Miracle-dz/UniFAR-FTUs huggingface dataset:
Time-resolved observation of protein allosteric communication

Significance Allostery describes the puzzling phenomenon of long-range communication between distant protein sites. Representing the elementary process of cell signaling, allosteric interactions also provide prime targets in pharmaceutical research. Although a number of thermodynamic models have been proposed, the dynamic process of allosteric communication itself is still not well understood. Accounting for recent time-resolved infrared spectroscopy experiments, this study uses extensive all-atom molecular dynamics simulations that envision a real-time picture of the way allostery works. Mediated by the propagation of stress, allostery is found to trigger structural and dynamical changes in a nonlinear and nonlocal fashion. Similarly as found for downhill folding, the hierarchy and exceeding structural heterogeneity of the process gives rise to strongly nonexponential kinetics. Allostery represents a fundamental mechanism of biological regulation that is mediated via long-range communication between distant protein sites. Although little is known about the underlying dynamical process, recent time-resolved infrared spectroscopy experiments on a photoswitchable PDZ domain (PDZ2S) have indicated that the allosteric transition occurs on multiple timescales. Here, using extensive nonequilibrium molecular dynamics simulations, a time-dependent picture of the allosteric communication in PDZ2S is developed. The simulations reveal that allostery amounts to the propagation of structural and dynamical changes that are genuinely nonlinear and can occur in a nonlocal fashion. A dynamic network model is constructed that illustrates the hierarchy and exceeding structural heterogeneity of the process. In compelling agreement with experiment, three physically distinct phases of the time evolution are identified, describing elastic response (≲0.1 ns), inelastic reorganization (∼100 ns), and structural relaxation (≳1μs). Issues such as the similarity to downhill folding as well as the interpretation of allosteric pathways are discussed.
Effectiveness of a Web-Based Self-Help Program for Suicidal Thinking in an Australian Community Sample: Randomized Controlled Trial

Background Treatment for suicidality can be delivered online, but evidence for its effectiveness is needed. Objective The goal of our study was to examine the effectiveness of an online self-help intervention for suicidal thinking compared to an attention-matched control program. Methods A 2-arm randomized controlled trial was conducted with assessment at postintervention, 6, and, 12 months. Through media and community advertizing, 418 suicidal adults were recruited to an online portal and were delivered the intervention program (Living with Deadly Thoughts) or a control program (Living Well). The primary outcome was severity of suicidal thinking, assessed using the Columbia Suicide Severity Rating Scale. Results Intention-to-treat analyses showed significant reductions in the severity of suicidal thinking at postintervention, 6, and 12 months. However, no overall group differences were found. Conclusions Living with Deadly Thoughts was of no greater effectiveness than the control group. Further investigation into the conditions under which this program may be beneficial is now needed. Limitations of this trial include it being underpowered given the effect size ultimately observed, a high attrition rate, and the inability of determining suicide deaths or of verifying self-reported suicide attempts. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12613000410752; https://www.anzctr. org.au/ Trial/Registration/TrialReview.aspx? id=364016 (Archived by WebCite at http://www.webcitation.org/6vK5FvQXy); Universal Trial Number U1111-1141-6595
Gene expression signatures associated with suppression of TRAMP prostate carcinogenesis by a kavalactone‐rich Kava fraction

Kava (Piper methysticum Forster) extract and its major kavalactones have been shown to block chemically induced lung tumor initiation in mouse models. Here we evaluated the chemopreventive effect of a kavalactone‐rich Kava fraction B (KFB), free of flavokavains, on carcinogenesis in a transgenic adenocarcinoma of mouse prostate (TRAMP) model and characterized the prostate gene expression signatures. Male C57BL/6 TRAMP mice were fed AIN93M diet with or without 0.4% KFB from 8 wk of age. Mice were euthanized at 16 or 28 wk. The growth of the dorsolateral prostate (DLP) lobes in KFB‐treated TRAMP mice was inhibited by 66% and 58% at the respective endpoint. Anterior and ventral prostate lobes in KFB‐treated TRAMP mice were suppressed by 40% and 49% at 28 wk, respectively. KFB consumption decreased cell proliferation biomarker Ki‐67 and epithelial lesion severity in TRAMP DLP, without detectable apoptosis enhancement. Real time qRT‐PCR detection of mRNA from DLP at 28 wk showed decreased expression of cell cycle regulatory genes congruent with Ki‐67 suppression. Microarray profiling of DLP mRNA indicated that “oncogene‐like” genes related to angiogenesis and cell proliferation were suppressed by KFB but tumor suppressor, immunity, muscle/neuro, and metabolism‐related genes were upregulated by KFB in both TRAMP and WT DLP. TRAMP mice fed KFB diet developed lower incidence of neuroendocrine carcinomas (NECa) (2 out of 14 mice) than those fed the basal diet (8 out of 14 mice, χ2 = 5.6, P < 0.025). KFB may, therefore, inhibit not only TRAMP DLP epithelial lesions involving multiple molecular pathways, but also NECa. © 2016 Wiley Periodicals, Inc.
Simulations of time-resolved fluorescence in multilayered biological tissues: applications to clinical data modeling

We present a computational code capable of simulating time-resolved fluorescence emission from multi-layered biological tissues, and apply this code to model tissue fluorescence emission data acquired in vivo during clinical endoscopy. The code for multi-layered media is based on a Monte Carlo model we developed previously to simulate time-resolved fluorescence propagation in a semi-infinite turbid medium. Here, the code is applied to simulate data acquired from measurements on tissues in the lower gastrointestinal tract. Clinical data were obtained in vivo during endoscopy using a portable time-resolved fluorescence spectrometer employing a single fiber-optic probe for excitation and detection. Tissue was modeled as a two-layered medium consisting of a mucosal layer of finite thickness above a sub-mucosal layer. The emitted fluorescence was considered as arising from mucosal epithelial cells, due to the presence of nicotinamide dinucleotide as the constituent fluorophore (lifetime τ = 1.5 ns), and from sub-mucosal structural proteins (collagen, lifetime τ = 5.2 ns). Simulations modeled changes in tissue pathology as a function of independently changing the mucosal layer thickness, the fluorophore absorption coefficients and the fluorescence quantum yields. It was observed that the emanating fluorescence from the mucosal layer changes by ~50-60% with these changes resulting in appreciable differences of ~2 ns in the average lifetimes. These simulations indicate that it may be possible to quantify the fluorescence observed from tissue based on both biochemical and histological criteria. The simulations may also be used to provide a useful method for designing and testing the efficacies of different fiber-probe geometries.
Retinal Vein Occlusion: Current Treatment

Retinal vein occlusion (RVO) is a pathology noted for more than 150 years. Although a lot has been written on the matter, it is still a frequent condition with multifactorial etiopathogenesis with many unclear aspects. The RVO pathogenesis has varied systemic and local implications that make it difficult to elaborate treatment guidelines. The management of the patient with RVO is very complex and a multidisciplinary approach is required in order to identify and correct the associated risk factors. Laser therapy remains the gold standard in RVO, but only modest functional improvement has been shown in branch retinal occlusion forms. Multicenter studies of intravitreal drugs present them as an option to combine with laser. Anti-vascular endothelial growth factor, corticosteroids and sustained-release implants are the future weapons to stop disease progression and get a better visual outcome. Consequently, it is useful to clarify some aspects of the pathology that allow a better patient management.
Isolation, identification, and pathological effects of beach sand bacterial extract on human skin keratinocytes in vitro

Background Beaches are recreational spots for people. However, beach sand contains harmful microbes that affect human health, and there are no established methods for either sampling and identifying beach-borne pathogens or managing the quality of beach sand. Method This study was conducted with the aim of improving human safety at beaches and augmenting the quality of the beach experience. Beach sand was used as a resource to isolate bacteria due to its distinctive features and the biodiversity of the beach sand biota. A selected bacterial isolate termed FSRS was identified as Pseudomonas stutzeri using 16S rRNA sequencing and phylogenetic analysis, and the sequence was deposited in the NCBI GenBank database under the accession number MF599548. The isolated P. stutzeri bacterium was cultured in Luria–Bertani growth medium, and a crude extract was prepared using ethyl acetate to examine the potential pathogenic effect of P. stutzeri on human skin. A human skin keratinocyte cell line (HaCaT) was used to assess cell adhesion, cell viability, and cell proliferation using a morphological analysis and a WST-1 assay. Result The crude P. stutzeri extract inhibited cell adhesion and decreased cell viability in HaCaT cells. We concluded that the crude extract of P. stutzeri FSRS had a strong pathological effect on human skin cells. Discussion Beach visitors frequently get skin infections, but the exact cause of the infections is yet to be determined. The beach sand bacterium P. stutzeri may, therefore, be responsible for some of the dermatological problems experienced by people visiting the beach.
Apoplastic recognition of multiple candidate effectors from the wheat pathogen Zymoseptoria tritici in the nonhost plant Nicotiana benthamiana

Summary The fungus Zymoseptoria tritici is a strictly apoplastic, host‐specific pathogen of wheat leaves and causal agent of septoria tritici blotch (STB) disease. All other plants are considered nonhosts, but the mechanism of nonhost resistance (NHR) to Z. tritici has not been addressed previously. We sought to develop Nicotiana benthamiana as a system to study NHR against Z. tritici. Fluorescence microscopy and quantitative reverse transcription polymerase chain reactions were used to establish the interaction between Z. tritici and N. benthamiana. Agrobacterium‐mediated transient expression was used to screen putative Z. tritici effector genes for recognition in N. benthamiana, and virus‐induced gene silencing (VIGS) was employed to determine the role of two receptor‐like kinases (RLKs), NbBAK1 and NbSOBIR1, in Z. tritici effector recognition. Numerous Z. tritici putative effectors (14 of 63 tested) induced cell death or chlorosis in N. benthamiana. For most, phenotypes were light‐dependent and required effector secretion to the leaf apoplastic space. Moreover, effector‐induced host cell death was dependent on NbBAK1 and NbSOBIR1. Our results indicate widespread recognition of apoplastic effectors from a wheat‐infecting fungal pathogen in a taxonomically distant nonhost plant species presumably by cell surface immune receptors. This suggests that apoplastic recognition of multiple nonadapted pathogen effectors may contribute to NHR.
Lightest to the Right: An Apparently Anomalous Displacement in Irish

This article analyzes mismatches between syntactic and prosodic constituency in Irish and attempts to understand those mismatches in terms of recent proposals about the nature of the syntax-prosody interface. It argues in particular that such mismatches are best understood in terms of Selkirk’s (2011) Match Theory, working in concert with constraints concerned with rhythm and phonological balance. An apparently anomalous rightward movement that seems to target certain pronouns and shift them rightward is shown to be fundamentally a phonological process: a prosodic response to a prosodic dilemma. The article thereby adds to a growing body of evidence for the role of phonological factors in shaping constituent order.
Hybrid particulate and fibrous injection molded composites : Carbon black/carbon fiber/polypropylene systems

The electrical properties of injection molded composite systems based on a polypropylene matrix and two types of carbonaceous fillers—carbon black (CB) and carbon fibers (CF)—were investigated. In addition to conductivity as a function of system compositions, conductivity profiles were studied. Inhomogeneous spatial distribution of CB particles in moldings containing either CB as a single filler or in combination with CF was found. Furthermore, unexpected fiber orientation transverse to the melt flow direction and disappearance of skin-core orientation pattern, typical for injection molded fiber filled composites, were observed in the two filler samples. An amplification of the shear-thinning behavior, characteristic for the polypropylene (PP) matrix, imposed by the inhomogeneity of the CB distribution resulting in flattening of the advancing melt front and velocity profile is suggested as underlying the observed phenomena. POLYM. COMPOS. , 26:454–464, 2005. © 2005 Society of Plastics Engineers
THE EARLY EARLY TYPE: DISCOVERY OF A PASSIVE GALAXY AT zspec ∼ 3

We present the discovery of a massive, quiescent galaxy at z = 2.99. We have obtained an Hubble Space Telescope WFC3 spectrum of this object and measured its redshift from the detection of a deep 4000 Å break consistent with an old population and a high metallicity. By stellar population modeling of both its grism spectrum and broadband photometry, we derive an age of ∼0.7 Gyr, implying a formation redshift of z > 4, and a mass >1011 M☉. Although this passive galaxy is the most distant confirmed so far, we find that it is slightly less compact than other z > 2 early types of similar mass, being overall more analogous to those z ∼ 1.6 field early-type galaxies. The discovery of this object shows that early-type galaxies are detectable to at least z = 3 and suggests that the diversity of structural properties found in z = 1.4–2 ellipticals to earlier epochs could have its origin in a variety of formation histories among their progenitors.
Spatial Correlation Analysis on Physical Unclonable Functions

The evaluation of the quality of physical unclonable functions (PUFs) is still under research. Most state-of-the-art metrics are found to measure only bias, while correlations, e.g., within the PUF response of a single device, remain unnoticed. In this paper, we introduce spatial autocorrelation analysis (SPACA), which is used in other fields of research, as a method to reveal correlations in the response of single-challenge PUFs. The presented statistics—Moran’s I, Geary’s c, and Join Count statistic—can be used to test the quality of an implementation using a set of sample devices as well as monitor ongoing production. Their results are also important for selecting an appropriate post-processing of the raw PUF response. Experiments on data sets from three different PUF implementations on field-programmable gate array and application-specific integrated circuit using SPACA show the capabilities of the introduced statistics. An efficient implementation of SPACA in MATLAB was developed to conduct the experiments. We discuss how SPACA can be used in practical testing and suggest to consider SPACA for a future test suite for PUFs.
Thermal properties of carbon nanofiber reinforced high-density polyethylene nanocomposites

Reinforcing polymers with the appropriate nanofillers is an effective way to obtain a variety of enhanced material properties. In this paper, high-density polyethylene nanocomposites reinforced with either pristine or silane-treated carbon nanofibers at various weight percentages (0.5 wt%, 1 wt%, and 3 wt%) were fabricated through melt-mixing and compressive processing. Silane coatings with two thicknesses, 2.8 nm and 46 nm, were applied on the oxidized carbon nanofibers to improve the interfacial bonding between the carbon nanofibers and the matrix. Scanning electron microscopy and transmission electron microscopy demonstrated the dispersion of carbon nanofibers and the strongly improved interfacial adhesion between the carbon nanofibers and high-density polyethylene matrix due to the silane coating. The thermal properties of high-density polyethylene / carbon nanofiber nanocomposites were characterized and compared with those of the neat high-density polyethylene. The measurement results showed that the thermal conductivity of the high-density polyethylene /carbon nanofiber nanocomposites increased with the carbon nanofiber loading. The enhancement of thermal conductivity was not only due to the high thermal conductivity of carbon nanofibers but also due to the interfacial quality between the carbon nanofibers and the high-density polyethylene matrix. The interfacial thermal contact resistance between the carbon nanofibers and the matrix was determined to be in the range of 0 . 88 × 10 - 6 m 2 K / W to 3 . 89 × 10 - 6 m 2 K / W . Furthermore, the coefficient of thermal expansion of the nanocomposite was found to be reduced by the incorporation of carbon nanofibers.
Systemic treatment-induced gastrointestinal toxicity: incidence, clinical presentation and management

The toxicity of cancer chemotherapy is among the most important factors limiting its use. Clear delineation and communication of benefits and risks is an essential component of treatment decisions. Gastrointestinal toxicity during chemotherapy is frequent and contributes to dose reductions, delays and cessation of cancer treatment. The development of intervention strategies that could eliminate an expected side effect of chemotherapy is vital. Physiologic changes that can increase the toxicity of chemotherapy are decreased stem cell reserves, decreased ability to repair cell damage, progressive loss of body protein, and accumulation of body fat. Symptoms only arise when physiological functions are altered. The gastrointestinal symptoms arising during cancer chemotherapy can often be cured if newly acquired, and if gastrointestinal physiological deficits are identified. Developing new chemotherapy regimens with similar efficacy but less toxicity should be a priority for future research.
Wayfinding and Glaucoma: A Virtual Reality Experiment

Purpose Wayfinding, the process of determining and following a route between an origin and a destination, is an integral part of everyday tasks. The purpose of this study was to investigate the impact of glaucomatous visual field loss on wayfinding behavior using an immersive virtual reality (VR) environment. Methods This cross-sectional study included 31 glaucomatous patients and 20 healthy subjects without evidence of overall cognitive impairment. Wayfinding experiments were modeled after the Morris water maze navigation task and conducted in an immersive VR environment. Two rooms were built varying only in the complexity of the visual scene in order to promote allocentric-based (room A, with multiple visual cues) versus egocentric-based (room B, with single visual cue) spatial representations of the environment. Wayfinding tasks in each room consisted of revisiting previously visible targets that subsequently became invisible. Results For room A, glaucoma patients spent on average 35.0 seconds to perform the wayfinding task, whereas healthy subjects spent an average of 24.4 seconds (P = 0.001). For room B, no statistically significant difference was seen on average time to complete the task (26.2 seconds versus 23.4 seconds, respectively; P = 0.514). For room A, each 1-dB worse binocular mean sensitivity was associated with 3.4% (P = 0.001) increase in time to complete the task. Conclusions Glaucoma patients performed significantly worse on allocentric-based wayfinding tasks conducted in a VR environment, suggesting visual field loss may affect the construction of spatial cognitive maps relevant to successful wayfinding. VR environments may represent a useful approach for assessing functional vision endpoints for clinical trials of emerging therapies in ophthalmology.
Approaching Regulatory Approval of Cardiovascular Regenerative Therapy.

> For the race is not always to the swift …. > > —Aesop (600–564 BC) After 25 years of research and well over a decade after the first randomized blinded clinical trials suggested benefit of stem cell therapy on cardiac performance, the field seems no closer to clinical approval of a product, and skepticism exists about the viability of the idea that myocardial regeneration can be effected. What has kept the field from crossing the finish line of clinical approval and is the goal in site? From a regulatory perspective, the efficacy and safety of regenerative approaches remain unproven.1 Despite significant expenditures of time and funding, definitive adequately powered trials have yet to be completed. Many of the challenges in the field of myocardial regeneration reflect obstacles in cardiovascular drug development as a whole. Improvements in the treatment of cardiovascular disease have resulted in dramatic reductions in cardiovascular mortality and have extended the life span of patients with cardiovascular disease but have also resulted in an increased prevalence of chronic conditions like congestive heart failure and refractory angina. These improvements in care have paradoxically increased the burden of disease and need for new therapies while exponentially increasing the number of patients required to demonstrate effectiveness. Recent estimates indicate that the cost of bringing a new drug to market increased from $140 million in the 1970s to >$2.5 billion in 2014 and tripled in the past decade alone.2 The implications of this can be seen in an example from the field of heart failure: although the CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study; published in 1987) proved a mortality benefit of angiotensin-converting enzyme inhibition after following up 253 patients for 6 months, the benefit of sacubitril/valsartan in 2014 required enrollment of >8000 patients and 27-month follow-up to demonstrate an effect on …