Miracle-dz/UniFAR-FTUs huggingface dataset:
NMR structure of the let-7 miRNA interacting with the site LCS1 of lin-41 mRNA from Caenorhabditis elegans

We have determined the 3D structure of a 34-nt RNA construct, herein named LCS1co, which mimics the interaction of let-7 microRNA (miRNA) to one of its complementary binding sites, LCS1, in the 3′-untranslated region of lin-41 mRNA by solution-state NMR spectroscopy. let-7 miRNAs control the timing of development of the nematode Caenorhabditis elegans and are highly conserved in mammals. The sequence and structure of the two conserved let-7 complementary sites, LCS1 and LCS2, in the 3′-untranslated region of lin-41 mRNA are important for a proper downregulation of lin-41. The high-resolution NMR structure reveals details of the binding of let-7 miRNA to lin-41 mRNA which involves formation of a complex with non-canonical structural elements within the seed region. LCS1co exhibits a stem-loop structure with two stems, an asymmetric internal loop and an adenine bulge. Comparison with the NMR solution-state structure of the let-7:lin-41 complex involving the LCS2-binding site shows that conformational freedom of the asymmetric internal loop of LCS1co correlates with a smaller bend between the upper and lower stems in comparison to the well-defined asymmetric loop of LCS2co.
Processing of the L1 52/55k Protein by the Adenovirus Protease: a New Substrate and New Insights into Virion Maturation

ABSTRACT Late in adenovirus assembly, the viral protease (AVP) becomes activated and cleaves multiple copies of three capsid and three core proteins. Proteolytic maturation is an absolute requirement to render the viral particle infectious. We show here that the L1 52/55k protein, which is present in empty capsids but not in mature virions and is required for genome packaging, is the seventh substrate for AVP. A new estimate on its copy number indicates that there are about 50 molecules of the L1 52/55k protein in the immature virus particle. Using a quasi-in vivo situation, i.e., the addition of recombinant AVP to mildly disrupted immature virus particles, we show that cleavage of L1 52/55k is DNA dependent, as is the cleavage of the other viral precursor proteins, and occurs at multiple sites, many not conforming to AVP consensus cleavage sites. Proteolytic processing of L1 52/55k disrupts its interactions with other capsid and core proteins, providing a mechanism for its removal during viral maturation. Our results support a model in which the role of L1 52/55k protein during assembly consists in tethering the viral core to the icosahedral shell and in which maturation proceeds simultaneously with packaging, before the viral particle is sealed.
Single- and Multiple-Dose Pharmacokinetics of Methylphenidate Administered as Methylphenidate Transdermal System or Osmotic-Release Oral System Methylphenidate to Children and Adolescents With Attention Deficit Hyperactivity Disorder

This was a 1-month, multicenter, open-label, randomized study to determine single- and multiple-dose pharmacokinetics of d,l-methylphenidate (MPH) after MPH transdermal system (MTS) and osmotic-release oral system MPH (OROS MPH) dosing in children (6-12 years) and adolescents (13-17 years) who had a diagnosis of attention deficit hyperactivity disorder. The pharmacokinetic population consisted of 33 children and 31 adolescents. Accumulation of d-MPH was 34% in children and 57% in adolescents after multiple fixed doses of MTS for 7 days and 76% and 94%, respectively, after 28 days of dosing. After 7 days of OROS MPH dosing, accumulation was 16% in children and 19% in adolescents; fixed doses of OROS MPH were not studied beyond 7 days. After escalating the doses to 30 mg per 9 hours for MTS, accumulation was 73% in children and 83% in adolescents after allowing for dose escalation. Corresponding values for OROS MPH after dose escalation to 54 mg were 33% in both age groups. Plasma l-MPH concentrations were approximately half those of d-MPH for MTS and negligible for OROS MPH. Overall, MTS accumulation was above that expected for single-dose pharmacokinetics of MTS and OROS MPH in both age groups. As a result of accumulation, systemic exposure to d-MPH in children after multiple escalating doses was 1.4- to 1.6-fold higher for MTS compared with OROS MPH, but similar in adolescents for both formulations. After all dosing, systemic exposure was greater in children compared with adolescents, consistent with lower body weight in children. Adverse events were mild to moderate for both formulations, and MTS dermal responses were mild.
Carane derivative stereoisomers of different local anaesthetic and antiplatelet activity similarly potentiate forskolin‐stimulated cyclic AMP response and bind to β‐adrenoceptors in the rat brain cortex

A carane derivative, KP‐23 [RS](–)‐4‐(2‐hydroxy‐3)N‐isopropylamino)‐propoxyimino)‐cis‐carane, was earlier described as a potential local anaesthetic and antiplatelet agent, and the following studies revealed that its R and S stereoisomers, KP‐23R and KP‐23S, have different potencies in the infiltration anaesthesia and platelet aggregation tests. The effects of these stereoisomers on the cyclic AMP (cAMP) generating system and the displacement of [3H]CGP 12177 (a β‐adrenoceptor ligand) from its binding sites in the rat cerebral cortical tissue were investigated. The stereoisomers did not affect the basal cAMP level, but, at concentrations between 10−4 and 10−3m, they elevated the forskolin‐induced accumulation of cAMP with similar potency. The compounds displaced [3H]CGP 12177, however the stereoisomer R was less potent than the racemic KP‐23 and the S form (Ki = 64.1 ± 5.9 nm, 161.1 ± 10 nm and 62.1 ± 5.6 nm for KP‐23, KP‐23R and KP‐23S, respectively). The fact that the stereoisomers differed in both tests only slightly, if at all, suggests that their pharmacological effects are not related to the action on the β‐adrenoceptor/adenylate cyclase system.
Habitat Selection by Greater Sage-Grouse During Winter in Southeastern Oregon

ABSTRACT. The distribution and geographic range of Greater Sage-Grouse (Centrocercus urophasianus) have been reduced by 56% since European settlement. Although loss and fragmentation of sagebrush (Artemisia spp.) habitats have been cited as the primary causes for the decline of the species, degradation of existing habitat also has been considered an important factor. Guidelines for protection and management of breeding and winter habitat have been developed for land managers, but winter habitat use has not been thoroughly described throughout the species' range, particularly for the western portion of its range in Oregon. We examined vegetation-type selection and use by Greater Sage-Grouse during winter (Nov–Feb) at 3 study areas in southeastern Oregon (1989–1992). Elevation gradients and vegetative communities differed among these 3 areas. Our objective was to examine the geographic variation in the selection and use of various vegetation types during winter, when sage-grouse distributions may be most restricted. We described differences in vegetation structure at the microhabitat scale among 3 areas and differences in vegetation-type selection at the macrohabitat scale. We found that the use of mixed sagebrush (basin big sagebrush [Artemisia tridentata tridentata]) and other shrubby vegetation types by sage-grouse was greater than expected at all 3 study areas. At the low- and high-elevation study areas, low sagebrush (Artemisia longiloba) vegetation types were selected more often than expected at random, which was contrary to our original hypotheses. Basin big sagebrush vegetation types were used in proportion to their availability at the 2 low-elevation study areas, and big sagebrush steppe was used less than available (avoided) at the low-elevation areas; these results were contrary to our original predictions. Such differences in selection among the study areas in southeastern Oregon create additional challenges for land managers, who are charged with managing habitats for sage-grouse use during autumn and winter in this portion of the species' geographic range.
A relative weights comparison of trauma‐related shame and guilt as predictors of DSM‐5 posttraumatic stress disorder symptom severity among US veterans and military members

OBJECTIVES Veterans and military service members have increased risk for post-traumatic stress disorder (PTSD) and consequent problems with health, psychosocial functioning, and quality of life. In this population and others, shame and guilt have emerged as contributors to PTSD, but there is a considerable need for research that precisely demonstrates how shame and guilt are associated with PTSD. This study examined whether a) trauma-related shame predicts PTSD severity beyond the effects of trauma-related guilt and b) shame accounts for a greater proportion of variance in PTSD symptoms than guilt. DESIGN We collected cross-sectional self-report data on measures of PTSD symptom severity based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, trauma-related shame, and trauma-related guilt via online survey. METHOD Participants included 61 US veterans and active duty service members. Hierarchical multiple regression and relative weights analysis were used to test hypotheses. RESULTS In step 1 of regression analysis, guilt was significantly associated with PTSD. However, when shame was added to the model, the effect of guilt became non-significant, and only shame significant predicted PTSD. Results from relative weights analysis indicated that both shame and guilt predicted PTSD, jointly accounting for 46% of the variance in PTSD. Compared to guilt, trauma-related shame accounted for significantly more explained variance in PTSD. CONCLUSIONS This study provided evidence that among US veterans and service members, trauma-related shame and guilt differ in their association with PTSD and that trauma-related shame, in particular, is associated with the severity of PTSD. PRACTITIONER POINTS Trauma-related shame and guilt explained almost half of the observed variance in PTSD symptom severity among this sample of US military veterans and service members. Trauma-related shame and guilt each made a unique contribution to PTSD severity after accounting for the similarity between these two emotions; however, shame was particularly associated with increased PTSD severity. These results highlight the importance of assessing and addressing trauma-related shame and guilt in PTSD treatment among military populations. We suggest that emotion- and compassion-focused techniques may be particularly relevant for addressing trauma-related shame and guilt. Limitations of the study Cross-sectional data does not allow for determination of causal relationships. Although sufficiently powered, the sample size is small. The present sample self-selected to participate in a study about stress and emotions.
A Distributed Decision Tree Algorithm and Its Implementation on Big Data Platforms

Decision tree algorithms are very popular in the field of data mining. This paper proposes a distributed decision tree algorithm and shows examples of its implementation on big data platforms. The major contribution of this paper is the novel KS-Tree algorithm which builds a decision tree in a distributed environment. KS-Tree is applied to some real world data mining problems and compared with state-of-the-art decision tree techniques that are implemented in R and Apache Spark. The results show that KS-Tree can achieve better results, especially with large data sets. Furthermore, we demonstrate that KS-Tree can be applied to various data mining tasks, such as variable selection.
Effects of ACL graft placement on in vivo knee function and cartilage thickness distributions

Injuries to the anterior cruciate ligament (ACL) frequently lead to early‐onset osteoarthritis. Despite advancement in surgical techniques, ACL reconstruction has a limited ability to prevent these degenerative changes. While previous studies have investigated knee function after ACL reconstruction, in vivo investigations of the effects of graft placement on in vivo joint function and cartilage health are limited. This review presents a series of studies that used novel imaging and 3D modeling techniques to determine the in vivo placement of the ACL graft on the femur using two different ACL reconstruction techniques. These techniques resulted in two distinct graft placement groups: one where the ACL was placed anatomically near the center of the native ACL footprint and another where the graft was placed anteroproximally on the femur, centered outside the ACL footprint. We quantified the effects of graft placement on graft deformation during in vivo loading and how these variables affected knee motion. Finally, we quantified whether femoral placement of the graft affected cartilage thickness. Our results demonstrate that achieving anatomic graft placement on the femur is critical to restoring native ACL function and normal knee kinematics. Knees with grafts that more closely restored normal ACL function, and thus knee motion, experienced less focal cartilage thinning than did those that experienced abnormal knee motion. These results suggest that achieving anatomic graft placement is a critical factor in restoring normal knee motion and potentially slowing the development of degenerative changes after ACL reconstruction. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1160–1170, 2017.
Brain-Derived Neurotrophic Factor Signaling Modulates Cocaine Induction of Reward-Associated Ultrasonic Vocalization in Rats

Cocaine exhibits high liability for inducing addictive behaviors, but the mechanisms of neuroplasticity underlying the behavioral effects remain unclear. As a crucial mediator of neuroplasticity in diverse functional models, brain-derived neurotrophic factor (BDNF) could contribute to the mechanisms of addiction-related neuroplasticity. Here, we addressed the hypothesis that cocaine increases synaptic dopamine, which induces BDNF protein expression to initiate addiction-related behavior in the rat. An enzyme-linked immunosorbent assay was used to measure BDNF protein expression in rat striatal tissues. For behavioral readout, we used a noninvasive measurement system to measure the emission of 50-kHz ultrasonic vocalization (USV), a response that correlates with electrical brain stimulation and conditioned place preference behavior in rodents. A single injection of cocaine significantly increased BDNF protein expression, but this effect was not further augmented by repeated cocaine administration. A single administration of cocaine elicited significant and dose-related USV responses, and the magnitude of the behavior increased with repeated drug administration. R-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390), but not raclopride, significantly attenuated cocaine-induced BDNF protein expression, whereas either the D1-like or D2-like receptor antagonist blocked cocaine-induced USV behavior. Furthermore, significant USV behavior was elicited by the nonselective dopamine agonist, apomorphine, but not by agonists that are selective for D1-like or D2-like receptors. Intracerebroventricular injection of the neurotrophin TrkB receptor inhibitor, K252a, blocked cocaine-induced USV behavior but not locomotor activity. These results suggest that neurotrophin signaling downstream of dopamine receptor function probably constitutes a crucial link in cocaine induction of USV behavior and may contribute to the mechanisms underlying the development of addiction-related behaviors.
Brain Injection of α-Synuclein Induces Multiple Proteinopathies, Gliosis, and a Neuronal Injury Marker

Intracerebral injection of amyloidogenic α-synuclein (αS) has been shown to induce αS pathology in the CNS of nontransgenic mice and αS transgenic mice, albeit with varying efficiencies. In this study, using wild-type human αS transgenic mice (line M20), we demonstrate that intracerebral injection of recombinant amyloidogenic or soluble αS induces extensive αS intracellular inclusion pathology that is associated with robust gliosis. Near the injection site, a significant portion of αS inclusions are detected in neurons but also in astrocytes and microglia. Aberrant induction of expression of the intermediate filament protein peripherin, which is associated with CNS neuronal injury, was also observed predominantly near the site of injection. In addition, many pSer129 αS-induced inclusions colocalize with the low-molecular-mass neurofilament subunit (NFL) or peripherin staining. αS inclusion pathology was also induced in brain regions distal from the injection site, predominantly in neurons. Unexpectedly, we also find prominent p62-immunoreactive, αS-, NFL-, and peripherin-negative inclusions. These findings provide evidence that exogenous αS challenge induces αS pathology but also results in the following: (1) a broader disruption of proteostasis; (2) glial activation; and (3) a marker of a neuronal injury response. Such data suggest that induction of αS pathology after exogenous seeding may involve multiple interdependent mechanisms.
Efficient optimization of hyper-parameters for least squares support vector regression

Support vector regression (SVR) comprises techniques for estimating functions based on a set of labelled training data vectors. The generalization performance of a regression function generated by an SVR method can highly depend on the choice of certain hyper-parameters like kernel parameters. A common approach to determine suitable values for the hyper-parameters is to use cross validation and a grid search method. In recent works the problem of optimizing the hyper-parameters has been modelled as bilevel optimization problem. For the case of least squares SVR we reformulate the bilevel problem into a single-level nonlinear programme with box constraints that only depends on the hyper-parameters. Moreover, we show how the objective function and its derivatives can be calculated efficiently so that fast standard methods for the optimization of a large number of hyper-parameters become applicable. Reliability and computational efficiency of the approach is demonstrated by means of several test problems.
Expression and Localization of Ryanodine Receptors in the Frog Semicircular Canal

Several experiments suggest an important role for store-released Ca2+ in hair cell organs: drugs targeting IP3 and ryanodine (RyRs) receptors affect release from hair cells, and stores are thought to be involved in vesicle recycling at ribbon synapses. In this work we investigated the semicircular canal distribution of RyRs by immunofluorescence, using slice preparations of the sensory epithelium (to distinguish cell types) and flat mounts of the simpler nonsensory regions. RyRs were present in hair cells, mostly in supranuclear spots, but not in supporting cells; as regards nonsensory regions, they were also localized in dark cells and cells from the ductus. No labeling was found in nerve terminals, although nerve branches could be observed in proximity to hair cell RyR spots. The differential expression of RyR isoforms was studied by RT-PCR and immunoblotting, showing the presence of RyRα in both ampulla and canal arm and RyRβ in the ampulla only.
Experimental separation of chaotic signals through synchronization

In this paper using a negative feedback scheme we study the problem of synchronizing two systems (each of them made of n independent chaotic circuits) through the transmission of a unique signal (i.e. a scalar variable). To find the appropriate values of the feedback gains, an approach based on the design of an asymptotic observer leading to a set of linear matrix inequalities is used for piecewise linear systems, while for systems with continuous nonlinearities a master stability function approach is adopted. Numerical results showing the suitability of the approach are reported. Furthermore, the experiment showing separation and synchronization of two pairs of chaotic circuits is discussed. Despite the presence of parameter mismatches, separation and synchronization of the two systems can be achieved. This is an experimental demonstration of the successful possibility of multiplexing two (or more) chaotic signals in the same channel.
Test and testability techniques for open defects in RAM address decoders

It is a prevalent assumption that all RAM address decoder defects can be modelled as RAM array faults influencing one or more RAM cells. Therefore, can be implicitly detected by testing the RAM matrix with the march tests. Recently, we came across some failures in embedded SRAMs which were not detected by the march tests. The carried out analysis demonstrated the presence of open defects in address decoders that cannot be modelled as the conventional coupling faults, therefore, are not detected by the march tests. In this article, we present the test and testability strategies for such hard-to-detect open defects.
LPS from Neisseria meningitidis is crucial for inducing monocyte- and microparticle-associated tissue factor activity but not for tissue factor expression

Neisseria meningitidis causes sepsis with coagulopathy. The present study evaluated the tissue factor (TF)-inducing capacity of bacterial LPS in different presentation forms, i.e. membrane-bound LPS versus purified LPS, and of non-LPS components of N. meningitidis. By using a wild-type N. meningitidis, a mutant N. meningitidis lacking LPS (LPS-deficient N. meningitidis), purified LPS from N. meningitidis and Escherichia coli, we measured TF-expression and TF-activity on human monocytes and microparticles (MPs). The effect of TF-modulators, such as phosphatidylserine (PS), tissue factor pathway inhibitor (TFPI) and recombinant IL-10 (rhIL-10) was investigated. In plasmas from meningococcal patients, fibrinopeptide A (FPA), LPS and IL-10 were quantified. Monocytes and MPs exposed to purified LPS or wild-type N. meningitidis had much higher TF-activity than monocytes and MPs exposed to LPS-deficient N. meningitidis (clot formation assay). Incubation with wild-type N. meningitidis, but also LPS-deficient N. meningitidis, resulted in TF-expression on monocytes (flow cytometry, qRT-PCR). Increased cellular TF-activity is associated with coincident surface-exposure of PS and the number of monocytes positive for both PS and TF was significantly higher for monocytes exposed to wild-type N. meningitidis (7.6%) compared with monocytes exposed to LPS-deficient N. meningitidis (1.8%). Treatment with rhIL-10 reduced monocyte- and MP-associated TF-activity, the number of monocytes positive for both TF and PS, and microvesiculation. Patients with meningococcal septicemia had significantly higher levels of LPS, FPA and IL-10 than patients with distinct meningitis. Our results indicate that LPS from N. meningitidis is crucial for inducing TF-activity, but not for monocyte- and MP-associated TF-expression. TF-activity seems to require coincident expression of TF and PS on monocytes, and LPS induces such double-positive monocytes.