interval (CI) and the area under the curve (AUC) for the QI are 0.621 to 0.805 with AUC 0.713, for the mTCI 0.673 to 0.838 with AUC 0.756, and for the SI 0.784 to 0.920 with AUC 0.852. The SI AUC is significantly larger than either the QI or mTCI AUC (P < 0.01). Conclusions The segmentability index SI is well suited to identify SD-OCT scans for which successful automated intraretinal layer segmentations can be expected. Translational Relevance Interpreting the quantification of SD-OCT images requires the underlying segmentation to be reliable, but standard SD-OCT quality metrics do not predict which segmentations are reliable and which are not. The segmentability index SI presented in this study does allow reliable segmentations to be identified, which is important for more accurate layer thickness analyses in research and population studies.
Infinite-horizon Linear Optimal Control of Markov Jump Systems without Mode Observation via State Feedback

In this paper, we consider stochastic optimal control of Markov Jump Linear Systems with state feedback but without observation of the jumping parameter. The proposed control law is assumed to be linear with constant gains that can be obtained from the necessary optimality conditions using an iterative algorithm. The proposed approach is demonstrated in a numerical example.
Association of Target Organ Damage With 24-Hour Systolic and Diastolic Blood Pressure Levels and Hypertension Subtypes in Untreated Chinese

The association of target organ damage with 24-hour systolic and diastolic blood pressure levels and ambulatory hypertension subtypes has not yet been examined in untreated Chinese patients. We measured left ventricular mass index by echocardiography (n=619), the urinary albumin:creatinine ratio (n=1047), and aortic pulse wave velocity by tonometry (n=1013) in 1047 untreated subjects (mean age, 50.6 years; 48.9% women). Normotension was a 24-hour systolic/diastolic blood pressure <130/<80 mm Hg. Hypertension subtypes were isolated diastolic hypertension and mixed systolic plus diastolic hypertension. We assessed associations of interest by multivariable-adjusted linear models. Using normotension as reference, mixed hypertension was associated with higher (P⩽0.003) left ventricular mass index (+4.31 g/m2), urinary albumin:creatinine ratio (+1.63 mg/mmol), and pulse wave velocity (+0.76 m/s); and isolated diastolic hypertension was associated with similar left ventricular mass index and pulse wave velocity (P≥0.39), but higher urinary albumin:creatinine ratio (+1.24 mg/mmol; P=0.002). In younger participants (<55 years), the mutually independent effect sizes associated with 1 SD increases in 24-hour systolic/diastolic blood pressure were +3.31/–0.36 g/m2 (P=0.009/0.79) for left ventricular mass index, +1.15/+1.14 mg/mmol (P=0.02/0.04) for the urinary albumin:creatinine ratio, and +0.54/–0.05 m/s (P<0.001/0.54) for pulse wave velocity. In older participants, these estimates were +3.58/+0.30 g/m2 (P=0.045/0.88), +1.23/+1.05 mg/mmol (P=0.002/0.54), and +0.76/–0.49 m/s (P<0.001/<0.001), respectively. In conclusion, 24-hour systolic blood pressure and mixed hypertension are major determinants of target organ damage irrespective of age and target organ, whereas 24-hour diastolic blood pressure and isolated diastolic hypertension only relate to the urinary albumin:creatinine ratio below middle age.
Hybrid simulations of mini-magnetospheres in the laboratory

Solar energetic ions are a known hazard to both spacecraft electronics and to manned space flights in interplanetary space missions that extend over a long period of time. A dipole-like magnetic field and a plasma source, forming a mini-magnetosphere, are being tested in the laboratory as means of protection against such hazards. We investigate, via particle-in-cell hybrid simulations, using kinetic ions and fluid electrons, the characteristics of the mini-magnetospheres. Our results, for parameters identical to the experimental conditions, reveal the formation of a mini-magnetosphere, whose features are scanned with respect to the plasma density, the plasma flow velocity and the intensity of the dipole field. Comparisons with a simplified theoretical model reveal a good qualitative agreement and excellent quantitative agreement for higher plasma dynamic pressures and lower B-fields.
Absence of synergy for monosynaptic Group I inputs between abdominal and internal intercostal motoneurons

Internal intercostal and abdominal motoneurons are strongly coactivated during expiration. We investigated whether that synergy was paralleled by synergistic Group I reflex excitation. Intracellular recordings were made from motoneurons of the internal intercostal nerve of T8 in anesthetized cats, and the specificity of the monosynaptic connections from afferents in each of the two main branches of this nerve was investigated. Motoneurons were shown by antidromic excitation to innervate three muscle groups: external abdominal oblique [EO; innervated by the lateral branch (Lat)], the region of the internal intercostal muscle proximal to the branch point (IIm), and muscles innervated from the distal remainder (Dist). Strong specificity was observed, only 2 of 54 motoneurons showing excitatory postsynaptic potentials (EPSPs) from both Lat and Dist. No EO motoneurons showed an EPSP from Dist, and no IIm motoneurons showed one from Lat. Expiratory Dist motoneurons fell into two groups. Those with Dist EPSPs and none from Lat (group A) were assumed to innervate distal internal intercostal muscle. Those with Lat EPSPs (group B) were assumed to innervate abdominal muscle (transversus abdominis or rectus abdominis). Inspiratory Dist motoneurons (assumed to innervate interchondral muscle) showed Dist EPSPs. Stimulation of dorsal ramus nerves gave EPSPs in 12 instances, 9 being in group B Dist motoneurons. The complete absence of heteronymous monosynaptic Group I reflex excitation between muscles that are synergistically activated in expiration leads us to conclude that such connections from muscle spindle afferents of the thoracic nerves have little role in controlling expiratory movements but, where present, support other motor acts.