Miracle-dz/UniFAR-FTUs huggingface dataset:
Target-induced conformational adaptation of calmodulin revealed by the crystal structure of a complex with nematode Ca(2+)/calmodulin-dependent kinase kinase peptide.

Calmodulin (CaM) is a ubiquitous calcium (Ca(2+)) sensor which binds and regulates protein serine/threonine kinases along with many other proteins in a Ca(2+)-dependent manner. For this multi-functionality, conformational plasticity is essential; however, the nature and magnitude of CaM's plasticity still remains largely undetermined. Here, we present the 1.8 A resolution crystal structure of Ca(2+)/CaM, complexed with the 27-residue synthetic peptide corresponding to the CaM-binding domain of the nematode Caenorhabditis elegans Ca(2+)/CaM-dependent kinase kinase (CaMKK). The peptide bound in this crystal structure is a homologue of the previously NMR-derived complex with rat CaMKK, but benefits from improved structural resolution. Careful comparison of the present structure to previous crystal structures of CaM complexed with unrelated peptides derived from myosin light chain kinase and CaM kinase II, allow a quantitative analysis of the differences in the relative orientation of the N and C-terminal domains of CaM, defined as a screw axis rotation angle ranging from 156 degrees to 196 degrees. The principal differences in CaM interaction with various peptides are associated with the N-terminal domain of CaM. Unlike the C-terminal domain, which remains unchanged internally, the N-terminal domain of CaM displays significant differences in the EF-hand helix orientation between this and other CaM structures. Three hydrogen bonds between CaM and the peptide (E87-R336, E87-T339 and K75-T339) along with two salt bridges (E11-R349 and E114-K334) are the most probable determinants for the binding direction of the CaMKK peptide to CaM.
The FAMACHA system for managing haemonchosis in sheep and goats by clinically identifying individual animals for treatment.

Escalating anthelmintic resistance has made it essential to develop alternative ways of worm management for reducing selection for worm resistance, and one of the most promising approaches is to treat only those animals unable to cope with worm challenge, thus favouring unselected worms originating from untreated animals. Only clinical evaluation of anaemia (FAMACHA system) and the body condition score are regarded as being of practical value or having potential, respectively, for repeatedly examining flocks or herds and identifying individuals for treatment. Only the FAMACHA system has been tested well enough for use under practical farming conditions. However, further investigation is needed on its effect on animal production, and methods to reduce labour. Trials over several seasons showed that most sheep under severe Haemonchus contortus challenge required no, or only one treatment over a full summer season. A small minority (usually < 5%) needed more than two treatments. Most sheep could cope without regular treatment. With sufficient training, clinical evaluation of anaemia was found reliable for practical use. The overwhelming majority of trainees (some poorly literate) were able to implement the FAMACHA system successfully. The dynamics of haemonchosis in a flock can easily be monitored. Farmers, farm workers and veterinarians all rated the system very highly (> 80%) and treatment costs dropped by approximately 58%. The heritability of FAMACHA values obtained by clinical evaluation was high at 0.55 +/- 0.17% in a Merino stud with +/- 550 young rams and ewes which were the progeny of 21 sires. The FAMACHA system may not be as applicable to goats as to sheep, but further work is necessary. The main benefits of the system are the reduction in treatments, its use for discriminating between animals of varying ability to cope with infection (thus allowing genetic selection), and its lowering of selection pressure on H. contortus for anthelmintic resistance.
Ethosome for Enhanced Transdermal Drug Delivery of Aceclofenac

The aim of the current investigation is to evaluate the transdermal potential of novel vesicular carrier, ethosomes, bearing aceclofenac, Non-steroidal anti-inflammatory drugs (NSAIDs) agents having limited transdermal permeation. Aceclofenac loaded ethosomal carriers were prepared, optimized and characterized for vesicular shape and surface morphology,(SEM) scanning electronic microscopy, vesicular size, entrapment efficiency, stability, in- vitro release study. The formulation (Etho5) having 3% phospholipids contant and 40% ethanol showing the grater entrapment (93.3%) and optimal average vesicle size of formulation (Etho5) determine by Malvern Zetamaster ZEM & 0. 696μm and zeta potential of formulation was -6.74 mV. The formulation (Etho12) having 3% phospholipids contant and 40% isopropyl alcohol showing the grater entrapment (95.7%). stability profile of prepared system assessed for 45 days. The vesicular suspension was kept in sealed vials (10ml) at 4 ± 2oC and at room temperature for 45 days no change is shown in the entrapment efficiency. The optimized ethosomal formulation showed transdermal flux (226.1 μg/cm²/hr) for ethanolic drug solution which is grater then that of isopropyl alcohol solution (159.0 μg/cm²/hr). The result advocates the potential of ethosome formulation to treat rheumatic disease where facilitated penetration of the drug into muscle and synovial fluid is desirable. In light of the data obtained from experimental work we can expect the ethosome formulation to be safe and very efficient as a drug carrier for systemic as well as topical delivery of drug, holding future in effective transdermal delivery. Keywords: Ethosome; Aceclofenac; Phospholipid; Transdermal
The Pressure Distribution in Thermally Bistable Turbulent Flows

We present a systematic numerical study of the effect of turbulent velocity fluctuations on the thermal pressure distribution in thermally bistable flows. The turbulent fluctuations are characterized by their rms Mach number M (with respect to the warm medium) and the energy injection (forcing) wavenumber kfor = 1/l, where l is the injection size scale in units of the box size L = 100 pc. The numerical simulations employ random turbulent driving generated in Fourier space rather than starlike heating, in order to allow for precise control of the parameters. Our range of parameters is 0.5 ≤ M ≤ 1.25 and 2 ≤ kfor ≤ 16. Our results are consistent with the picture that as either of these parameters is increased, the local ratio of turbulent crossing time to cooling time decreases, causing transient structures in which the effective behavior is intermediate between the thermal-equilibrium and adiabatic regimes. As a result, the effective polytropic exponent γe of the simulations ranges between ~0.2 and ~1.1, and the mean pressure of the diffuse gas is generally reduced below the thermal equilibrium pressure Peq, while that of the dense gas is increased with respect to Peq. The fraction of high-density zones (n > 7.1 cm-3) with P > 104 cm-3 K increases from roughly 0.1% at kfor = 2 and M = 0.5 to roughly 70% for kfor = 16 and M = 1.25. A preliminary comparison with the recent pressure measurements of Jenkins in C I favors our case with M = 0.5 and kfor = 2. In all cases, the dynamic range of the pressure in any given density interval is larger than one order of magnitude, and the total dynamic range, summed over the entire density range, typically spans 3-4 orders of magnitude. The total pressure histogram widens as the Mach number is increased, and moreover develops near-power-law tails at high (low) pressures when γe ≲ 0.5 (γe ≳ 1), which occurs at kfor = 2 (kfor = 16) in our simulations. The opposite side of the pressure histogram decays rapidly, in an approximately lognormal form. This behavior resembles that of the corresponding density histograms, in spite of the large scatter of the pressure in any given density interval. Our results show that turbulent advection alone can generate large pressure scatters, with power-law high-P tails for large-scale driving, and provide validation for approaches attempting to derive the shape of the pressure histogram through a change of variable from the known form of the density histogram, such as that performed by Mac Low et al.
Regulation of pulmonary vascular tone in the perinatal period.

In the fetus, gas exchange occurs in the placenta and not in the lung. Conse­ quently, pulmonary vascular resistance is high, pulmonary blood flow is low (about 35 ml/minlkg fetal body wt in near-term fetal lambs), and right ven­ tricular output is thereby directed through the ductus arteriosus toward the placenta for gas exchange. At the time of birth and the onset of ventilation, pulmonary vascular resistance falls, and pulmonary blood flow rapidly in­ creases approximately tenfold (31). Failure of the pulmonary circulation to undergo this transition at birth results in persistent pulmonary hypertension of the newborn (PPHN), a condition that can result in significant morbidity and mortality. Many factors regulate pulmonary blood flow in this critical perinatal period: These include mechanical influences and the release of a variety of vasoactive substances. Recent evidence suggests that vasoactive mediators produced-and released by the pulmonary vascular endothelium, either locally or into the circulation (paracrine or endocrine function), are central to many of these phenomena. This review discusses current knowledge dealing with the regulation of blood flow in the normal fetal, transitional, and postnatal pulmonary circulations, and possible aberrations in these regulatory mecha­ nisms associated with PPHN. We place particular emphasis on newer infor­ mation relating to the role of the pulmonary vascular endothelium in regulation
The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor

In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as ‘designer drugs’ and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.
Beckwith-Wiedemann syndrome and assisted reproduction technology (ART)

Beckwith-Wiedemann syndrome (BWS) is a model imprinting disorder resulting from mutations or epimutations affecting imprinted genes on chromosome 11p15.5. 1 The classical clinical features of BWS are macroglossia, pre- and/or postnatal overgrowth, and anterior abdominal wall defects (umbilical hernia or exomphalos). Additional more variable features include hemihypertrophy, neonatal hypoglycaemia, facial naevus flammeus, ear pits and creases, renal anomalies, and an increased risk of embryonal tumours.2 Most cases of BWS are sporadic and ∼20% of these have uniparental disomy (paternal isodisomy) for a variable region of chromosome 11 which always includes the 11p15.5 imprinted gene cluster.3–5 Up to 60% of sporadic BWS patients have epigenetic changes at differentially methylated regions within 11p15.5 that are associated with alterations in the imprinting or expression of paternally expressed genes, such as IGF2 and KCNQ1OT , or maternally expressed genes, such as H19 and CDKN1C . 1 Thus, 5–10% have epigenetic alterations at the IGF2 / H19 loci (the maternal H19 and IGF2 alleles display paternal allele methylation and expression patterns with biallelic IGF2 expression and silencing of H19 expression),6 and 40–50% have loss of maternal allele methylation at a differentially methylated region (KvDMR1) within an intron of KCNQ1 . KvDMR1 loss of methylation is associated with biallelic expression of KCNQ1OT . 7–9 The epigenetic alterations at H19 / IGF2 or KvDMR1 are thought to result from defects at two putative imprinting control centres (BWSIC1 and BWSIC2, respectively). 1 The precise nature of the putative BWSIC2 is unknown and therefore the origin of these putative BWSIC2 defects is unknown. Weksberg et al 10 showed a clear association between monozygotic twinning and BWS with KvDMR1 loss of methylation and suggested two possible explanations: (1) that discordance for BWS in monozygotic twins is caused by unequal splitting of the inner cell mass …
The feasibility of eyes-free touchscreen keyboard typing

Typing on a touchscreen keyboard is very difficult without being able to see the keyboard. We propose a new approach in which users imagine a Qwerty keyboard somewhere on the device and tap out an entire sentence without any visual reference to the keyboard and without intermediate feedback about the letters or words typed. To demonstrate the feasibility of our approach, we developed an algorithm that decodes blind touchscreen typing with a character error rate of 18.5%. Our decoder currently uses three components: a model of the keyboard topology and tap variability, a point transformation algorithm, and a long-span statistical language model. Our initial results demonstrate that our proposed method provides fast entry rates and promising error rates. On one-third of the sentences, novices' highly noisy input was successfully decoded with no errors.
PLANETS AROUND LOW-MASS STARS (PALMS). V. AGE-DATING LOW-MASS COMPANIONS TO MEMBERS AND INTERLOPERS OF YOUNG MOVING GROUPS

We present optical and near-infrared adaptive optics (AO) imaging and spectroscopy of 13 ultracool (>M6) companions to late-type stars (K7–M4.5), most of which have recently been identified as candidate members of nearby young moving groups (YMGs; 8–120 Myr) in the literature. Three of these are new companions identified in our AO imaging survey, and two others are confirmed to be comoving with their host stars for the first time. The inferred masses of the companions (∼10–100 MJup) are highly sensitive to the ages of the primary stars; therefore we critically examine the kinematic and spectroscopic properties of each system to distinguish bona fide YMG members from old field interlopers. The new M7 substellar companion 2MASS J02155892–0929121 C (40–60 MJup) shows clear spectroscopic signs of low gravity and, hence, youth. The primary, possibly a member of the ∼40 Myr Tuc-Hor moving group, is visually resolved into three components, making it a young low-mass quadruple system in a compact (≲100 AU) configuration. In addition, Li i λ6708 absorption in the intermediate-gravity M7.5 companion 2MASS J15594729+4403595 B provides unambiguous evidence that it is young (≲200 Myr) and resides below the hydrogen-burning limit. Three new close-separation (<1″) companions (2MASS J06475229–2523304 B, PYC J11519+0731 B, and GJ 4378 Ab) orbit stars previously reported as candidate YMG members, but instead are likely old (≳1 Gyr) tidally locked spectroscopic binaries without convincing kinematic associations with any known moving group. The high rate of false positives in the form of old active stars with YMG-like kinematics underscores the importance of radial velocity and parallax measurements to validate candidate young stars identified via proper motion and activity selection alone. Finally, we spectroscopically confirm the cool temperature and substellar nature of HD 23514 B, a recently discovered M8 benchmark brown dwarf orbiting the dustiest-known member of the Pleiades.
Spatial Distribution of Cerebral White Matter Lesions Predicts Progression to Mild Cognitive Impairment and Dementia

Context White matter lesions (WML) increase the risk of dementia. The relevance of WML location is less clear. We sought to determine whether a particular WML profile, based on the density and location of lesions, could be associated with an increased risk of mild cognitive impairment (MCI) or dementia over the following 7 years. Methods In 426 healthy subjects from a cohort of community-dwelling people aged 65 years and over (ESPRIT Project), standardized cognitive and neurological evaluations were repeated after 2, 4 and 7 years. Patterns of WML were computed with a supervised data mining approach (decision trees) using the regional WML volumes (frontal, parietal, temporal, and occipital regions) and the total WML volume estimated at baseline. Cox proportional hazard models were then constructed to study the association between WML patterns and risk of MCI/dementia. Results Total WML volume and percentage of WML in the temporal region proved to be the best predictors of progression to MCI and dementia. Specifically, severe total WML load with a high proportion of lesions in the temporal region was significantly associated with the risk of developing MCI or dementia. Conclusions Above a certain threshold of damage, a pattern of WML clustering in the temporal region identifies individuals at increased risk of MCI or dementia. As this WML pattern is observed before the onset of clinical symptoms, it may facilitate the detection of patients at risk of MCI/dementia.
Obesity in total hip arthroplasty: DOES IT MAKE A DIFFERENCE?

Aims The purpose of our study is to summarise the current scientific findings regarding the impact of obesity on total hip arthroplasty (THA); specifically the influence of obesity on the timing of THA, incidence of complications, and effect on clinical and functional outcomes. Materials and Methods We performed a systematic review that was compliant with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines to identify prospective studies from the PubMed/Medline, Embase, and Cochrane Library databases that evaluated primary THA in obese (body mass index (BMI) ≤ 30 kg/m2) patients. Results There were 17 articles included in the review, which encompassed 13 722 THA patients. Analysis of the included studies showed that, when compared with non‐obese patients, obesity was associated with younger age at time of primary THA, and an increased incidence of complications (up to four‐fold). Results were mixed on the influence of obesity on the outcomes of primary THA, with three studies showing a detrimental effect on outcomes of a BMI ≥30 kg/m2, while eight studies showed no effect. Conclusion Obesity is associated with significantly younger age at time of primary THA and obese patients are likely to experience a higher rate of peri‐operative complications. More investigation is needed into the effect of obesity on clinical outcomes, as the current literature is mixed.
Fibroblast Growth Factor Signaling Pathway in Endothelial Cells Is Activated by BMPER to Promote Angiogenesis

Objective—Previously, we have identified bone morphogenetic protein endothelial cell precursor–derived regulator (BMPER) to increase the angiogenic activity of endothelial cells in a concentration-dependent manner. In this project, we now investigate how BMPER acts in concert with key molecules of angiogenesis to promote blood vessel formation. Approach and Results—To assess the effect of BMPER on angiogenesis-related signaling pathways, we performed an angiogenesis antibody array with BMPER-stimulated endothelial cells. We detected increased basic fibroblast growth factor (bFGF/FGF-2) expression after BMPER stimulation and decreased expression of thrombospondin-1. Additionally, FGF receptor-1 expression, phosphorylation, FGF signaling pathway activity, and cell survival were increased. Consistently, silencing of BMPER by small interfering RNA decreased bFGF and FGF receptor-1 expression and increased thrombospondin-1 expression and cell apoptosis. Next, we investigated the interaction of BMPER and the FGF signaling pathway in endothelial cell function. BMPER stimulation increased endothelial cell angiogenic activity in migration, Matrigel, and spheroid assays. To block FGF signaling, an anti-bFGF antibody was used, which effectively inhibited the proangiogenic BMPER effect. Accordingly, BMPER-silenced endothelial cells under bFGF stimulation showed decreased angiogenic activity compared with bFGF control. We confirmed these findings in vivo by subcutaneous Matrigel injections with and without bFGF in C57BL/6_Bmper+/− mice. Aortic ring assays of C57BL/6_Bmper+/− mice confirmed a specific effect for bFGF but not for vascular endothelial growth factor. Conclusions—Taken together, the proangiogenic BMPER effect in endothelial cells is mediated by inhibition of antiangiogenic thrombospondin-1 and enhanced expression and activation of the FGF signaling pathway that is crucial in the promotion of angiogenesis.
Patient dose in radiologically guided interventional vascular procedures: conventional versus digital systems.

PURPOSE To calculate the difference in the patient radiation dose in radiologically guided interventional vascular procedures between conventional and digital systems and to estimate the effective dose and the energy imparted with the digital system. MATERIALS AND METHODS A total of 318 procedures (in 318 patients) in 15 different examination groups were analyzed. The dose-area product was determined by using a transmission chamber fitted to an x-ray-tube light-beam diaphragm; the effective dose was determined by using software. RESULTS Urinary and biliary tract procedures showed small differences in the average dose-area product between conventional and digital systems. The dose-area products in the vascular procedures were higher with the digital than with the conventional system. The average effective dose and energy imparted were 0.88 mSv and 129 mJ, respectively, in the subcutaneous placement of a reservoir for analgesic administration and as much as 25.7 mSv and 829 mJ, respectively, in spermatic vein embolization. CONCLUSION The dose-area product was higher with the digital system than with the conventional system in 13 of the 15 groups. To reduce the patient dose in vascular interventional radiology procedures, the training of personnel and the frequent use of conventional fluoroscopy and low-dose imaging are required.