Miracle-dz/UniFAR-FTUs huggingface dataset:
Toward defining the anatomo‐proteomic puzzle of the human brain: An integrative analysis

The human brain is exceedingly complex, constituted by billions of neurons and trillions of synaptic connections that, in turn, define ∼900 neuroanatomical subdivisions in the adult brain (Hawrylycz et al. An anatomically comprehensive atlas of the human brain transcriptome. Nature 2012, 489, 391‐399). The human brain transcriptome has revealed specific regional transcriptional signatures that are regulated in a spatiotemporal manner, increasing the complexity of the structural and molecular organization of this organ (Kang et al. Spatio‐temporal transcriptome of the human brain. Nature 2011, 478, 483–489). During the last decade, neuroproteomics has emerged as a powerful approach to profile neural proteomes using shotgun‐based MS, providing complementary information about protein content and function at a global level. Here, we revise recent proteome profiling studies performed in human brain, with special emphasis on proteome mapping of anatomical macrostructures, specific subcellular compartments, and cerebrospinal fluid. Moreover, we have performed an integrative functional analysis of the protein compilation derived from these large‐scale human brain proteomic studies in order to obtain a comprehensive view of human brain biology. Finally, we also discuss the potential contribution of our meta‐analysis to the Chromosome‐centric Human Proteome Project initiative.
New agents modulating the renin-angiotensin-aldosterone system—Will there be a new therapeutic option?

The renin-angiotensin-aldosterone system (RAAS) is more complex than it was originally regarded. According to the current subject knowledge, there are two main axes of the RAAS: (1) angiotensin-converting enzyme (ACE)-angiotensin II-AT1 receptor axis and (2) ACE2-angiotensin-(1-7)-Mas receptor axis. The activation of the first axis leads to deleterious effects, including vasoconstriction, endothelial dysfunction, thrombosis, inflammation, and fibrosis; therefore, blocking the components of this axis is a highly rational and commonly used therapeutic procedure. The ACE2-Ang-(1-7)-Mas receptor axis has a different role, since it often opposes the effects induced by the classical ACE-Ang II-AT1 axis. Once the positive effects of the ACE2-Ang-(1-7)-Mas axis were discovered, the alternative ways of pharmacotherapy activating this axis of RAAS appeared. This article briefly describes new molecules affecting the RAAS, namely: recombinant human ACE2, ACE2 activators, angiotensin-(1-7) peptide and non-peptide analogs, aldosterone synthase inhibitors, and the third and fourth generation of mineralocorticoid receptor antagonists. The results of the experimental and clinical studies are encouraging, which leads us to believe that these new molecules can support the treatment of cardiovascular diseases as well as cardiometabolic disorders.
Heat shock protein 72 on tumor cells: a recognition structure for natural killer cells.

Evidence is accumulating that members of the heat shock protein 70 (HSP70) family are found on the cell surface of certain tumor cells where they elicit a strong antitumor immune response. We demonstrated that HSP72, the major heat-inducible form of the HSP70 group, is located on the cell surface of approximately 60% of the human colon carcinoma cells CX2 with two different mAbs by indirect immunofluorescence, by electron microscopy, and by selective cell surface biotinylation. In an effort to analyze the role of HSP72 cell surface expression as a tumor-specific recognition structure within an "autologous" tumor system, the CX2 cells were separated into a stably HSP72 high expressing (CX+: >90%) and a stably HSP72 low expressing (CX-: <20%) subline. The expression "autologous" was written in parentheses to indicate that the colon carcinoma sublines CX+ and CX- derived from the original CX2 tumor cell line differ with respect to the cell surface expression pattern of HSP72, whereas they exhibit an identical cell surface expression pattern of MHC and cellular adhesion molecules (e.g., intercellular cellular adhesion molecule, neural cellular adhesion molecule, vascular cellular adhesion molecule). Within this "autologous" tumor cell system, we demonstrate that the sensitivity to lysis mediated by adherent non-MHC-restricted effector cells correlates (p < 0.05) with the amount of HSP72 that is expressed on the cell surface. Blocking studies using an HSP72-specific mAb revealed that HSP72 might act in an MHC-unrestricted manner as a tumor-specific recognition structure for a distinct NK cell population.
Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor.

PURPOSE A phase I and pharmacologic study was undertaken to determine the maximum-tolerated dose (MTD), describe the principal toxicities, and characterize the pharmacologic behavior of topotecan, which is a semisynthetic analog of camptothecin with broad preclinical antitumor activity and the first topoisomerase I-targeting agent to enter clinical development in the United States since studies of sodium camptothecin over 2 decades ago. PATIENTS AND METHODS Thirty-minute infusions of topotecan were administered daily for 5 consecutive days every 3 weeks to patients with advanced solid malignancies at doses ranging from 0.5 to 2.5 mg/m2/d. RESULTS At doses of 1.5 and 2.0 mg/m2, grade 3 and 4 neutropenia occurred in most courses; however, neutropenia was brief and rarely associated with fevers or treatment delays. Neutropenia was more severe in patients with extensive prior treatment than in minimally pretreated patients, but these differences were not substantial. At 2.5 mg/m2, topotecan induced profound and prolonged neutropenia that was frequently associated with fever and treatment delays in minimally pretreated patients. Topotecan also induced mild depressions in the hematocrit level in the majority of courses; however, precipitous drops requiring transfusional therapy occurred in 14% of courses and suggested a drug-induced hemolytic effect. Unlike sodium camptothecin, hemorrhagic cystitis was not observed. Thrombocytopenia, skin rash, diarrhea, and vomiting occurred infrequently and were modest in severity. Responses were observed in non-small-cell lung carcinoma and platinum-refractory ovarian carcinoma. Drug disposition in plasma was described by a biexponential model, with renal elimination accounting for 38.7% of drug disposition. Topotecan was rapidly hydrolyzed in vivo to a less active, open-ring form. CONCLUSIONS Neutropenia is the dose-limiting toxicity, and 1.5 mg/m2 is the recommended starting dose of topotecan for both minimally and heavily pretreated patients in future phase II trials, with escalation to 2.0 mg/m2 if treatment is well tolerated. Non-small-cell lung and platinum-refractory ovarian carcinomas should be among those evaluated in phase II trials of topotecan.
Bayesian Nonparametric Learning of Cloth Models for Real-Time State Estimation

Robotic solutions to clothing assistance can significantly improve quality of life for the elderly and disabled. Real-time estimation of the human–cloth relationship is crucial for efficient learning of motor skills for robotic clothing assistance. The major challenge involved is cloth-state estimation due to inherent nonrigidity and occlusion. In this study, we present a novel framework for real-time estimation of the cloth state using a low-cost depth sensor, making it suitable for a feasible social implementation. The framework relies on the hypothesis that clothing articles are constrained to a low-dimensional latent manifold during clothing tasks. We propose the use of manifold relevance determination (MRD) to learn an offline cloth model that can be used to perform informed cloth-state estimation in real time. The cloth model is trained using observations from a motion capture system and depth sensor. MRD provides a principled probabilistic framework for inferring the accurate motion-capture state when only the noisy depth sensor feature state is available in real time. The experimental results demonstrate that our framework is capable of learning consistent task-specific latent features using few data samples and has the ability to generalize to unseen environmental settings. We further present several factors that affect the predictive performance of the learned cloth-state model.
Activation/Deactivation Cycle of Redox-controlled Thylakoid Protein Phosphorylation

Signal transduction via light-dependent redox control of reversible thylakoid protein phosphorylation has evolved in plants as a unique mechanism for controlling events related to light energy utilization. Here we report for the first time that protein phosphorylation can be activated without light or the addition of reducing agents by a transient exposure of isolated thylakoid membranes to low pH in darkness. The activation of the kinase after incubation of dark-adapted thylakoids at pH 4.3 coincides with an increase in the plastoquinol:plastoquinone ratio up to 0.25. However, rapid plastoquinol reoxidation (<1 min) at pH 7.4 contrasts with the slow kinase deactivation (t = 4 min), which indicates that the redox control is not directly dependent on the plastoquinone pool. Use of inhibitors and a cytochrome bf-deficient mutant of Lemna demonstrate the involvement of the cytochrome bf complex in the low-pH induced protein phosphorylation. EPR spectroscopy shows that subsequent to the transient low pH treatment and transfer of the thylakoids to pH 7.4, cytochrome f, the Rieske Fe-S center, and plastocyanin become reduced and are not reoxidized while the kinase is slowly deactivated. However, the deactivation correlates with a decrease of the EPR g signal of the reduced Rieske Fe-S center, which is also affected by quinone analogues that inhibit the kinase. Our data point to an activation mechanism of thylakoid protein phosphorylation that involves the binding of plastoquinol to the cytochrome bf complex in the vicinity of the reduced Rieske Fe-S center.
Type IV collagenase(s) and TIMPs modulate endothelial cell morphogenesis in vitro

It has been proposed that proteases are important in endothelial cell behavior. We examined the contribution of the gelatinase/type IV collagenase system in an in vitro model of endothelial differentiation. Human umbilical vein endothelial cells rapidly align and form networks of tubes when cultured on a basement membrane preparation, Matrigel. Zymograms of culture supernates demonstrate a 72‐kD and a 92‐kD gelatinase activity; the cells produce most of the 72‐kD gelatinase, whereas the 92‐kD activity is derived entirely from the Matrigel. Addition of antibodies against type IV gelatinase/collagenase decreases the area of the tube network. Both tissue inhibitors of metalloproteinases, TIMP‐1 and TIMP‐2, similarly decrease tube formation when added to cultures. Conversely, exogenous recombinant 72‐kD gelatinase increases tube‐forming activity. The effects of the anti‐gelatinase antibodies and the TIMPs are not additive. Inhibition by either antibodies or TIMPs is greatest when they are added at culture initiation, suggesting that the protease activity is important in the early steps of morphogenesis. However, culture of the cells on Matrigel does not increase early expression of mRNA for the 72‐kD gelatinase. Expression of message for the enzyme actually decreases during the course of the assay, while transcription of mRNA for TIMPs increases, further supporting the concept that collagenases facilitate an early event in tube formation. These data demonstrate that gelatinase/type IV collagenase activity is important in endothelial cell morphogenesis on Matrigel, and suggest a role for collagenases in formation of new capillaries in vivo. © 1993 Wiley‐Liss, Inc.
A life-like virtual cell membrane using discrete automata

A framework is presented that captures the discrete and probabilistic nature of molecular transport and reaction kinetics found in a living cell as well as formally representing the spatial distribution of these phenomena. This particle or agent-based approach is computationally robust and complements established methods. Namely it provides a higher level of spatial resolution than formulations based on ordinary differential equations (ODE) while offering significant advantages in computational efficiency over molecular dynamics (MD). Using this framework, a model cell membrane has been constructed with discrete particle agents that respond to local component interactions that resemble flocking or herding behavioural cues in animals. Results from simulation experiments are presented where this model cell exhibits many of the characteristic behaviours associated with its biological counterpart such as lateral diffusion, response to osmotic pressure gradients, membrane growth and cell division. Lateral diffusion rates and estimates for the membrane modulus of elasticity derived from these simple experiments fall well within a biologically relevant range of values. More importantly, these estimates were obtained by applying a simple qualitative tuning of the model membrane. Membrane growth was simulated by injecting precursor molecules into the proto-cell at different rates and produced a variety of morphologies ranging from a single large cell to a cluster of cells. The computational scalability of this methodology has been tested and results from benchmarking experiments indicate that real-time simulation of a complete bacterial cell will be possible within 10 years.
Landing adaptations after ACL reconstruction.

PURPOSE The purpose of this study was to determine whether fully rehabilitated ACL reconstructed (ACLr) recreational athletes utilize adapted lower-extremity joint kinematics and kinetics during a high-demand functional task. METHODS The kinematic and kinetic performance of 11 healthy and 11 hamstring ACLr recreational athletes were compared during a 60-cm vertical drop landing. RESULTS At initial ground contact, the ACLr group demonstrated greater hip extension and ankle plantarflexion compared with the healthy group. The peak vertical ground-reaction force was not different between groups, but the ACLr group delayed the time to its occurrence. The knee extensors provided the major energy absorption function for both groups; however, the ACLr group performed 37% more ankle plantarflexor work and 39% less hip extensor work compared with the healthy group. CONCLUSIONS The hamstring ACLr recreational athletes utilized an adapted landing strategy that employed the hip extensor muscles less and the ankle plantarflexor muscles more. The harvesting of the medial hamstring muscles for ACL reconstruction may contribute to the utilization of this protective landing strategy.
The osmotically sensitive potassium and sodium compartments of synaptosomes.

1. Synaptosomes are pinched-off nerve terminals whose components can be liberated by osmotic ;shock'. A synaptosome preparation run through a Sephadex column that was eluted with an iso-osmotic solution retained its small ions, whereas when the column was eluted hypo-osmotically the small ions were lost. In this way the osmotically sensitive Na(+) and K(+) of synaptosomes were measured. Measurements of the lactate dehydrogenase occluded within the synaptosome were also made. The release of osmotically sensitive Na(+) and K(+) and occluded lactate dehydrogenase had similar characteristics with respect to the degree of osmotic ;shock' necessary and the action of lytic agents. 2. The distribution of osmotically sensitive Na(+), K(+) and occluded lactate dehydrogenase in the subfractions of a crude mitochondrial preparation was examined. The synaptosome fraction was the richest source of these constituents. 3. On standing at 5 degrees in iso-osmotic solution Na(+) and K(+) were lost from synaptosomes, whereas the amount of occluded lactate dehydrogenase remained stable, suggesting that the synaptosome membrane retained its integrity but that Na(+) and K(+) diffused through it out of the osmotically sensitive compartment. 4. The uptake of Na(+) and K(+) into the osmotically sensitive compartment was examined. At 5 degrees the rates of uptake of Na(+) and K(+) were found to be equal to the rates of loss of these ions when correction to a uniform concentration gradient had been made. K(+) travelled across the membrane slightly faster than Na(+), the rate of K(+) movement being about 1.0mumuequiv. cm. (-2)sec. (-1) under a concentration gradient of 0.1m. Active transport is not thought to contribute to the ion movements under the conditions used. 5. The amount of K(+) taken up into the osmotically sensitive compartment as a function of the external concentration was examined. Since the uncharged molecule d-[(14)C]galactose distributes across the synaptosome membrane similarly to K(+) there is not thought to be a synaptosomal trans-membrane potential. The volume of the osmotically sensitive compartment was measured by this method and found to agree with estimates of the synaptosomal volume made from morphological studies. In media of low ionic strength synaptosomes exhibit a Donnan effect. 6. It is concluded from these studies that the osmotically sensitive compartment represents the inner volume of the synaptosome, which is completely separated from the outside environment by a diffusion barrier having many of the general properties of a biological membrane.
Humanoid robot avatars: An ‘in the wild’ usability study

In this paper, we report a breaching study to explore the use of a tele-operated humanoid avatar from both the perspective of the robot operator and the perspective of interlocutors. Humanoid robot avatars provide capabilities that video conferencing and mobile remote presence devices lack, particularly in multi-party conversations. Specifically, we were interested whether new users encountering a tele-operated humanoid avatar in a public setting would spontaneously use head movements and arm gestures to allow better conversational flow and group interaction. Video data shows that both operators and interlocutors initially explore the system's capabilities. Most operators used social gestures such as waving and pointing, as well as gaze which in turn led to related social responses from interlocutors. Interview data additionally show that robot operators and interlocutors rated the experience very positively. This paper discusses the implications of our findings for the design of `in the wild' experiments and the usability of tele-operated humanoid avatars.
Effects of pleiotropy on predictions concerning mutation-selection balance for polygenic traits.

Previous mathematical analyses of mutation-selection balance for metric traits assume that selection acts on the relevant loci only through the character(s) under study. Thus, they implicitly assume that all of the relevant mutation and selection parameters are estimable. A more realistic analysis must recognize that many of the pleiotropic effects of loci contributing variation to a given character are not known. To explore the consequences of these hidden effects, I analyze models of two pleiotropically connected polygenic traits, denoted P1 and P2. The actual equilibrium genetic variance for P1, based on complete knowledge of all mutation and selection parameters for both P1 and P2, can be compared to a prediction based solely on observations of P1. This extrapolation mimics empirically obtainable predictions because of the inevitability of unknown pleiotropic effects. The mutation parameters relevant to P1 are assumed to be known, but selection intensity is estimated from the within-generation reduction of phenotypic variance for P1. The extrapolated prediction is obtained by substituting these parameters into formulas based on single-character analyses. Approximate analytical and numerical results show that the level of agreement between these univariate extrapolations and the actual equilibrium variance depends critically on both the genetic model assumed and the relative magnitudes of the mutation and selection parameters. Unless per locus mutation rates are extremely high, i.e., generally greater than 10(-4), the widely used gaussian approximation for genetic effects at individual loci is not applicable. Nevertheless, the gaussian approximations predict that the true and extrapolated equilibria are in reasonable agreement, i.e., within a factor of two, over a wide range of parameter values. In contrast, an alternative approximation that applies for moderate and low per locus mutation rates predicts that the extrapolation will generally overestimate the true equilibrium variance unless there is little selection associated with hidden effects. The tendency to overestimate is understandable because selection acts on all of the pleiotropic manifestations of a new mutation, but equilibrium covariances among the characters affected may not reveal all of this selection. This casts doubt on the proposal that much of the additive polygenic variance observed in natural populations can be explained by mutation-selection balance. It also indicates the difficulty of critically evaluating this hypothesis.
Premorbid diet and the prognosis of women with breast cancer.

BACKGROUND Consumption of a high-fat diet has been associated with poor survival in breast cancer patients. However, studies examining this association are limited and have not used adjustment of energy in their estimates. PURPOSE The effect of usual diet before diagnosis of breast cancer on the risk of dying of breast cancer was examined in a cohort of women with breast cancer from the National Breast Screening Study (NBSS) in Canada. METHODS From a cohort of 89,835 women in the NBSS, a total of 1270 histologically confirmed cases of invasive carcinoma of the breast were identified by active follow-up, supplemented by passive follow-up involving record linkage to provincial cancer registries. Of these, 678 case patients who had completed a diet history and were diagnosed from January 1982 up to June 1992 formed the cohort for this investigation. Diet was ascertained from a self-administered diet-history questionnaire. Mortality data were obtained by linkage to the Canadian Mortality Data Base of Statistics Canada, provincial cancer registries, and annual follow-up of cases through physicians. Risk of dying and survival probabilities were estimated by the Cox proportional hazards method and the actuarial life-table method. RESULTS There were 83 deaths in this study cohort of 678 women; 76 deaths were due to breast cancer, and the remaining seven resulted from other causes. The 5-year survival rate was 90%. For every 5% increase in energy from saturated fat, the risk of dying of breast cancer increased by 50% (hazard ratio = 1.50; 95% confidence interval [CI]: 1.08-2.08). No significant increase in risk was seen with total fat intake (hazard ratio = 1.21; 95% CI = 0.91-1.61) or oleic acid intake (hazard ratio = 1.25; 95% CI = 0.90-1.74). There was a lower risk of dying of breast cancer in the highest quartiles of beta carotene intake (hazard ratio = 0.48; 95% CI = 0.23-0.99) and vitamin C intake (hazard ratio = 0.43; 95% CI: 0.21-0.86); both vitamins showed a significant dose-response relationship (P for trend, < or = .05). These effects varied with menopausal status at diagnosis and tumor characteristics. CONCLUSIONS These results suggest an increased risk of dying of breast cancer with higher intakes of saturated fat before diagnosis and slightly reduced risk with higher intakes of beta carotene and vitamin C. IMPLICATIONS More attention should be paid to premorbid dietary habits in relation to breast cancer prognosis. Further studies, however, need to be done with full ascertainment of dietary changes prior to and subsequent to diagnosis.