Miracle-dz/UniFAR-FTUs huggingface dataset:
Unidirectional allostery in the regulatory subunit RIα facilitates efficient deactivation of protein kinase A

Significance Activation and deactivation of protein kinase A (PKA) are triggered by cAMP binding to and unbinding from two tandem domains of the regulatory subunit. Evidence indicates that both binding and unbinding of two cAMPs are ordered. Whereas sequential binding to the inactive holoenzyme complex can be attributed to masking of one binding site by the catalytic subunit, sequential unbinding from the regulatory subunit appears related to unidirectional allosteric communication between the two domains, although the mechanism for unidirectionality has been a mystery. Here, we present a solution through molecular dynamics simulations. One of the two cAMPs acts as a bridge between the domains and thereby gates interdomain communication. Directionality of allostery can facilitate PKA deactivation and may have broad functional importance. The holoenzyme complex of protein kinase A is in an inactive state; activation involves ordered cAMP binding to two tandem domains of the regulatory subunit and release of the catalytic subunit. Deactivation has been less studied, during which the two cAMPs unbind from the regulatory subunit to allow association of the catalytic subunit to reform the holoenzyme complex. Unbinding of the cAMPs appears ordered as indicated by a large difference in unbinding rates from the two sites, but the cause has remained elusive given the structural similarity of the two tandem domains. Even more intriguingly, NMR data show that allosteric communication between the two domains is unidirectional. Here, we present a mechanism for the unidirectionality, developed from extensive molecular dynamics simulations of the tandem domains in different cAMP-bound forms. Disparate responses to cAMP releases from the two sites (A and B) in conformational flexibility and chemical shift perturbation confirmed unidirectional allosteric communication. Community analysis revealed that the A-site cAMP, by forming across-domain interactions, bridges an essential pathway for interdomain communication. The pathway is impaired when this cAMP is removed but remains intact when only the B-site cAMP is removed. Specifically, removal of the A-site cAMP leads to the separation of the two domains, creating room for binding the catalytic subunit. Moreover, the A-site cAMP, by maintaining interdomain coupling, retards the unbinding of the B-site cAMP and stalls an unproductive pathway of cAMP release. Our work expands the perspective on allostery and implicates functional importance for the directionality of allostery.
Exploring the Mechanisms of Self-Control Improvement

Good self-control is central to success across life domains, from school to work to relationships. In this article, we provide a framework to better understand how self-control can be improved. Using cybernetic principles, we identify and integrate important mechanisms for self-control improvement that have previously been overlooked. The cybernetic model suggests that control relies on three separate processes: setting goals, monitoring when behavior diverges from goals, and implementing behavior aligned with goals. Within each of these stages, we incorporate recent research identifying key features of good self-control, including setting the “right kind” of goals; the role of conflict detection, attention, and emotional acceptance in goal monitoring; and the effects of fatigue, shifting priorities, and intentions on implementing behavioral changes. Self-control is not easy, but by revealing it as reliant on these diverse processes, we offer a more comprehensive perspective on self-control, as well as routes through which it can be improved.
Biogenesis of phased siRNAs on membrane-bound polysomes in Arabidopsis

Small RNAs are central players in RNA silencing, yet their cytoplasmic compartmentalization and the effects it may have on their activities have not been studied at the genomic scale. Here we report that Arabidopsis microRNAs (miRNAs) and small interfering RNAs (siRNAs) are distinctly partitioned between the endoplasmic reticulum (ER) and cytosol. All miRNAs are associated with membrane-bound polysomes (MBPs) as opposed to polysomes in general. The MBP association is functionally linked to a deeply conserved and tightly regulated activity of miRNAs – production of phased siRNAs (phasiRNAs) from select target RNAs. The phasiRNA precursor RNAs, thought to be noncoding, are on MBPs and are occupied by ribosomes in a manner that supports miRNA-triggered phasiRNA production, suggesting that ribosomes on the rough ER impact siRNA biogenesis. This study reveals global patterns of cytoplasmic partitioning of small RNAs and expands the known functions of ribosomes and ER. DOI: http://dx.doi. org/10.7554/eLife.22750. 001
Smart Hydrogels for Pharmaceutical Applications

The latest development in the field of smart hydrogels application as drugs carriers is shown in this chapter. Hydrogels are three-dimensional polymer network consisting of at least one hydrophilic monomer. They are insoluble in water, but in the excess presence of water or physiological fluids, swell to the equilibrium state. The amount of absorbed water depends on the chemical composition and the crosslinking degree of 3D hydrogel network and reaches over 1000% of the xerogel weight. Stimuli-responsive hydrogels exhibit significant change of their properties (swelling, color, transparency, conductivity, shape) due to small changes in the external environment conditions (pH, ionic strength, temperature, light wavelength, magnetic or electric fields, ultrasound, or a combination thereof). This smart hydrogels, with different physical and chemical properties, chemical structure and technology of obtaining, show great potential for application in the pharmaceutical industry. The application of smart hydrogels is very promising and at the beginning of the development and exploitation.
Metabolic syndrome, haemostasis and thrombosis

Summary The metabolic syndrome (metS), a concurrence of abdominal fat, disturbed glucose and insulin metabolism, dyslipidemia, and hypertension has been strongly associated not only with subsequent development of type 2 diabetes but also with athero-thrombosis. The physiopathology of this association is complex. The metS affects the thrombogenicity of circulating blood. Apart from its effect on platelets, a procoagulant and hypofibrinolytic state has been identified; mainly the result of the inflammatory state, dyslipidemia, and liver fat accumulation that accompany the MetS. Among haemostasis disturbances, the strong rise in the inhibitor of plasminogen activator type 1 plasma level is the most documented abnormality implicating the participation of the oxidative stress and inflammatory state developed during the metS. Endothelial dysfunction is also a central feature. Moreover, secretion products of fat tissues (adipokines) are now thought to have direct modulating effects on the vascular and the circulating cells. In support of these data, the metS, may predispose not only to atherosclerosis but also to venous thrombosis.
Collateral blood flow in different cerebrovascular hierarchy provides endogenous protection in cerebral ischemia

Collateral blood flow as vascular adaptions to focal cerebral ischemia is well recognized. However, few studies directly investigate the dynamics of collateral vessel recruitment in vivo and little is known about the effect of collateral blood flow in different cerebrovascular hierarchy on the neuropathology after focal ischemic stroke. Here, we report that collateral blood flow is critically involved in blood vessel compensations following regional ischemia. We occluded a pial arteriole using femtosecond laser ablating under the intact thinned skull and documented the changes of collateral flow around the surface communication network and between the surface communication network and subsurface microcirculation network using in vivo two photon microscopy imaging. Occlusion of the pial arteriole apparently increased the diameter and collateral blood flow of its leptomeningeal anastomoses, which significantly reduced the cortical infarction size. This result suggests that the collateral flow via surface communicating network connected with leptomeningeal anastomoses could greatly impact on the extent of infarction. We then further occluded the target pial arteriole and all of its leptomeningeal anastomoses. Notably, this type of occlusion led to reversals of blood flow in the penetrating arterioles mainly proximal to the occluded pial arteriole in a direction from the subsurface microcirculation network to surface arterioles. Interesting, the cell death in the area of ischemic penumbra was accelerated when we performed occlusion to cease the reversed blood flow in those penetrating arterioles, suggesting that the collateral blood flow from subsurface microcirculation network exerts protective roles in delaying cell death in the ischemic penumbra. In conclusion, we provide the first experimental evidence that collateral blood vessels at different cerebrovascular hierarchy are endogenously compensatory mechanisms in brain ischemia.
The Accuracy of Hospital Discharge Diagnosis Codes for Major Birth Defects: Evaluation of a Statewide Registry With Passive Case Ascertainment.

CONTEXT Birth defects prevention, research, education, and support activities can be improved through surveillance systems that collect high-quality data. OBJECTIVE To estimate the overall and defect-specific accuracy of Florida Birth Defects Registry (FBDR) data, describe reasons for false-positive diagnoses, and evaluate the impact of statewide case confirmation on frequencies and prevalence estimates. DESIGN Retrospective cohort evaluation study. PARTICIPANTS A total of 8479 infants born to Florida resident mothers between January 1, 2007, and December 31, 2011, and diagnosed with 1 of 13 major birth defects in the first year of life. MAIN OUTCOME MEASURES Positive predictive value: calculated overall (proportion of FBDR-identified cases confirmed by medical record review, regardless of which of the 13 defects were confirmed) and defect-specific (proportion of FBDR-identified cases confirmed by medical record review with the same defect) indices. RESULTS The FBDR's overall positive predictive value was 93.3% (95% confidence interval, 92.7-93.8); however, there was variation in accuracy across defects, with positive predictive values ranging from 96.0% for gastroschisis to 54.4% for reduction deformities of the lower limb. Analyses suggested that International Classification of Diseases, Ninth Edition, Clinical Modification, codes, upon which FBDR diagnoses are based, capture the general occurrence of a defect well but often fail to identify the specific defect with high accuracy. Most infants with false-positive diagnoses had some type of birth defect that was incorrectly documented or coded. If prevalence rates reported by the FBDR for these 13 defects were adjusted to incorporate statewide case confirmation, there would be an overall 6.2% rate reduction from 82.6 to 77.5 per 10 000 live births. CONCLUSIONS A statewide birth defects surveillance system, relying on linkage of administrative databases, is capable of achieving high accuracy (>93%) for identifying infants with any one of the 13 major defects included in this study. However, the level of accuracy and the ability to minimize false-positive diagnoses vary depending on the defect.
MARINE WHOLE SEDIMENT TOXICITY TESTS FOR USE IN TEMPERATE AND TROPICAL AUSTRALIAN ENVIRONMENTS : CURRENT STATUS

Sediments have long been recognised as a source of contaminants in marine environments and, as a result, interim sediment quality guidelines were included in the ANZECC/ARMCANZ (2000) water quality guidelines. While toxicity tests with benthic temperate species have been developed and incorporated into marine sediment toxicity assessments over the past 10 years, there has been limited test development with benthic tropical species. This paper reviews the current status of whole sediment toxicity tests in Australia for tropical and temperate marine ecosystems and highlights (i) the lack of whole sediment toxicity tests available for generating sediment toxicity data for tropical ecosystems, (ii) the lack of chronic whole sediment tests and sensitivity data for temperate or tropical benthic species, and (iii) important factors to consider when selecting relevant tropical test species for toxicity test development. Further development of whole sediment tests should focus on ecologically relevant species, chronic endpoints and the use of appropriate sediment spiking procedures to determine test sensitivity to contaminants. These tests will provide an additional line of evidence for use in sediment assessments and enable the derivation of improved cause-effect based sediment quality guidelines for both tropical and temperate ecosystems.
Habitat Association and Seasonality in a Mosaic and Bimodal Hybrid Zone between Chorthippus brunneus and C. jacobsi (Orthoptera: Acrididae)

Understanding why some hybrid zones are bimodal and others unimodal can aid in identifying barriers to gene exchange following secondary contact. The hybrid zone between the grasshoppers Chorthippus brunneus and C. jacobsi contains a mix of allopatric parental populations and inter-mingled bimodal and unimodal sympatric populations, and provides an ideal system to examine the roles of local selection and gene flow between populations in maintaining bimodality. However, it is first necessary to confirm, over a larger spatial scale, previously identified associations between population composition and season and habitat. Here we use cline-fitting of one morphological and one song trait along two valley transects, and intervening mountains, to confirm previously identified habitat associations (mountain versus valley) and seasonal changes in population composition. As expected from previous findings of studies on a smaller spatial scale, C. jacobsi dominated mountain habitats and mixed populations dominated valleys, and C. brunneus became more prevalent in August. Controlling for habitat and incorporating into the analysis seasonal changes in cline parameters and the standard errors of parental trait values revealed wider clines than previous studies (best estimates of 6.4 to 24.5 km in our study versus 2.8 to 4.7 km in previous studies) and increased percentage of trait variance explained (52.7% and 61.5% for transects 1 and 2 respectively, versus 17.6%). Revealing such strong and consistent patterns within a complex hybrid zone will allow more focused examination of the causes of variation in bimodality in mixed populations, in particular the roles of local selection versus habitat heterogeneity and gene flow between differentiated populations.
Towards time-of-flight PET with a semiconductor detector

The feasibility of using Cerenkov light, generated by energetic electrons following 511 keV photon interactions in the semiconductor TlBr, to obtain fast timing information for positron emission tomography (PET) was evaluated. Due to its high refractive index, TlBr is a relatively good Cerenkov radiator and with its wide bandgap, has good optical transparency across most of the visible spectrum. Coupling an SiPM photodetector to a slab of TlBr (TlBr-SiPM) yielded a coincidence timing resolution of 620 ps FWHM between the TlBr-SiPM detector and a LFS reference detector. This value improved to 430 ps FWHM by applying a high pulse amplitude cut based on the TlBr-SiPM and reference detector signal amplitudes. These results are the best ever achieved with a semiconductor PET detector and already approach the performance required for time-of-flight. As TlBr has higher stopping power and better energy resolution than the conventional scintillation detectors currently used in PET scanners, a hybrid TlBr-SiPM detector with fast timing capability becomes an interesting option for further development.
A set-theoretic model reference adaptive control architecture for disturbance rejection and uncertainty suppression with strict performance guarantees

ABSTRACT Research in adaptive control algorithms for safety-critical applications is primarily motivated by the fact that these algorithms have the capability to suppress the effects of adverse conditions resulting from exogenous disturbances, imperfect dynamical system modelling, degraded modes of operation, and changes in system dynamics. Although government and industry agree on the potential of these algorithms in providing safety and reducing vehicle development costs, a major issue is the inability to achieve a-priori, user-defined performance guarantees with adaptive control algorithms. In this paper, a new model reference adaptive control architecture for uncertain dynamical systems is presented to address disturbance rejection and uncertainty suppression. The proposed framework is predicated on a set-theoretic adaptive controller construction using generalised restricted potential functions.The key feature of this framework allows the system error bound between the state of an uncertain dynamical system and the state of a reference model, which captures a desired closed-loop system performance, to be less than a-priori, user-defined worst-case performance bound, and hence, it has the capability to enforce strict performance guarantees. Examples are provided to demonstrate the efficacy of the proposed set-theoretic model reference adaptive control architecture.
Smart Conformists: Children and Adolescents Associate Conformity With Intelligence Across Cultures.

The current study used a novel methodology based on multivocal ethnography to assess the relations between conformity and evaluations of intelligence and good behavior among Western (U.S.) and non-Western (Ni-Vanuatu) children (6- to 11-year-olds) and adolescents (13- to 17-year-olds; N = 256). Previous research has shown that U.S. adults were less likely to endorse high-conformity children as intelligent than Ni-Vanuatu adults. The current data demonstrate that in contrast to prior studies documenting cultural differences between adults' evaluations of conformity, children and adolescents in the United States and Vanuatu have a conformity bias when evaluating peers' intelligence and behavior. Conformity bias for good behavior increases with age. The results have implications for understanding the interplay of conformity bias and trait psychology across cultures and development.
International Journal of Biological & Medical Research Histopathological Spectrum of Endometrium in Dysfuctional Uterine Bleeding a B a a C Original Article

Dysfunctional Uterine Bleeding (DUB) is one of the most common and significant gynaecological complaints seen in about 10-15% of women attending a gynaecological clinic. DUB is excessive abnormal bleeding from the endometrium that is unrelated to any anatomic lesions of the genital tract. The largest incidence of DUB is in the women of the childbearing age group and menorrhagia was more common in that age group. The objective was to study histopathological patterns of endometrium in DUB and clinicopathological correlation. Total 190 cases diagnosed as DUB are included. The commonest age group was 31-40 years (45.26%) and is seen most commonly in the multiparous women (71.58%). Menorrhagia was the commonest bleeding pattern found in 139 (73.16%) cases. Histopathologically commonest endometrial pattern associated with DUB is endometrial hyperplasia seen in 76 (46%) cases followed by proliferative endometrium in 42 (22.10%) cases. No age was exempted from DUB. Menorrhagia was the commonest bleeding pattern.
Ischemia reduces inter‐alpha inhibitor proteins in the brain of the ovine fetus

Hypoxic‐ischemic (HI) brain injury is a major cause of neurological abnormalities in the perinatal period. Inflammation contributes to the evolution of HI brain injury. Inter‐alpha inhibitor proteins (IAIPs) are a family of proteins that are part of the innate immune system. We have reported that endogenous IAIPs exhibit developmental changes in ovine brain and that exogenous IAIP treatment reduces neuronal death in HI neonatal rats. However, the effects of HI on endogenous IAIPs in brain have not been previously examined. In this study, we examined the effects of ischemia‐reperfusion on endogenous IAIPs levels in fetal sheep brain. Cerebral cortex, cerebellum, cervical spinal cord, choroid plexus, and CSF were snap frozen from sham control fetuses at 127 days gestation and after 30‐min of carotid occlusion and 4‐, 24‐, and 48‐h of reperfusion. IAIP levels were determined by Western immunoblot. IAIP expressions of the 250 kDa Inter‐alpha inhibitor (IaI) and 125 kDa Pre‐alpha inhibitor (PaI) in cerebral cortex and PaI in cerebellum were reduced (p < 0.05) 4‐h after ischemia compared with controls and returned toward control levels 24‐ and 48‐h after ischemia. CSF PaI and IaI were reduced 48 h after ischemia. We conclude that IAIPs in cerebral cortex and cerebellum are reduced by brain ischemia, and return toward control levels between 24 and 48 h after ischemia. However, changes in CSF IAIPs were delayed, exhibiting decreases 48 h after ischemia. We speculate that the decreases in endogenous IAIPs reflect increased utilization, potentially suggesting that they have endogenous neuroprotective properties. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 726–737, 2017
Directed natural forces of affinity between a bacterium and mineral

The formation of a bond between a bacterium and a mineral is ultimately controlled by forces that operate over length scales of a few nanometers. This manuscript presents evidence that bacteria may actively modulate forces at the cell-mineral interface to promote contact with specific mineral phases. Nano- to pico-Newton forces were measured between goethite (FeOOH) and each of two species of Gram negative bacteria (Escherichia coli and Shewanella oneidensis )i n aqueous solution of varying oxygen concentration. The interactions were dominated by electrostatic and steric forces as either bacterium approached to within 10 to 12 nm of the surface of goethite. The van der Waals force exhibited an influence on each bacterium-mineral pair at separations of 2 nm. These types of nonspecific forces were all that were observed for the E. coli-goethite pair. However, S. oneidensis exhibited a selective disposition to form a specific bond with goethite, particularly under anaerobic conditions. These data suggest that S. oneidensis is able to perceive and recognize the surface of metal oxyhydroxides and regulate attractive forces at the cell-oxide interface. This may be a vestige of the close evolutionary linkage between iron oxyhydroxides and metal-reducing bacteria like Shewanella, which can use Fe(III) in the crystal structure of a mineral as a terminal electron acceptor.