bluuebunny/crossref_metadata_2025 huggingface dataset:
Xenorhabdus bovienii strain jolietti uses a type 6 secretion system to kill closely related Xenorhabdus strains
Authors: Kochanowsky Rebecca M , Bradshaw Christine , Forlastro Isabel , Stock S Patricia
Published: April 2020

Xenorhabdus bovienii strain jolietti (XBJ) is a Gram-negative bacterium that interacts with several organisms as a part of its life cycle. It is a beneficial symbiont of nematodes, a potent pathogen of a wide range of soil-dwelling insects and also has the ability to kill soil- and insect-associated microbes. Entomopathogenic Steinernema nematodes vector XBJ into insects, releasing the bacteria into the insect body cavity. There, XBJ produce a variety of insecticidal toxins and antimicrobials. XBJ's genome also encodes two separate Type Six Secretion Systems (T6SSs), structures that allow bacteria to inject specific proteins directly into other cells, but their roles in the XBJ life cycle are mostly unknown. To probe the function of these T6SSs, we generated mutant strains lacking the key structural protein Hcp from each T6SS and assessed phenotypes related to different parts of XBJ's life cycle. Here we demonstrate that one of the T6SSs is more highly expressed in in vitro growth conditions and has antibacterial activity against other Xenorhabdus strains, and that the two T6SSs have a redundant role in biofilm formation.
The Recognition of Human Rights: A Threefold Myth
Authors: Schilling Theodor
Published: April 2020

The discussion of the recognition of human rights by law suffers from the acceptance of three myths: that recognition is provided for in human rights instruments, that there exist moral norms ready to be recognised by law and that recognition is what happens when a legal norm that corresponds to a moral precept is adopted. To counter the first myth, the article undertakes a close reading of the relevant passages of human rights instruments. To counter the second myth, the article observes that there exist few if any universally valid moral norms ready to be recognised by law but an abundance of other moral precepts. To counter the third myth, the article argues that what happens is rather the replication of the content of a moral precept in law. From all these, it follows that there cannot be any necessary connection between moral norms or other precepts and legal human rights. This distinctness of moral precepts and legal human rights, it is argued in conclusion, is apt to strengthen legal human rights protection: it diminishes the influence ‘traditional values’ might otherwise have on this protection.
Adventures scaling the realized niche, saving the world, and searching for values
Authors: Dayton Paul K
Published: April 2020

I describe my unlikely path into marine science from a childhood in the Arizona desert and Oregon woods. Without realizing it, I developed a sense of place in nature and the value of open interdisciplinary communication among diverse scientists. My undergraduate education emphasized physiological adaptations to the environment or what might now be considered the “fundamental niche”, and my graduate thinking was inspired by a population/community based evolutionary understanding of how strong interactions define a “realized niche”. I have attempted to define strong interactions in three different ecosystems. This difficult problem is confounded by the loss of natural systems resulting from human impacts. I discuss my frustrations with eroding conservation efforts in a society that is rapidly devaluing nature and consider how we might recover our most fundamental values. I conclude that there is an urgent need to improve field-based teaching of undergraduate non-majors about nature and to be much more effective in our interactions with the general public. If we hope to have our legacy include a liveable world with natural places, we urgently need to act unilaterally to shift some of our values and reward systems towards the challenge of educating the undergraduates and especially the general public.
Improved Recognition of 25-Hydroxyvitamin D2 by 2 Automated Immunoassays
Authors: Geno K Aaron , Tolan Nicole V , Singh Ravinder J , Nerenz Robert D
Published: April 2020

Background

Despite recommendations to limit vitamin D testing to specific clinical scenarios, test volume remains high in many clinical laboratories. Automated total vitamin D immunoassays frequently under- or over-recover 25-hydroxyvitamin D2 [25(OH)D2], making accurate assessment of vitamin D status difficult in patients taking high-dose 25(OH)D2 supplements. Mass spectrometry-based methods offer excellent recovery of 25(OH)D2 but are not practical for use in all laboratories. In this study, we evaluated 2 automated immunoassays against an LC–MS/MS method performed at a national reference laboratory.

Methods

A method comparison against LC–MS/MS was performed for the Roche Elecsys Vitamin D total II assay and the IDS-iSYS 25 VitDS immunoassays using 49 patient specimens submitted for clinical 25(OH)D measurement. Mean bias was calculated, and vitamin D status was determined for each specimen according to the 2011 Endocrine Society clinical practice guidelines.

Results

Theil–Sen regression lines relative to LC–MS/MS were y = 0.88x + 2.94 for Roche and y = 1.03x + 2.48 for IDS. Mean bias (±SD) in samples with 25(OH)D2 concentrations less than 5 ng/mL was −0.25 ng/mL (±6.30) for Roche and −1.45 ng/mL (±6.82) for the IDS. Mean bias (±SD) in samples with 25(OH)D2 concentrations greater than 5 ng/mL was −3.19 ng/mL (±6.61) for Roche and 5.52 ng/mL (±6.36) for IDS. Median percentage recovery of 25(OH)D2 was 87.1% (interquartile range 76.0–111.3) for Roche and 120.6% (interquartile range: 105.3–133.4) for IDS. Vitamin D status was misclassified in 7 samples by the Roche assay and 3 by the IDS assay. For all but one of the discordant pairs, the immunoassay result was within 1.7 ng/mL of the diagnostic cutoff.

Conclusions

The automated immunoassays evaluated here demonstrate improved recovery of 25(OH)D2 relative to previous generations. Both are acceptable for use in the determination of vitamin D status.
Anti–Domain I β2-Glycoprotein I Antibodies and Activated Protein C Resistance Predict Thrombosis in Antiphospholipid Syndrome: TAC(I)T Study
Authors: Zuily Stephane , de Laat Bas , Guillemin Francis , Kelchtermans Hilde , Magy-Bertrand Nadine , Desmurs-Clavel Hélène , Lambert Marc , Poindron Vincent , de Maistre Emmanuel , Dufrost Virginie , Risse Jessie , Shums Zakera , Norman Gary L , de Groot Philip G , Lacolley Patrick , Lecompte Thomas , Regnault Véronique , Wahl Denis
Published: April 2020

Background

Antibodies binding to domain I of β2-glycoprotein I (aDI) and activated protein C (APC) resistance are associated with an increased risk of thrombosis in cross-sectional studies. The objective of this study was to assess their predictive value for future thromboembolic events in patients with antiphospholipid antibodies (aPL) or antiphospholipid syndrome.

Methods

This prospective multicenter cohort study included consecutive patients with aPL or systemic lupus erythematosus. We followed 137 patients (43.5 ± 15.4 year old; 107 women) for a mean duration of 43.1 ± 20.7 months.

Results

We detected aDI IgG antibodies by ELISA in 21 patients. An APC sensitivity ratio (APCsr) was determined using a thrombin generation–based test. The APCsr was higher in patients with anti–domain I antibodies demonstrating APC resistance (0.75 ± 0.13 vs 0.48 ± 0.20, P < 0.0001). In univariate analysis, the hazard ratio (HR) for thrombosis over time was higher in patients with aDI IgG (3.31 [95% CI, 1.15–9.52]; P = 0.03) and patients with higher APC resistance (APCsr >95th percentile; HR, 6.07 [95% CI, 1.69–21.87]; P = 0.006). A sensitivity analysis showed an increased risk of higher aDI IgG levels up to HR 5.61 (95% CI, 1.93–16.31; P = 0.01). In multivariate analysis, aDI IgG (HR, 3.90 [95% CI, 1.33–11.46]; P = 0.01) and APC resistance (HR, 4.98 [95% CI, 1.36–18.28]; P = 0.02) remained significant predictors of thrombosis over time.

Conclusions

Our study shows that novel tests for antibodies recognizing domain I of β2-glycoprotein I and functional tests identifying APC resistance are significant predictors of thrombosis over time and may be useful for risk stratification.
COVID-19 transforms health care through telemedicine: Evidence from the field
Authors: Mann Devin M , Chen Ji , Chunara Rumi , Testa Paul A , Nov Oded
Published: April 2020

This study provides data on the feasibility and impact of video-enabled telemedicine use among patients and providers and its impact on urgent and nonurgent healthcare delivery from one large health system (NYU Langone Health) at the epicenter of the coronavirus disease 2019 (COVID-19) outbreak in the United States. Between March 2nd and April 14th 2020, telemedicine visits increased from 102.4 daily to 801.6 daily. (683% increase) in urgent care after the system-wide expansion of virtual urgent care staff in response to COVID-19. Of all virtual visits post expansion, 56.2% and 17.6% urgent and nonurgent visits, respectively, were COVID-19–related. Telemedicine usage was highest by patients 20 to 44 years of age, particularly for urgent care. The COVID-19 pandemic has driven rapid expansion of telemedicine use for urgent care and nonurgent care visits beyond baseline periods. This reflects an important change in telemedicine that other institutions facing the COVID-19 pandemic should anticipate.
Radiation Doses and Risks in Breast Screening
Authors: Hendrick R Edward
Published: April 2020

This article describes radiation doses and cancer risks of digital breast imaging technologies used for breast cancer detection. These include digital mammography (DM), digital breast tomosynthesis (DBT), and newer technologies such as contrast-enhanced digital or spectral mammography (CEM), whole-breast computed tomography, breast-specific gamma imaging (BSGI), molecular breast imaging (MBI), and positron emission mammography (PEM). This article describes the basis for radiation risk estimates, compares radiation doses and risks, and provides benefit-to-radiation-risk ratios for different breast imaging modalities that use ionizing radiation.

Current x-ray–based screening modalities such as DM and DBT have small to negligible risks of causing radiation-induced cancers in women of normal screening age. Possible new screening modalities such as CEM have similar small cancer risks. Potential screening modalities that involve radionuclide injection such as BSGI, MBI, and PEM have significantly higher cancer risks unless efficient detection systems and reduced administered doses are used. Benefit-to-radiation-risk estimates are highly favorable for screening with DM and other modalities having comparable (or higher) cancer detection rates and comparably low radiation doses.
The Long-Term Costs of Government Surveillance: Insights from Stasi Spying in East Germany
Authors: Lichter Andreas , Löffler Max , Siegloch Sebastian
Published: April 2020

We investigate the long-run effects of government surveillance on civic capital and economic performance, studying the case of the Stasi in East Germany. Exploiting regional variation in the number of spies and administrative features of the system, we combine a border discontinuity design with an instrumental variable strategy to estimate the long-term, post-reunification effect of government surveillance. We find that a higher spying density led to persistently lower levels of interpersonal and institutional trust in post-reunification Germany. We also find substantial and long-lasting economic effects of Stasi surveillance, resulting in lower income, higher exposure to unemployment, and lower self-employment.
Numerical simulations of wave fields for acoustic logging while drilling tools in a fluid-filled trough
Authors: Sun Zhifeng , Tang Xiaoming , He Xiao , Liu Xien
Published: April 2020

Examinations of acoustic logging tools in the workshop are significant for checking the performance of every unit before field downhole measurements. It is more convenient to test the tools in a horizontally placed open trough rather than in a vertical closed pipe. To ensure the tools can excite and receive the signals from the trough well (i.e. the pipe waves), we should figure out the wave propagation in such an asymmetric structure. We aim for acoustic logging while drilling (LWD) signals from the fluid-filled trough. Both monopole and quadrupole wave fields are studied through the 3D finite difference model. For monopole acoustic logging, first-arrival full waves are the major concern. The propagation velocities of first-arriving pipe waves do not change with opening angles of the trough. The pipe wave speeds are exactly the same as those in closed pipes of the same sizes; while the amplitudes decrease with increasing opening angles. For quadrupole LWD, velocities of pipe waves have few correlations with opening angles and transducer azimuths. The quadrupole source can even excite the monopole collar waves in the trough, which become the first arrivals of the full waves. The quadrupole pipe waves show a trend of being weaker with increasing opening angles. If the opening angle of the trough is too large, the quadrupole pipe waves could totally be covered by other wavelets. To excite clearer pipe wave signals in the trough, it is suggested that an opening angle as small as possible is optimal for the tests.
Data protection and ethics requirements for multisite research with health data: a comparative examination of legislative governance frameworks and the role of data protection technologies†
Authors: Scheibner James , Ienca Marcello , Kechagia Sotiria , Troncoso-Pastoriza Juan Ramon , Raisaro Jean Louis , Hubaux Jean-Pierre , Fellay Jacques , Vayena Effy
Published: April 2020

Personalised medicine can improve both public and individual health by providing targeted preventative and therapeutic healthcare. However, patient health data must be shared between institutions and across jurisdictions for the benefits of personalised medicine to be realised. Whilst data protection, privacy, and research ethics laws protect patient confidentiality and safety they also may impede multisite research, particularly across jurisdictions. Accordingly, we compare the concept of data accessibility in data protection and research ethics laws across seven jurisdictions. These jurisdictions include Switzerland, Italy, Spain, the United Kingdom (which have implemented the General Data Protection Regulation), the United States, Canada, and Australia. Our paper identifies the requirements for consent, the standards for anonymisation or pseudonymisation, and adequacy of protection between jurisdictions as barriers for sharing. We also identify differences between the European Union and other jurisdictions as a significant barrier for data accessibility in cross jurisdictional multisite research. Our paper concludes by considering solutions to overcome these legislative differences. These solutions include data transfer agreements and organisational collaborations designed to `front load' the process of ethics approval, so that subsequent research protocols are standardised. We also allude to technical solutions, such as distributed computing, secure multiparty computation and homomorphic encryption.
Schistosomiasis and cancer: Experience from a zonal hospital in Tanzania and opportunities for prevention
Authors: Lodhia Jay , Mremi Alex , Pyuza Jeremia J , Bartholomeo Nicholas , Herman Ayesiga M
Published: April 2020

Schistosomiasis infection is endemic in many parts of Tanzania. The morbidity due to Schistosomiasis and its association with cancer remains to be of great concern and poses greater challenge that needs to be assessed. Cancer is an increasing public health problem in most sub-Saharan African countries, and yet, cancer control programs and the provision of early detection and treatment services are limited despite this increasing burden. This article aims to discuss case series of patients diagnosed with urinary bladder, prostate and colorectal cancer together with Schistosoma infection. We further highlight the opportunities for combating new Schistosomiasis infection, a potential to reduce its oncological complications particularly in low-resource setting.
Non-steady heating of cool cores of galaxy clusters by ubiquitous turbulence and AGN
Authors: Fujita Yutaka , Cen Renyue , Zhuravleva Irina
Published: April 2020

Recent cosmological simulations have shown that turbulence should be generally prevailing in clusters because clusters are continuously growing through matter accretion. Using one-dimensional hydrodynamic simulations, we study the heating of cool-core clusters by the ubiquitous turbulence as well as feedback from the central active galactic nuclei (AGNs) for a wide range of cluster and turbulence parameters, focusing on the global stability of the core. We find that the AGN shows intermittent activities in the presence of moderate turbulence similar to the one observed with Hitomi. The cluster core maintains a quasi-equilibrium state for most of the time because the heating through turbulent diffusion is nearly balanced with radiative cooling. The balance is gradually lost because of slight dominance of the radiative cooling, and the AGN is ignited by increased gas inflow. Finally, when the AGN bursts, the core is heated almost instantaneously. Thanks to the pre-existing turbulence, the heated gas is distributed throughout the core without becoming globally unstable and causing catastrophic cooling, and the core recovers the quasi-equilibrium state. The AGN bursts can be stronger in lower mass clusters. Predictions of our model can be easily checked with future X-ray missions like XRISM and Athena.
Colliding-wind binary systems: diffusive shock acceleration and non-thermal emission
Authors: Pittard J M , Vila G S , Romero G E
Published: April 2020

We present a model for the non-thermal emission from a colliding-wind binary. Relativistic protons and electrons are assumed to be accelerated through diffusive shock acceleration (DSA) at the global shocks bounding the wind–wind collision region. The non-linear effects of the backreaction due to the cosmic ray pressure on the particle acceleration process and the cooling of the non-thermal particles as they flow downstream from the shocks are included. We explore how the non-thermal particle distribution and the keV−GeV emission changes with the stellar separation and the viewing angle of the system, and with the momentum ratio of the winds. We confirm earlier findings that DSA is very efficient when magnetic field amplification is not included, leading to significantly modified shocks. We also find that the non-thermal flux scales with the binary separation in a complicated way and that the anisotropic inverse Compton emission shows only a moderate variation with viewing angle due to the spatial extent of the wind–wind collision.
Thermal convection in the crust of the dwarf planet – I. Ceres
Authors: Formisano M , Federico C , Castillo-Rogez J , De Sanctis M C , Magni G
Published: April 2020

Ceres is the largest body in the Main Belt, and it is characterized by a large abundance of water ice in its interior. This feature is suggested by its relatively low bulk density (2162 kg m−3), while its partial differentiation into a rocky core and icy crust is suggested by several geological and geochemical features: minerals and salts produced by aqueous alteration, icy patches on the surface, and lobate morphology interpreted as surface flows. In this work, we explore how the composition can influence the characteristics of thermal convection in the crust of Ceres. Our results suggest that the onset of thermal convection is difficult and when it occurs, it is short lived, which could imply that Ceres preserved deep liquid until present, as recently suggested by the work of Castillo-Rogez et al. Moreover, cryovolcanism could be driven by diapirism (chemical convection) rather than thermal convection.
Heavy element evolution in the inner regions of the Milky Way
Authors: Matteucci F , Vasini A , Grisoni V , Schultheis M
Published: April 2020

We present results for the evolution of the abundances of heavy elements (O, Mg, Al, Si, K, Ca, Cr, Mn, Ni, and Fe) in the inner Galactic regions (RGC ≤ 4 kpc). We adopt a detailed chemical evolution model already tested for the Galactic bulge and compare the results with Apache Point Observatory Galactic Evolution Experiment data. We start with a set of yields from the literature that are considered the best to reproduce the abundance patterns in the solar vicinity. We find that, in general, the predicted trends nicely reproduce the data but in some cases either the trend or the absolute values of the predicted abundances need to be corrected, even by large factors, in order to reach the best agreement. We suggest how the current stellar yields should be modified to reproduce the data and we discuss whether such corrections are reasonable in the light of the current knowledge of stellar nucleosynthesis. However, we also critically discuss the observations. Our results suggest that Si, Ca, Cr, and Ni are the elements for which the required corrections are the smallest, while for Mg and Al moderate modifications are necessary. On the other hand, O and K need the largest corrections to reproduce the observed patterns, a conclusion already reached for solar vicinity abundance patterns, with the exception of oxygen. For Mn, we apply corrections already suggested in previous works.
Thrombectomy Technique Predicts Outcome in Posterior Circulation Stroke—Insights from the STAR Collaboration
Authors: Alawieh Ali M , Eid Maya , Anadani Mohammad , Sattur Mithun , Maier Ilko L , Feng Wuwei , Goyal Nitin , Starke Robert M , Rai Ansaar , Fargen Kyle M , Psychogios Marios-Nikos , De Leacy Reade , Grossberg Jonathan A , Keyrouz Salah G , Dumont Travis M , Kan Peter , Lena Jonathan , Liman Jan , Arthur Adam S , Elijovich Lucas , Mccarthy David J , Saini Vasu , Wolfe Stacey Q , Mocco J , Fifi Johanna T , Nascimento Fábio A , Giles James A , Allen Michelle , Crosa Roberto , Fox W Christopher , Gory Benjamin , Spiotta Alejandro M ,   on behalf of Stroke Thrombectomy and Aneurysm Registry (STAR) Collaborators
Published: April 2020

BACKGROUND

Randomized controlled trials evaluating mechanical thrombectomy (MT) for acute ischemic stroke predominantly studied anterior circulation patients. Both procedural and clinical predictors of outcome in posterior circulation patients have not been evaluated in large cohort studies.

OBJECTIVE

To investigate technical and clinical predictors of functional independence after posterior circulation MT while comparing different frontline thrombectomy techniques.

METHODS

In a retrospective multicenter international study of 3045 patients undergoing MT for stroke between 06/2014 and 12/2018, 345 patients had posterior circulation strokes. MT was performed using aspiration, stent retriever, or combined approach. Functional outcomes were assessed using the 90-d modified Rankin score dichotomized into good (0-2) and poor outcomes (3-6).

RESULTS

We included 2700 patients with anterior circulation and 345 patients with posterior circulation strokes. Posterior patients (age: 60 ± 14, 46% females) presented with mainly basilar occlusion (80%) and were treated using contact aspiration or ADAPT (39%), stent retriever (31%) or combined approach (19%). Compared to anterior strokes, posterior strokes had delayed treatment (500 vs 340 min, P < .001), higher national institute of health stroke scale (NIHSS) (17.1 vs 15.7, P < .01) and lower rates of good outcomes (31% vs 43%, P < .01). In posterior MT, diabetes (OR = 0.28, 95%CI: 0.12-0.65), admission NIHSS (OR = 0.9, 95%CI: 0.86-0.94), and use of stent retriever (OR = 0.26, 95%CI: 0.11-0.62) or combined approach (OR = 0.35, 95%CI: 0.12-1.01) vs ADAPT were associated with lower odds of good outcome. Stent retriever use was associated with lower odds of good outcomes compared to ADAPT even when including patients with only basilar occlusion or with successful recanalization only.

CONCLUSION

Despite similar safety profiles, use of ADAPT is associated with higher rates of functional independence after posterior circulation thrombectomy compared to stent retriever or combined approach in large “real-world” retrospective study.
Policing During the Time of Corona: The Indian Context
Authors: Biswas Debajyoti , Sultana Parvin
Published: April 2020

According to Oxford COVID-19 Government Response Tracker, India has the most stringent lockdown as compared to other nations and has scored 100% in the scale; nevertheless, there had been sporadic incidence of attacks on police personnel and medical workers in different parts of India. This article argues that such resistance comes from two broad factors: (i) a collective scepticism that has built up among certain section of people and (ii) a tool of defiance against the government. In order to quell such resistance, community leaders and the police can play a very crucial role. In order to establish the above hypotheses, a quantitative approach of the events that have occurred in India during the lockdown period of 21 days shall be considered.
Feasibility study of the K+d → K0pp reaction for the Θ+ pentaquark
Authors: Sekihara Takayasu , Kim Hyun-Chul , Hosaka Atsushi
Published: April 2020

We investigate theoretically the $K^{0} p$ invariant mass spectrum of the $K^{+} d \to K^{0} p p$ reaction and scrutinize how the signal of the “$\Theta ^{+}$” pentaquark, if it exists, emerges in the $K^{0} p$ spectrum. The most prominent advantage of this reaction is that we can clearly assess whether the “$\Theta ^{+}$” exists or not as a direct-formation production without significant backgrounds, in contrast to other reactions such as photoproduction and $\pi$-induced productions. We show that while the impulse or single-step scattering process can cover the “$\Theta ^{+}$” energy region with an initial kaon momentum $k_{\rm lab} \approx 0.40 \text{ GeV} / c$ in the laboratory frame, the contributions from double-step processes may have a potential possibility to reach the “$\Theta ^{+}$” energy region with a higher kaon momentum $k_{\rm lab} \sim 1 \text{ GeV} / c$. Assuming that the full decay width of the “$\Theta ^{+}$” is around $0.5 \text{ MeV}$, we predict that the magnitude of the peak corresponding to the “$\Theta^+$” is around a few hundred $\mu \text{b}$ to $1 \text{ mb}$ with the momentum of the kaon beam $k_{\rm lab} \approx 0.40 \text{ GeV} / c$ while it is around $\lesssim 1 ~\mu \text{b}$ with $k_{\rm lab} \approx 0.85 \text{ GeV} / c$. Thus, the “$\Theta^+$” peak is more likely to be seen at $k_{\mathrm{lab}} \approx 0.40 \text{ GeV} / c$ than at $k_{\mathrm{lab}} \approx 0.85 \text{ GeV} / c$.
A Study of Microcirculation in the Foot of Dark‐Skin Africans and Light‐Skin Caucasians.
Authors: Akambase Jonas Atulebire , Kozlov Valentine Ivanovich , Akambase Joseph Atule , Poku Frank Adusei , Gurova Olga Aleksandrovna , Kokoreva Tatyana Valerevna
Published: April 2020

The aim of this research is to study the racial differences in the microcirculation of the foot among dark‐skin Africans (DSA – 20 males) and light‐skin Caucasians (LSC – 20 males) using laser doppler flowmetry (LDF). The participants were all males between the ages of 18 to 20. The average values of the microcirculation parameters (PM) in the subjects with high (DSA) and low (LSC) degree of skin pigmentation on the first toe of the foot were [Plantar surface: Blood perfusion – 6.8±0.8 perfusion units (PU), Flux – 1.8±0.4 perfusion units (PU), Fluxmotion index – 1.3±0.19; Dorsal surface: Blood perfusion – 3.3±0.6 perfusion unit (PU), Flux – 1.8±0.4 perfusion units, Fluxmotion index – 0.6±0.1] and [Plantar surface: Blood perfusion – 7.2±0.7 perfusion units (PU), Flux – 1.9±0.2 perfusion units (PU), Fluxmotion index – 1.4±0.16; Dorsal surface: Blood perfusion – 4.7±0.6 perfusion unit (PU), Flux – 1.5±0.1 perfusion units, Fluxmotion index – 1.1±0.1], respectively. Our research reported no significant difference in the microcirculation parameters on the plantar surface of the first toe in both DSA and LSC. This indicates that both groups at the level of the microcirculatory system triggered the same type of regulatory mechanisms. On the dorsal surface of the first toe, where there is significant difference in melanin content, we recorded significant differences in the parameters of microcirculation. Thus, blood perfusion in LSC was 30% higher than in DSA. However, on the dorsal surface of the first toe, flux was 87% higher in those surveyed with less melanin (LSC) than in those surveyed with more melanin (DSA). The average Fluxmotion index on the dorsal surface of the first toe was 45% higher in those with less melanin than in those with more melanin. In conclusion, we can hypothesize that the high content of melanin in the skin shields the probing signal, leading to a decrease in Laser Doppler Flowmetry metrics.

Support or Funding Information

Research supported by the Department of Human Anatomy at RUDN University, Moscow, Russia

Measurement of microcirculation in the foot of a light‐skin Caucasian using Laser Doppler Flowmetry (Lakk‐OP).

Figure 1

Measurement of microcirculation in the foot of a dark‐skin African using Laser Doppler Flowmetry (Lakk‐OP).

Figure 2
Keratin 19 Promotes Cell Cycle by Regulating GSK3B‐Cyclin D3 Pathway in Breast Cancer Cells
Authors: Sharma Pooja , Chung Byung Min (Justin)
Published: April 2020

Keratin 19 (K19) is a cytoskeletal protein that is utilized as a diagnostic and prognostic marker in select human carcinomas. Despite the positive correlation between higher expression of K19 in tumor and worse patient survival, the role of K19 in breast cancer remains unclear. We previously used K19 knockout (KO) MCF7 breast cancer cells to identify that K19 is required for proper cell cycle progression. Specifically, K19 regulated expression of D‐type cyclins (cyclin D1 and cyclin D3) which promote the G1/S transition. We found that K19 interacts with cyclin D3, and a loss of K19 resulted in decreased protein stability of cyclin D3. To better understand how K19 prevents cyclin D3 degradation, we examined the cyclic adenosine 3′,5′‐monophosphate (cAMP) signaling pathway where cAMP induction causes glycogen synthase kinase GSK3B to promote cyclin D3 degradation. When cells were treated with forskolin to elevate intracellular cAMP level, cyclin D3 turnover was increased in the absence of K19, suggesting that K19 inhibits GSK3B from degrading cyclin D3. Indeed, inhibiting GSK3B activity using LiCl and GSK3B expression via siRNA rescued the cyclin D3 level in K19 KO cells. These data suggest that K19 plays an important role in GSK3B‐mediated cyclin D3 degradation. By using molecular biology tools and biochemical approaches, we are in the process of characterizing specifics of K19‐dependent regulation of cyclin D3 stability including identification of GSK3B and K19 domains responsible for their interaction. We aim to provide evidences for a novel mechanism by which a cytoskeletal protein stabilizes a cell cycle regulator and promotes proper cell cycle progression.

Schematic model for the role of K19 in regulation of GSK3B‐mediated cyclin D3 degradation.

(a) K19 serve as scaffold for both for GSK3B and cyclin D3, preventing GSK3B to access cyclin D3.

(b) In absence of K19, GSK3B has a full access to cyclin D3 for degradation.

Figure 1
Cell‐assembled Extracellular Matrix (CAM) as a Biomaterial for Building Vascular Grafts
Authors: L’Heureux Nicolas
Published: April 2020

Sheets of human CAM, produced by cultured cells in vitro, have been rolled to produce completely biological tissue‐engineered vascular grafts (TEVGs). Despite a rapid and successful progression to clinical trials, this approach remains complex. Our novel strategy is to produce TEVG with yarns produced from CAM sheets using a textile‐based approach. This strategy is faster, more reliable, more versatile and more easily automated. CAM sheets can be cut in ribbons of various widths, which can also be twisted to make threads. Yarn (ribbons or threads) can be processed in different ways: devitalized (freezing/dehydration/freezing/rehydration cycle), decellularized (8 mM CHAPS, 1 M NaCl, 25 mM EDTA, 0.12 M NaOH) and/or gamma‐sterilized (25 kGy). We have evaluated the effect of these processing steps on the histological and mechanical properties of the yarn. We have also assessed the impact of these steps on the remodeling (histological and mechanical) of the yarn after subcutaneous implantation in a nude rat for up to 6 months. Results showed that the human CAM‐based yarn creates very little inflammatory reaction and is essentially only mildly remodeled by the host response. However, some processing steps do lead to increased reactivity and decreased performance in vivo. Woven vessels display remarkable mechanical properties without the need for synthetic scaffolding or chemical crosslinking. An allogeneic large animal model is in development to address remodeling in an allogeneic setting in an immunologically competent recipient. Because it can be produced according to specific mechanical and physical specifications, and because it can be used with standard textile assembly methods, the CAM can truly be called a “bio‐material”. More importantly, because of its native‐like structure, this material has the potential to be accepted by the host without significant immune responses and to support a long‐term “physiological” remodeling process.

Support or Funding Information

National Institute of Health Small Business Innovation Research (SBIR) program (HL105010), the Ministère de la Recherche et de l’Enseignement Supérieur, the Chaire Senior de l’Initiative d’Excellence de l’Université de Bordeaux (IdEx Bordeaux), the Agence Nationale de la Recherche (ANR‐16‐CE18‐0024‐01), the Région Nouvelle Aquitaine (2016‐1R30402), and the European Research Council (Advanced Grant # 785908).

A thread and a woven vessel made from human CAM.

Figure 1
Not just for patterning anymore: Hox genes function in skeletal stem cells throughout life
Authors: Wellik Deneen M. , Song Jane Y.
Published: April 2020

Hox genes play fundamental and highly conserved roles in vertebrates patterning of the axial and limb skeleton during embryonic development. We have shown that Hox genes continue to be regionally‐expressed through postnatal development and adult life. Hox‐expressing cells are observed only within a subset of the stromal cells defined as progenitor‐enriched mesenchymal stem/stromal cells. Using a Hoxa11‐CreERT2 allele, we show that Hox‐expressing cells lineage label into chondrocytes, osteoblasts, osteocytes and adipose cells at all stages of life, during growth, homeostasis and in response to injury. Further, lineage labeling from any stage, including during embryogenesis, results in the permanent labeling of a self‐renewing skeletal stem cell population, confirming that Hox‐expressing cells are bona fide skeletal stem cells throughout the life of the animal. However, whether Hox genes continue to function after embryonic stages has never been demonstrated. Embryonic patterning roles and perinatal lethality has prevented this question from being addressed. Using our newly generated Hoxd11 conditional allele and temporally restricted deletion only at adult stages, we show that Hox genes continue to play critical roles in skeletal maintenance and repair throughout life. Loss of Hox function leads to dramatic and progressive perturbations in skeletal integrity with loss of collagen organization, and defective osteocyte and osteoblast formation. Loss of Hox function does not lead to loss of the skeletal stem cell population, but rather an inability of early‐stage progenitors to properly differentiate into functional chondrocytes and osteoblasts. How Hox transcription factors direct these differentiation processes throughout the life of the animal is the focus of current investigations.

Support or Funding Information

NIH NIAMS R01 AR 061402 and R61 AR073523

Hox Skeletal Lineage

Figure 1
Blood level of alpha‐1 antitrypsin in the course of acute myocardial infarction patients: A possible clinical significance
Authors: Khatib Said Y. , AlGhamdi Abdulaziz , Adnan Mohammed H. , AlSaeed Asim H. , AlAhmadi Ali H. , Abdelrahman Amr
Published: April 2020

Introduction

Wide experimental evidence has proved Alpha 1 antitrypsin, which is released from the liver, to protect lung tissue from damage during inflammation. There is experimental evidence also suggests such protection is extended to myocardial tissues during myocardial ischemia/infarction.

Objective

The aim of the study was to determine the levels and the time course of A1AT in the plasma of myocardial infarction patients over 96 hours and compare it with healthy subject as control.

Methods

Blood samples were collected from patients (n=40) arriving at emergency department at 1, 4, 24, 48 and 96 hrs after diagnosis and admission to King Salman Cardiac Center, in King Fahad Medical City in Riyadh, Saudi Arabia. Blood samples were collected in purple top tubes containing EDTA to prevent blood coagulation. Blood plasma was separated by centrifugation with in 3 hrs of collection. Plasma was decanted and stored until analyzed. Alpha 1 antitrypsin was determined in all patients’ blood samples using human Eliza kits( abcam USA). In addition control blood samples were collected from 20 healthy individuals.

Results

A1AT levels were significantly less in MI patients (1025±77 ug/ml at 96 hrs, P<001) compared to (1655±128 ug/ml) (mean ± SEM) in controls. It was very interesting to find those patients win whom the decrease in A1AT was >50 % of control values, they did not survive and passed away (deceased) (673+71 ug/ml, n=3). Also the levels of A1AT after an MI attack was comparable and not significant in hypertensive compared to non‐hypertensive or in STEMI and Non‐STEMI patients but was significantly (P<0.03) higher in non‐smokers (1457+163, n=27) compared to smokers (1153±155, n=10).

Conclusion

The plasma level of A1AT is suggested to be important in providing some protection to myocardial cells during an MI attack. A1AT levels seem to drop shortly following an MI attack. The drop in the level is larger in smokers. In those patients in whom the level of A1AT drops to more about 50 % of normal values they are less likely to survive the MI attack. More studies are needed to confirm the above findings.

Support or Funding Information

We acknowledge the financial support from the research center at King Fahad Medical City, Riyadh, Saudi Arabia

Figure 1Figure 2
Activation of lysophosphatidic acid receptors regulate differentiation of hematopoietic stem cells in myeloid lineage
Authors: Lin Kuan-Hung , Chiang Jui-Chung , Yao Chao-Ling , Lee Hsinyu
Published: April 2020

Lysophosphatidic acid (LPA) is a membrane‐derived lysophospholipid that exists in plasma and platelet. It exerts its functions through activating various LPA receptors (LPARs), which belong to the family of G‐protein coupled receptors (GPCRs). Activation of LPARs has been implicated for important roles during stem cell differentiation. However, how LPA affects human hematopoietic stem cell (HSC) differentiation and underlying lineages remains elusive. In our previous studies, we have demonstrated that activation of LPA receptor 3 (LPA3) promotes erythropoiesis in human HSC and zebrafish. In the present study, pharmacological approach was adopted to further elucidate the functions of LPA receptors during red blood cell (RBC) differentiation. Treatment of LPA2 agonist GRI977143 suppressed erythropoiesis, whereas activation of LPA3 by 2S‐OMPT promoted RBC differentiation both in vitro and in vivo. Furthermore, our results demonstrated a negative role of LPA3 during platelet differentiation both in vitro and in vivo. Moreover, the expression pattern of LPA receptors correlated to the hematopoietic transcriptional factors GATA1 and GATA2 in different stages of myeloid progenitors. In addition, manipulation of these GATA factors affected the expression level of LPA2 and LPA3. By luciferase assays, we demonstrated that the promoter region of LPAR2 and LPAR3 were regulated by these GATA factors. Mutation of identified GATA‐Binding‐Sites (GBS) in the region abrogate the luciferase activities, suggested that LPA2and LPA3 are regulated by GATA factors. In addition, chromatin immunoprecipitation assays confirmed the directly interaction between GATA factors and promoter region of LPARs. Taken together, our results suggested that the expression level of LPA2 and LPA3, which may be determined by GATA factors, is a regulatory switch for the lineage commitment in myeloid progenitors. The pharmacological activation of LPA receptor subtypes represents a novel strategyfor regulating erythropoiesis.

LPA receptors are expressed at different stages during myeloid differentiation. GATA switch, which is an important molecular switch in hematopoiesis, cause the difference of expressional pattern of LPA receptor in different lineage.

Figure 1
Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation of Lornoxicam to Develop Personalized Drug Optimization regarding to CYP2C9 Genetic Polymorphism
Authors: CHO CHANGKEUN , LIM CHANGWOO , OH KYUNGYUL , SHIN HYOBIN , JUNG EUIHYUN , LEE CHOONGMIN , BYEON JIYOUNG , LEE SEOKYONG
Published: April 2020

Lornoxicam is a non‐steroidal anti‐inflammatory drug (NSAID) of oxicam class that has analgesic and anti‐inflammatory effects. Lornoxicam decreases various prostaglandin synthesis via inhibition of cyclo‐oxygenase (COX). Lornoxicam is primarily metabolized to 5’‐hydroxy lornoxicam through cytochrome P450 2C9 (CYP2C9) enzyme. Polymorphism of the CYP2C9 enzyme, e.g., CYP2C9*3 and CYP2C9*13, are associated with decreased activity of CYP2C9. Consequently, the difference of CYP2C9 activity by polymorphism triggers diverse drug concentration and response despite equal dose administration. For individual drug optimization, we develop a predictable pharmacokinetic model based on physiological characteristics related to CYP2C9 activity. In our research, 13 healthy Korean male subjects were included in the pharmacokinetic study of lornoxicam. All subjects were divided into three different CYP2C9*1/*1, CYP2C9*1/*3, and CYP2C9*1/*13 groups. 8mg dose of lornoxicam was administered to individual subjects. After administration, venous blood samples were collected and analyzed by HPLC‐UV method. Pharmacokinetic parameter values were predicted using PBPK software, PK‐Sim® 8. Vmax and Km parameter values were adjusted to reflect a difference in CYP2C9 activity based on in vitro CYP2C9 kinetic studies of lornoxicam. Simulated pharmacokinetic data were compared to our clinical data for the development and verification of the lornoxicam model and assessed for validity using a 99.998% confidence interval and two‐fold error criteria. In our clinical trial, pharmacokinetic parameters, e.g., AUCinf, Cmax, Tmax, and half‐life, were considerably changed in CYP2C9*1/*3 and CYP2C9*1/*13 groups compared to CYP2C9*1/*1 group. Firstly, AUCinf, Cmax, Tmax, and half‐life values are 2730.2, 655.7, 2.2, 2.74 in CYP2C9*1/*1 group, secondly 5464, 815.3, 1.6, 4.99 in CYP2C9*1/*3, finally 5315, 935.1, 2.3, 5.19 in CYP2C9*1/*13 respectively. For predicted data for this is as follows: 3099.2, 640.9, 1.5, 2.9 in CYP2C9*1/*1, 5312.5, 748.3, 1.6, 5.2 in CYP2C9*1/*3, 5551, 782.7, 1.6, 4.17 in CYP2C9*1/*13. Based on these result, simulated values were within suitable assessment for model development. Values for verification conducted simulation in Chinese ethnic also were fit in the assessment. Therefore, the PBPK model of lornoxicam was confirmed development successfully. Unfortunately, we could not find pharmacokinetic profiles in the ethnic group except the Chinese. So, we verified the PBPK model by conducting simulation only in Chinese ethnic. Because of this limitation, we expect to be able to develop a more validated model through the verification of various ethnic in further studies.

PBPK model of lornoxicam in CYP2C9*1/*1 genotypes.

Figure 1

PBPK model of lornoxicam in CYP2C9*1/*3 genotypes. Km and Vmax values were scaled

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Insights from 20 Years of the Molecule of the Month and PDB‐101
Authors: Zardecki Christine , Berman Helen M. , Burley Stephen K. , Goodsell David S.
Published: April 2020

For 20 years, Molecule of the Month articles have highlighted the functional stories of the 3D structures found in the Protein Data Bank (PDB). The PDB is the primary archive of atomic structures of biological molecules, currently providing open access to more than 150,000 structures studied by researchers around the world. The wealth of knowledge embodied in this resource is remarkable, with structures that allow exploration of nearly any biomolecular topic, from basic science of genetic mechanisms, to the mechanisms of photosynthesis, to central biomedical topics like cancer therapy, and the fight against infectious disease. The central motivation behind the Molecule of the Month is to provide a user‐friendly introduction to this rich body of data, charting a path for users to get started with finding and exploring the many available structures.

Molecule of the Month articles and images are freely available at the education portal PDB‐101 (http://pdb101.rcsb.org/), offering an ongoing resource for molecular biology educators and students around the world. Features are used to develop additional PDB‐101 materials, from posters to interactive animations.

PDB‐101 usage, trends, and impact are described.

Support or Funding Information

PDB‐101 and the RCSB PDB are funded by the National Science Foundation (DBI‐1832184), the US Department of Energy (DE‐SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM133198.

Image of Measles Virus Proteins from the March 2019 Molecule of the Month. The article has been viewed more than 13,000 times to date.

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Synthetic Anatomy: arts based learning to explore the possibilities of form and function
Authors: Wingate Richard James , Williams Darren , Sagoo Mandeep , Wilson Leigh Jane
Published: April 2020

We have developed an interdisciplinary module for students in their second year of undergraduate education which imports, into anatomy, the techniques and perspectives of success & assessment practices of art school. The module brings together biomedical engineers and anatomy students to speculate on and design imagined bodies that probe the boundaries of clinical, evolutionary and developmental anatomy. The students produce a technical and critical reflective portfolio and participate in a small, collaborative group project to 3D print imagined anatomy. Teaching and assessment emphasise the freedom to take risks and learn from failed avenues of investigation. A key emphasis is on structural exploration and experimentation coupled with reflection rather than literature review or writing per se. Technical teaching on 3D prints is accompanied by class workshops that explore the dimensions of documentation, the language of visual presentation and value of reflection. Workshops are led by visiting artists and we have applied the technique of the “crit”, which is a widely used form of group reflection in art and architecture schools, as a means of delivering a high degree of rigour into the science classroom. Projects are completed by mixed teams of engineering and anatomy students. There is no exam but a final “show” of projects is assessed on outcomes that are in part designed by the class at the start of the module. For learning outcomes and assessment, in addition to applying a technical and cognitive taxonomy we have introduced elements of Bloom’s less well‐known, affective taxonomy to authentically assess student commitment, pride, value and engagement. We have found that students are highly satisfied with their learning experience regardless of assessed outcome and show an extraordinary commitment to the course. Our emerging conclusion is that by paying attention to the material craft of science and exploring and reflecting on its community of practice, we can design and deliver modules that are a more valid preparation for higher level research both in terms of skills and passion for this subject.

Support or Funding Information

Kings College London Cultural Institute

Student project work from the Synthetic Anatomy module

Figure 1